Article

The Bed Nucleus of the Stria Terminalis: A Target Site for Noradrenergic Actions in Opiate Withdrawal

Annals of the New York Academy of Sciences

June 1999
877(1):486 - 498

DOI:10.1111/j.1749-6632.1999.tb09284.x

Authors:

Yan Zhu

University of Pennsylvania

Hyperactivity of brain norepinephrine (NE) systems has long been implicated in mechanisms of opiate withdrawal (OW). However, little is known about where elevated NE may act to promote OW. Here we report that the bed nucleus of the stria terminalis (BNST), the densest NE target in the brain, is critical for NE actions in OW. (1) Many BNST neurons become Fos+ after OW. Pretreatment with the β antagonist, propranolol, markedly reduces OW symptoms and the number of Fos+ cells in the BNST. (2) Numerous neurons in the nucleus tractus solitarius (A2 neurons) and the A1 cell group are triple labeled for tyrosine hydroxylase, a retrograde tracer from the BNST, and Fos after OW, revealing numerous NE neurons that project to the BNST from the medulla that are stimulated by OW. Fewer such triple-labeled neurons were found in the locus caeruleus. (3) Behavioral studies reveal that local microinjections of selective β-adrenergic antagonists into the BNST attenuate OW symptoms. In particular, withdrawal-induced place aversion is abolished by bilateral microinjection of a cocktail of selective beta 1 (betaxolol) plus the beta 2 (ICI 181,555) antagonists (1.0 nmol each/0.5 μL per side) into the BNST. Similar results were obtained with neurochemically selective lesions of the ventral ascending NE bundle, the pathway for A1 and A2 projections to the BNST. Similar lesions of the dorsal NE bundle of projections from the locus caeruleus had no effect on either aversive or somatic withdrawal symptoms. Together, these results indicate that β-receptor activation in the BNST is critical for aversive withdrawal symptoms, and that A1 and A2 neurons in the medulla are the source of this critical NE.

Manual segmentation of the paraventricular nucleus of the hypothalamus and the dorsal and ventral bed nucleus of stria terminalis using multimodal 7 Tesla structural MRI: probabilistic atlases for a stress-control triad

Article

Full-text available

Oct 2023
BRAIN STRUCT FUNCT

The paraventricular nucleus of the hypothalamus (PVN) is uniquely capable of proximal control over autonomic and neuroendocrine stress responses, and the bed nucleus of the stria terminalis (BNST) directly modulates PVN function, as well as playing an important role in stress control itself. The dorsal BNST (dBNST) is predominantly preautonomic, while the ventral BNST (vBNST) is predominantly viscerosensory, receiving dense noradrenergic signaling. Distinguishing the dBNST and vBNST, along with the PVN, may facilitate our understanding of dynamic interactions among these regions. T1-weighted MPRAGE and high resolution gradient echo (GRE) modalities were acquired at 7T. GRE was coregistered to MPRAGE and segmentations were performed in MRIcroGL based on their Atlas of the Human Brain depictions. The dBNST, vBNST and PVN were manually segmented in 25 participants; 10 images were rated by 2 raters. These segmentations were normalized and probabilistic atlases for each region were generated in MNI space, now available as resources for future research. We found moderate–high inter-rater reliability [n = 10; Mean Dice (SD); PVN = 0.69 (0.04); dBNST = 0.77 (0.04); vBNST = 0.62 (0.04)]. Probabilistic atlases were reverse normalized into native space for six additional participants that were segmented but not included in the original 25. We also found moderate to moderate–high reliability between the probabilistic atlases and manual segmentations [n = 6; Mean Dice (SD); PVN = 0.55 (0.12); dBNST = 0.60 (0.10); vBNST = 0.47 (0.12 SD)]. By isolating these hypothalamic and BNST subregions using ultra-high field MRI modalities, more specific delineations of these regions can facilitate greater understanding of mechanisms underlying stress-related function and psychopathology.

Opioid withdrawal: role in addiction and neural mechanisms

Article

Full-text available

May 2023
PSYCHOPHARMACOLOGY

Withdrawal from opioids involves a negative affective state that promotes maintenance of drug-seeking behavior and relapse. As such, understanding the neurobiological mechanisms underlying withdrawal from opioid drugs is critical as scientists and clinicians seek to develop new treatments and therapies. In this review, we focus on the neural systems known to mediate the affective and somatic signs and symptoms of opioid withdrawal, including the mesolimbic dopaminergic system, basolateral amygdala, extended amygdala, and brain and hormonal stress systems. Evidence from preclinical studies suggests that these systems are altered following opioid exposure and that these changes mediate behavioral signs of negative affect such as aversion and anxiety during withdrawal. Adaptations in these systems also parallel the behavioral and psychological features of opioid use disorder (OUD), highlighting the important role of withdrawal in the development of addictive behavior. Implications for relapse and treatment are discussed as well as promising avenues for future research, with the hope of promoting continued progress toward characterizing neural contributors to opioid withdrawal and compulsive opioid use.

Solitary Nitric Oxide Signaling Mediates Mild Stress-Induced Anxiety and Norepinephrine Release in the Bed Nucleus of the Stria Terminalis during Protracted Ethanol Withdrawal

Article

Full-text available

Nov 2021
BEHAV NEUROL

Ethanol withdrawal (EtOHW) alters the pattern of neurohormonal and behavioral response toward internal and external stimuli, which mediates relapse to alcohol use even after a long period of abstinence. Increased noradrenergic signaling from the nucleus tractus solitarius (NTS) to the bed nucleus of the stria terminalis (BNST) during EtOHW underlies withdrawal-induced anxiety, while nitric oxide synthase (NOS) inhibitors injected into the periaqueductal area attenuate EtOHW-induced anxiety. Therefore, this study investigated the involvement of NOS within the NTS in anxiety and increased norepinephrine (NE) release in the BNST during protracted EtOHW in rats exposed to a mild stress. Rats were intraperitoneally administered 3 g/kg/day EtOH for 21 days followed by 28 days of withdrawal, and on the 28th day of withdrawal, the rats were subjected to restraint stress for 7 minutes. The elevated plus maze test was employed to evaluate anxiety-like behavior in rats, and in vivo microdialysis was used to measure the extracellular NE level in the BNST. In elevated plus maze tests, EtOHW rats but not EtOH-naive rats exhibited anxiety-like behavior when challenged with 7-minute mild restraint stress, which was, respectively, mitigated by prior intra-NTS infusion of the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME), or selective neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI). Each of these agents also decreased the plasma corticosterone levels in EtOHW rats. In in vivo microdialysis, prior intra-NTS infusion of carboxy-PTIO, L-NAME, or 7-NI attenuated the mild stress-induced NE release in the BNST of EtOHW rats. Additionally, EtOHW rats showed increased solitary nNOS gene and protein expression. Moreover, the anxiolytic effect of intra-NTS administration of 7-NI was abolished by subsequent intra-NTS administration of sodium nitroprusside. These results suggest that elevation of solitary nitric oxide signaling derived from nNOS mediates stress-precipitated anxiety and norepinephrine release in the BNST during protracted EtOHW. 1. Introduction Relapse is a major barrier in alcoholism therapy [1]. Ethanol withdrawal (EtOHW) leads to adaptation of neurotransmission in the brain that often persists long after complete remission of EtOHW symptoms. This adaptation sensitizes physiological and behavioral responses to internal and external stimuli, characterized by exacerbated pathophysiological responses toward mild stress or even nonstress stimuli [2]. This phenomenon during EtOHW is a stress sensitization that mimics the allodynia in pain medicine in which innocuous stimuli provoke a painful sensation, resulting in relapse even after a long period of abstinence [3]. Elevated anxiety during EtOHW is the major negative emotional component for alcoholism relapse [4], and several lines of evidence indicate that a heightened norepinephrine (NE) signaling in the bed nucleus of the stria terminalis (BNST) is responsible for it. The BNST is a component of the extended amygdala; NE signaling in the BNST along with corticotrophin releasing factor (CRF) is the key factor mediating the anxiety associated with withdrawal of drugs of abuse [5]. NE triggers the extracellular release of CRF, and EtOHW increases the extracellular NE level in the central nucleus of the amygdala (another component of the extended amygdala) [6] and the CRF level in the BNST [7], which underlie EtOHW-induced anxiety. EtOH and morphine share many pharmacological similarities including induction of extracellular NE release in the BNST [8], and extracellular NE release is increased in the BNST in both spontaneous and naloxone-precipitated morphine withdrawal [9, 10]. Therefore, the extracellular NE level may be enhanced in the BNST during EtOHW in association with elevated anxiety. Moreover, Valdez et al. [11] reported that acute mild-restraint stress (AMRS) produced significant anxiety in rats during protracted EtOHW but not in their EtOH-naive counterparts, indicating an allodynia-like phenomenon. Taken together, these observations suggest that AMRS may induce sensitized NE release in the BNST, which is associated with anxiety in rats during protracted EtOHW. The BNST is a complex consisting of multiple nuclei, broadly divided into anterior and posterior, dorsal and ventral, and medial and lateral parts, and it is heavily innervated by noradrenergic projections arising from both A1/A2 in the nucleus tractus solitarius (NTS) and A6 (locus coeruleus) [12]. However, immunocytochemical and retrograde tracer analyses indicated that the noradrenergic inputs to the ventral BNST (vBNST) are derived mainly from the NTS-A2 [13, 14] and are critical for the negative emotions induced by withdrawal of drugs of abuse. For example, opiate withdrawal precipitated by opioid receptor antagonists was shown to increase NE release in the vBNST and to enhance c-Fos expression in both the vBNST and vBNST-projecting NTS-A2 neurons, whereas intra-vBNST infusion of β-adrenergic antagonists reduced the withdrawal-associated conditioned place aversion [14–16]. Neurochemical lesions of the noradrenergic bundle originating from the NTS-A2, but not from A6, attenuated the withdrawal aversion [14]. These observations suggest increased activity in the NTS-vBNST noradrenergic pathway during withdrawal of drugs of abuse, which is attributed to activation of NTS-A2 neurons. A wide range of neurotransmitters and neuropeptides, including glutamate, gamma-aminobutyric acid (GABA), nitric oxide (NO), galanin, and neuropeptide Y, are present in the NTS-A2 and regulate NE neuronal activities [17]. It is well documented that NO synthase (NOS) inhibiters have anxiolytic effects [18–20]; moreover, the NO system plays an important role in EtOHW anxiety and NE release induced by drug abuse. Bonassoli et al. [21] reported that EtOHW activated NO-producing neurons in the brainstem, while local infusion of NOS inhibitors into the brainstem regions such as the periaqueductal gray matter area and the dorsal raphe nucleus mitigates EtOHW anxiety [22, 23]. Our previous studies indicated that acute nicotine induces NE release in the hypothalamus and amygdala via the NTS NO pathway [24, 25]. These findings suggest that the NTS NO system may mediate the enhanced NTS-vBNST noradrenergic activities during protracted EtOHW. Taken together, all the above observations lead to speculation that there may be abnormally heightened NTS-vBNST NE neuronal activities mediated by the NTS NO system during protracted EtOHW, which underlie anxiety in response to challenge with otherwise innocuous stimuli. To test this, in the present study, rats were exposed to a 7-minute AMRS during protracted EtOHW, and the effects of intra-NTS infusion of NOS inhibitors on anxiety-like behavior and NE release in the vBNST of EtOHW rats were examined. 2. Materials and Methods 2.1. Animals and Surgery Eight-week-old male Sprague–Dawley rats (250-270 g) were provided by the Laboratory Animal Center at Qiqihar Medical University (Qiqihar, China) and housed in individual cages under standardized conditions (12 : 12 hour light/dark cycle, 21–23°C, free access to food and water). All rats were randomly assigned to the various experimental groups. All experimental procedures were approved by the Animal Care and Use Committee of Qiqihar Medical University (approval number: QMUAECC-2016-28) and were performed adhering to the National Institutes of Health guidelines. After 7 days of acclimatization, the rats were stereotactically (Kopf Instruments, Tujunga, CA) implanted with bilateral microinjection guide cannulae targeting the NTS and/or a unilateral microdialysis probe guide cannula targeting the right ventral vBNST under sodium pentobarbital (50 mg/kg, intraperitoneally) anesthesia. In brief, after fixing the rat on the instrument, a longitudinal midline incision was made on the shaved and disinfected scalp, creating the surgical window by exposing the bregma and the lambda and clearing the skull surface using sterile cotton-tips dipped in 3% H2O2 solution. The coordinates of the bregma and the lambda were used to level the skull and act as the references, and the hydrogen peroxide solution (also a disinfectant) was used to eliminate the soft tissues to prevent a possible infection afterward. After the confirmation of a horizontally levelled skull, three small holes were drilled on the skull, respectively, targeting the right ventral vBNST and both sides of the NTS according to their coordinates, and guide cannulae were implanted through the holes and secured with two small screws and dental cement. The coordinates of the NTS and vBNST relative to bregma, according to the atlas of Paxinos and Watson [26], were as follows: anterior–posterior, −13.6 and−0.3 mm; medial–lateral, 0.8 and 1.4 mm; and dorsal ventral, 6.5 and 7.5 mm, respectively. The microinjection guide cannulae were positioned 1.5 mm above the targets. During the surgery, a small amount of lubricant eye ointment was applied to each rat to prevent corneal damage, and antibiotics and pain killers were also used for the postsurgery care. At the end of each experiment, the rats were euthanized and decapitated, the brain was extracted and stored at -80°C, and then coronal cryotome sections were made to observe the probe and injection positions, and if more accurate histological confirmation was desired, a Coomassie blue staining was used; finally, the rats with the correct targets were included for statistical analysis. 2.2. Experimental Protocols and Collection of Blood and NTS Tissues After a 7-day recovery period after the surgery, the rats were intraperitoneally administered 3 g/kg/day EtOH (20% w/v) or saline for 21 days followed by 28 days of withdrawal. On the 28th day of EtOHW or saline withdrawal, the rats received 7-minute AMRS in a 6.4-cm-diameter plastic cylinder constructed from a 500 mL mineral water bottle and underwent in vivo microdialysis or a behavioral test in an elevated plus maze (EPM) (Figure 1). (a) Schedule of EtOHW

Somatostatin-expressing neurons in the Bed Nucleus of the Stria Terminalis

Thesis

Full-text available

Jan 2018

Lauri Elsilä

The bed nucleus of the stria terminalis (BNST) is currently widely studied due to its impact in the anxiety-, stress-, and fear-related behaviours, as well as in addiction. The BNST is highly heterogeneous brain area constituting of set of subnuclei and a variety of neuron populations, properties of which have only partially been revealed by the earlier research. One of the neuron populations, on which only a very little research has been conducted, is the somatostatin (Sst) expressing neurons, highly abundant in the anterodorsal part of the BNST (adBNST), especially in oval and juxtacapsular nuclei of the BNST. This work aims to elucidate the connectivity of this Sst-neuron population, and their role in the behaviours related to BNST activation, particularly the anxiety-, reward-, and drug withdrawal-related behaviours. To specifically study the somatostatin neuron population in the adBNST, I targeted the neurons using stereotaxic delivery of AAV-vectors encoding a myristylated green fluorescent protein (GFP) for neuronal tracing to Sst-Cre-tdTomato reporter line mice (n=2), and Cre-inducible hM3Dq-DREADDs to Sst-IRES-Cre mice (n=21), with Cre-inducible mCherry fluorescent protein as a control (n=20). The mice were treated with activation-inducing 1.0 mg/kg i.p. clozapine-N-oxide (CNO) 30 min prior to the behavioural tests. To assess acute anxiety-like behaviour, I used the elevated-plus maze paradigm and a modified open field test, in which a novel object is introduced to the arena in the middle of the trial. To study the potential effect on reward-associated behaviours, I used the biased conditioned place preference (CPP) test, and for the withdrawal-linked behaviours, we used a method to precipitate the withdrawal symptoms with naltrexone in subchronically morphine-treated mice (n=9 hM3Dq, n=8 control). The neuronal tracing revealed that the adBNST Sst-neurons project to areas known to partake in stress and fear reactions as well as in autonomic and homeostatic control. Namely, projections were seen in medial and central amygdaloidal nuclei, lateral hypothalamus, periaqueductal grey, ventral pallidum, and parabrachial nucleus. In the elevated-plus maze, the CNO-induced activation of the Sst-neurons did not have any effect on the locomotor activity of the mice between the groups. At the same time, Sst activation did not seem to have any significant effect on the time the mice spent in the open arms, nor in the exploratory activities, like the frequency of the head dips or the stretch-attend postures. In line with these results, no effect on the movement between the groups was observed in the open field test. Similarly, no differences in anxiety-related behaviours, like in the time spent in the centre of the arena or in the number of contacts with the novel object during the last phase of the test, were observed. The CPP test failed to show any meaningful rewarding or aversive properties of CNO-induced activation of the Sst-neurons, while the movement rates of the groups during the conditioning trials were not different in statistically significant way. As for the withdrawal symptoms, all the mice showed the predetermined symptoms, but the test failed to show any differences between the study groups. The neuronal tracing revealed connectivity for the adBNST Sst-neurons with brain regions involved in fear-and anxiety behaviour, social encounters, and autonomic control. In spite of this, the CNO-induced chemogenetic activation of the adBNST Sst-neurons failed to show any significant behavioural effects in the chosen paradigms for anxiety-, and reward-related behaviours, and for withdrawal symptoms. Further research is needed to dissect the Sst-subcircuitry of adBNST, both in order to verify the observed output regions, and to elucidate the role these neurons play in modification of behavioural phenotypes.

CB1 Receptor Antagonism in the Bed Nucleus of the Stria Terminalis Interferes With Affective Opioid Withdrawal in Rats

Article

Full-text available

Aug 2017

The bed nucleus of the stria terminalis (BNST) is a region of the extended amygdala that is implicated in addiction, anxiety, and stress related behaviors. This region has been identified in mediating the aversive state of naloxone-precipitated morphine withdrawal (MWD) and cannabinoid Type I (CB1) receptors have been found to modulate neurotransmission within this region. Previous findings suggest that the CB1 antagonist/inverse agonist, AM251, administered systemically or by infusion into the central nucleus of the amygdala (CeA) prevented the aversive affective properties of MWD as measured by conditioned place aversion learning. As well, when administered systemically or by infusion into the basolateral nucleus of the amygdala (BLA) or the interoceptive insular cortex, the monoaclyglycerol lipase (MAGL) inhibitor, MJN110 (which elevates 2-arachidonlyglycerol), also prevented a naloxone-precipitated MWD induced place aversion. Given the connectivity of these regions and the BNST, the present study sought to determine whether cannabinoid modulation of the BNST would also prevent the affective properties of naloxone precipitated MWD-induced place aversion learning. Prior to conditioning trials, rats received intra-BNST infusions of AM251, in Experiment 1, or MJN110 in Experiment 2. AM251, but not MJN110, prevented the establishment of the MWD-induced place aversion. The current findings emphasize an important role for the BNST in opioid withdrawal and suggest that the ameliorative effects of systemically administered CB1 antagonists are mediated, in part, by their actions within this region.

Targeting of Locus Ceruleus Noradrenergic Neurons Expressing Human Interleukin-2 Receptor �-Subunit in Transgenic Mice by a Recombinant Immunotoxin anti-Tac(Fv)-PE38: A Study for Exploring Noradrenergic Influence upon Anxiety-Like and Depression-Like Behaviors

Article

Mar 2011

Gopal Das

An ascending vagal sensory-central noradrenergic pathway modulates retrieval of passive avoidance memory

Preprint

Full-text available

Apr 2024

Background: Visceral feedback from the body is often subconscious, but plays an important role in guiding motivated behaviors. Vagal sensory neurons relay gut feelings to noradrenergic (NA) neurons in the caudal nucleus of the solitary tract (cNTS), which in turn project to the anterior ventrolateral bed nucleus of the stria terminalis (vlBNST) and other hypothalamic-limbic forebrain regions. Prior work supports a role for these circuits in modulating memory consolidation and extinction, but a potential role in retrieval of conditioned avoidance remains untested. Results: To examine this, adult male rats underwent passive avoidance conditioning. We then lesioned gut-sensing vagal afferents by injecting cholecystokinin-conjugated saporin toxin (CSAP) into the vagal nodose ganglia (Experiment 1), or lesioned NA inputs to the vlBNST by injecting saporin toxin conjugated to an antibody against dopamine-beta hydroxylase (DSAP) into the vlBNST (Experiment 2). When avoidance behavior was later assessed, rats with vagal CSAP lesions or NA DSAP lesions displayed significantly increased conditioned passive avoidance. Conclusions: These new findings support the view that a gut vagal afferent-to-cNTSNA-to-vlBNST circuit plays a role in modulating the expression/retrieval of learned passive avoidance. Overall, our data suggest a dynamic modulatory role of vagal sensory feedback to the limbic forebrain in integrating interoceptive signals with contextual cues that elicit conditioned avoidance behavior.

Nucleus of the solitary tract A2 neurons control feeding behaviors via projections to the paraventricular hypothalamus

Article

Full-text available

Sep 2022

Hindbrain NTS neurons are highly attuned to internal physiological and external environmental factors that contribute to the control of food intake but the relevant neural phenotypes and pathways remain elusive. Here, we investigated the role of NTS A2 neurons and their projections in the control of feeding behaviors. In male TH Cre rats, we first confirmed selective targeting of NTS A2 neurons and showed that chemogenetic stimulation of these neurons significantly suppressed dark cycle food intake, deprivation re-feed and high fat diet intake. Despite reducing intake, activation of NTS A2 neurons had no effect on food approach, anxiety-like behaviors, locomotor activity, blood glucose levels nor did it induce nausea/malaise, thus revealing a selective role for these neurons in the consummatory aspect of food intake control. Pathway-specific mapping and manipulation of NTS A2 neurons showed that these effects were mediated by NTS A2 neurons projecting to the paraventricular nucleus of the hypothalamus (PVH) because chemogenetic activation of these projections, but not projections to bed nucleus of the stria terminalis (BNST), reduced food intake. Cell-type specific analyses demonstrated that activation of NTS A2 neurons recruited both PVH oxytocin (OT)- and corticotropin-releasing factor (CRF)-expressing neurons, and plasma analyses showed increased plasma corticosterone following NTS A2 stimulation. While we also showed that chemogenetic inhibition of NTS A2 neurons attenuated the intake inhibitory effects of CCK, the specificity of transgene expression was low. Together, these findings showed that NTS A2 neurons are sufficient to control the consummatory aspects of feeding, regardless of energy status or food palatability and identified their projections to PVH, but not BNST, in food intake control.

Sex and metabolic state interact to influence expression of passive avoidance memory in rats: Potential contribution of A2 noradrenergic neurons

Article

Jun 2021
PHYSIOL BEHAV

Competing motivational drives coordinate behaviors essential for survival. For example, interoceptive feedback from the body during a state of negative energy balance serves to suppress anxiety-like behaviors and promote exploratory behaviors in rats. Results from past research suggest that this shift in motivated behavior is linked to reduced activation of specific neural populations within the caudal nucleus of the solitary tract (cNTS). However, the potential impact of metabolic state and the potential role of cNTS neurons on conditioned avoidance behaviors has not been examined. The present study investigated these questions in male and female rats, using a task in which rats learn to avoid a context (i.e., a darkened chamber) after it is paired with a single mild footshock. When rats later were tested for passive avoidance of the shock-paired chamber, male rats tested in an overnight food-deprived state and female rats (regardless of feeding status) displayed significantly less avoidance compared to male rats that were fed ad libitum prior to testing. Based on prior evidence that prolactin-releasing peptide (PrRP)-positive noradrenergic neurons and glucagon-like peptide 1 (GLP1)-positive neurons within the cNTS are particularly sensitive to metabolic state, we examined whether these neural populations are activated in conditioned rats after re-exposure to the shock-paired chamber, and whether neural activation is modulated by metabolic state. Compared to the control condition, chamber re-exposure activated PrRP+ noradrenergic neurons and also activated neurons within the anterior ventrolateral bed nucleus of the stria terminalis (vlBNST), which receives dense input from PrRP+ terminals, in both male and female rats when fed ad libitum. In parallel with sex differences in passive avoidance behavior, PrRP+ neurons were less activated in female vs. male rats after chamber exposure. GLP1+ neurons were not activated in either sex. In both sexes, overnight food deprivation before chamber re-exposure reduced activation of PrRP+ neurons, and also reduced vlBNST activation. Our results support the view that PrRP+ noradrenergic neurons and their inputs to the vlBNST contribute to the expression of passive avoidance memory, and that this contribution is modulated by metabolic state.

Sex and metabolic state interact to influence expression of passive avoidance memory in rats: Potential contribution of A2 noradrenergic neurons

Preprint

Full-text available

Feb 2021

Competing motivational drives coordinate behaviors essential for survival. For example, interoceptive feedback from the body during a state of negative energy balance serves to suppress anxiety-like behaviors and promote exploratory behaviors in rats. Results from past research suggest that this shift in motivated behavior is linked to reduced activation of specific neural populations within the caudal nucleus of the solitary tract (cNTS). However, the potential impact of metabolic state and the potential role of cNTS neurons on conditioned avoidance behaviors has not been examined. The present study investigated these questions in male and female rats, using a task in which rats learn to avoid a context (i.e., a darkened chamber) after it is paired with a single mild footshock. When rats later were tested for passive avoidance of the shock-paired chamber, male rats tested in an overnight food-deprived state and female rats (regardless of feeding status) displayed significantly less avoidance compared to male rats that were fed ad libitum prior to testing. Based on prior evidence that prolactin-releasing peptide (PrRP)-positive noradrenergic neurons and glucagon-like peptide 1 (GLP1)-positive neurons within the cNTS are particularly sensitive to metabolic state, we examined whether these neural populations are activated in conditioned rats after re-exposure to the shock-paired chamber, and whether neural activation is modulated by metabolic state. Compared to the control condition, chamber re-exposure activated PrRP+ noradrenergic neurons and also activated neurons within the anterior ventrolateral bed nucleus of the stria terminalis (vlBNST), which receives dense input from PrRP+ terminals. In parallel with sex differences in passive avoidance behavior, PrRP+ neurons were less activated in female vs. male rats after chamber exposure. GLP1+ neurons were not activated in either sex. Overnight food deprivation before chamber re-exposure reduced activation of PrRP+ neurons, and also reduced vlBNST activation. Our results support the view that PrRP+ noradrenergic neurons and their inputs to the vlBNST contribute to the expression of passive avoidance memory, and that this contribution is modulated by metabolic state.

The amygdalar opioid system

Article

Full-text available

Jan 2020

This chapter reviews the anatomy and physiological effects of the opioid peptides and their receptors in the amygdala, and behavioral responses during genetic or pharmacological manipulations of the amygdalar opioid system in preclinical studies and what is known from human imaging studies. The amygdalar opioid system consists of the neuropeptides enkephalin, dynorphin, and β-endorphin, and their receptors, which are localized throughout the amygdala. Enkephalins activate both mu and delta-opioid receptors (MOR, DOR), while dynorphin activates kappa opioid receptors (KOR). Opioid receptor activation has postsynaptic inhibitory effects on selected neuronal populations in the amygdala, as well as presynaptically inhibiting both GABA and glutamate release. The amygdalar opioid system plays important roles in nociception, stress and anxiety-related responses, associative learning and conditioned fear, ethanol effects, and opiate dependence or withdrawal. Historically studies focused on enkephalin and MOR-mediated effects, although roles for the dynorphin/KOR system and actions of enkephalin via DOR are emerging.

Vagal Interoceptive Modulation of Motivated Behavior

Article

Full-text available

Mar 2018
PHYSIOLOGY

In addition to regulating the ingestion and digestion of food, sensory feedback from gut to brain modifies emotional state and motivated behavior by subconsciously shaping cognitive and affective responses to events that bias behavioral choice. This focused review highlights evidence that gut-derived signals impact motivated behavior by engaging vagal afferents and central neural circuits that generally serve to limit or terminate goal-directed approach behaviors, and to initiate or maintain behavioral avoidance.

The intersection of stress and reward: BNST modulation of aversive and appetitive states

Article

Jan 2018

The bed nucleus of the stria terminalis (BNST) is widely acknowledged as a brain structure that regulates stress and anxiety states, as well as aversive and appetitive behaviours. The diverse roles of the BNST are afforded by its highly modular organisation, neurochemical heterogeneity, and complex intrinsic and extrinsic circuitry. There has been growing interest in the BNST in relation to psychopathologies such as anxiety and addiction. Although research on the human BNST is still in its infancy, there have been extensive preclinical studies examining the molecular signature and hodology of the BNST and their involvement in stress and reward seeking behaviour. This review examines the neurochemical phenotype and connectivity of the BNST, as well as electrophysiological correlates of plasticity in the BNST mediated by stress and/or drugs of abuse.

Opiate dependence induces cell type-specific plasticity of intrinsic membrane properties in the rat juxtacapsular bed nucleus of stria terminalis (jcBNST)

Article

Full-text available

Dec 2017
PSYCHOPHARMACOLOGY

RationaleDrugs of abuse can alter circuit dynamics by modifying synaptic efficacy and/or the intrinsic membrane properties of neurons. The juxtacapsular subdivision of the bed nucleus of stria terminalis (jcBNST) has unique connectivity that positions it to integrate cortical and amygdala inputs and provide feed-forward inhibition to the central nucleus of the amygdala (CeA), among other regions. In this study, we investigated changes in the synaptic and intrinsic properties of neurons in the rat jcBNST during protracted withdrawal from morphine dependence using a combination of conventional electrophysiological methods and the dynamic clamp technique. ResultsA history of opiate dependence induced a form of cell type-specific plasticity characterized by reduced inward rectification associated with more depolarized resting membrane potentials and increased membrane resistance. This cell type also showed a lower rheobase when stimulated with direct current (DC) pulses as well as a decreased firing threshold under simulated synaptic bombardment with the dynamic clamp. Morphine dependence also decreased excitatory postsynaptic potential amplification, suggesting the downregulation of the persistent Na+ current (INaP). Conclusion These findings show that a history of morphine dependence leads to persistent cell type-specific plasticity of the passive membrane properties of a jcBNST neuronal population, leading to an overall increased excitability of such neurons. By altering the activity of extended amygdala circuits where they are embedded, changes in the integration properties of jcBNST neurons may contribute to emotional dysregulation associated with drug dependence and withdrawal.

BDNF Alterations in Brain Areas and the Neurocircuitry Involved in the Antidepressant Effects of Ketamine in Animal Models, Suggest the Existence of a Primary Circuit of Depression

Article

Full-text available

Aug 2022

Major depressive disorder is one of the primary causes of disability and disease worldwide. The therapy of depression is prevalently based on monoamine reuptake blockers; consequently, investigations aimed to clarify the aetiology of depression have mostly looked at brain areas innervated by monamines and brain circuitry involved in inputs and outputs of these areas. The recent approval of esketamine as a rapid-acting antidepressant drug in treatment-resistant depression, has definitively projected glutamatergic transmission as a key constituent in the use of new drugs in antidepressant therapy. In this review we have examined the role of several brain areas: namely, the hippocampus, the medial Prefrontal Cortex (mPFC), the nucleus accumbens (NAc), the Lateral Habenula (LHb), the amygdala and the Bed Nucleus of Stria Terminalis (BNST). The reason for undertaking an in-depth review is due to their significant role in animal models of depression, which highlight their inter-connections as well as their inputs and outputs. In particular, we examined the modification of the expression and release of the brain derived neurotrophic factor (BDNF) and associated changes in dendritic density induced by chronic stress in the above areas of animal models of depression (AnMD). We also examined the effectiveness of ketamine and standard antidepressants in reversing these alterations, with the aim of identifying a brain circuit where pathological alteration might trigger the appearance of depression symptoms. Based on the role that these brain areas play in the generation of the symptoms of depression, we assumed that the mPFC, the NAc/Ventral Tegmental Area (VTA) and the hippocampus form a primary circuit of depression, where regular performance can endure resilience to stress. We have also examined how this circuit is affected by environmental challenges and how the activation of one or more areas, including amygdala, LHb or BNST can produce local detrimental effects that spread over specific circuits and generate depression symptoms. Furthermore, we also examined how, through their outputs, these three areas can negatively influence the NAc/VTA-PFC circuit directly or through the BNST, to generate anhedonia, one of the most devastating symptoms of depression.

The Elusive “Switch Process” in Bipolar Disorder and Photoperiodism: A Hypothesis Centering on NADPH Oxidase-Generated Reactive Oxygen Species Within the Bed Nucleus of the Stria Terminalis

Article

Full-text available

Jun 2022

Martin Norman Raitiere

One of the most striking and least understood aspects of mood disorders involves the “switch process” which drives the dramatic state changes characteristic of bipolar disorder. In this paper we explore the bipolar switch mechanism as deeply grounded in forms of seasonal switching (for example, from summer to winter phenotypes) displayed by many mammalian species. Thus we develop a new and unifying hypothesis that involves four specific claims, all converging to demonstrate a deeper affinity between the bipolar switch process and the light-sensitive (photoperiodic) nonhuman switch sequence than has been appreciated. First, we suggest that rapid eye movement (REM) sleep in both human and nonhuman plays a key role in probing for those seasonal changes in length of day that trigger the organism's characteristic involutional response (in certain animals, hibernation) to shorter days. Second, we claim that this general mammalian response requires the integrity of a neural circuit centering on the anterior bed nucleus of the stria terminalis. Third, we propose that a key molecular mediator of the switch process in both nonhumans and seasonal humans involves reactive oxygen species (ROS) of a particular provenance, namely those created by the enzyme NADPH oxidase (NOX). This position diverges from one currently prominent among students of bipolar disorder. In that tradition, the fact that patients afflicted with bipolar-spectrum disorders display indices of oxidative damage is marshaled to support the conclusion that ROS, escaping adventitiously from mitochondria, have a near-exclusive pathological role. Instead, we believe that ROS, originating instead in membrane-affiliated NOX enzymes upstream from mitochondria, take part in an eminently physiological signaling process at work to some degree in all mammals. Fourth and finally, we speculate that the diversion of ROS from that purposeful, genetically rooted seasonal switching task into the domain of human pathology represents a surprisingly recent phenomenon. It is one instigated mainly by anthropogenic modifications of the environment, especially “light pollution.”

Involvement of the Dorsal Vagal Complex in Alcohol-Related Behaviors

Article

Full-text available

Mar 2022

The neurobiological mechanisms that regulate the development and maintenance of alcohol use disorder (AUD) are complex and involve a wide variety of within and between systems neuroadaptations. While classic reward, preoccupation, and withdrawal neurocircuits have been heavily studied in terms of AUD, viable treatment targets from this established literature have not proven clinically effective as of yet. Therefore, examination of additional neurocircuitries not classically studied in the context of AUD may provide novel therapeutic targets. Recent studies demonstrate that various neuropeptides systems are important modulators of alcohol reward, seeking, and intake behaviors. This includes neurocircuitry within the dorsal vagal complex (DVC), which is involved in the control of the autonomic nervous system, control of intake of natural rewards like food, and acts as a relay of interoceptive sensory information via interactions of numerous gut-brain peptides and neurotransmitter systems with DVC projections to central and peripheral targets. DVC neuron subtypes produce a variety of neuropeptides and transmitters and project to target brain regions critical for reward such as the mesolimbic dopamine system as well as other limbic areas important for the negative reinforcing and aversive properties of alcohol withdrawal such as the extended amygdala. This suggests the DVC may play a role in the modulation of various aspects of AUD. This review summarizes the current literature on neurotransmitters and neuropeptides systems in the DVC (e.g., norepinephrine, glucagon-like peptide 1, neurotensin, cholecystokinin, thyrotropin-releasing hormone), and their potential relevance to alcohol-related behaviors in humans and rodent models for AUD research. A better understanding of the role of the DVC in modulating alcohol related behaviors may lead to the elucidation of novel therapeutic targets for drug development in AUD.

Increase in Conditioned Place Preference and Feeding After Mu-opioid Activation in the Bed Nucleas of the Stria Terminalis

Thesis

Jan 2009

Ryan Selleck

http://deepblue.lib.umich.edu/bitstream/2027.42/63927/1/selleck_ryan_2009.pdf

Consideration of sex as a biological variable in the translation of pharmacotherapy for stress-associated drug seeking

Article

Full-text available

Jul 2021

Stress is a frequent precipitant of relapse to drug use. Pharmacotherapies targeting a diverse array of neural systems have been assayed for efficacy in attenuating stress-induced drug-seeking in both rodents and in humans, but none have shown enough evidence of utility to warrant routine use in the clinic. We posit that a critical barrier in effective translation is inattention to sex as a biological variable at all phases of the research process. In this review, we detail the neurobiological systems implicated in stress-induced relapse to cocaine, opioids, methamphetamine, and cannabis, as well as the pharmacotherapies that have been used to target these systems in rodent models, the human laboratory, and in clinical trials. In each of these areas we additionally describe the potential influences of biological sex on outcomes, and how inattention to fundamental sex differences can lead to biases during drug development that contribute to the limited success of large clinical trials. Based on these observations, we determine that of the pharmacotherapies discussed only α2-adrenergic receptor agonists and oxytocin have a body of research with sufficient consideration of biological sex to warrant further clinical evaluation. Pharmacotherapies that target β-adrenergic receptors, other neuroactive peptides, the hypothalamic-pituitary-adrenal axis, neurosteroids, and the endogenous opioid and cannabinoid systems require further assessment in females at the preclinical and human laboratory levels before progression to clinical trials can be recommended.

Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success?

Article

Full-text available

Apr 2021

Repurposing ketamine in the therapy of depression could well represent a breakthrough in understanding the etiology of depression. Ketamine was originally used as an anesthetic drug and later its use was extended to other therapeutic applications such as analgesia and the treatment of addiction. At the same time, the abuse of ketamine as a recreational drug has generated a concern for its psychotropic and potential long-term effects; nevertheless, its use as a fast acting antidepressant in treatment-resistant patients has boosted the interest in the mechanism of action both in psychiatry and in the wider area of neuroscience. This article provides a comprehensive overview of the actions of ketamine and intends to cover: (i) the evaluation of its clinical use in the treatment of depression and suicidal behavior; (ii) the potential use of ketamine in pediatrics; (iii) a description of its mechanism of action; (iv) the involvement of specific brain areas in producing antidepressant effects; (v) the potential interaction of ketamine with the hypothalamic-pituitary-adrenal axis; (vi) the effect of ketamine on neuronal transmission in the bed nucleus of stria terminalis and on its output; (vii) the evaluation of any gender-dependent effects of ketamine; (viii) the interaction of ketamine with the inflammatory processes involved in depression; (ix) the evaluation of the effects observed with single or repeated administration; (x) a description of any adverse or cognitive effects and its abuse potential. Finally, this review attempts to assess whether ketamine’s use in depression can improve our knowledge of the etiopathology of depression and whether its therapeutic effect can be considered an actual cure for depression rather than a therapy merely aimed to control the symptoms of depression.

Cues conditioned to withdrawal and negative reinforcement: Neglected but key motivational elements driving opioid addiction

Article

Full-text available

Apr 2021

Opioid use disorder (OUD) is a debilitating disorder that affects millions of people. Neutral cues can acquire motivational properties when paired with the positive emotional effects of drug intoxication to stimulate relapse. However, much less research has been devoted to cues that become conditioned to the aversive effects of opioid withdrawal. We argue that environmental stimuli promote motivation for opioids when cues are paired with withdrawal (conditioned withdrawal) and generate opioid consumption to terminate conditioned withdrawal (conditioned negative reinforcement). We review evidence that cues associated with pain drive opioid consumption, as patients with chronic pain may misuse opioids to escape physical and emotional pain. We highlight sex differences in withdrawal-induced stress reactivity and withdrawal cue processing and discuss neurocircuitry that may underlie withdrawal cue processing in dependent individuals. These studies highlight the importance of studying cues associated with withdrawal in dependent individuals and point to areas for exploration in OUD research.

Neurochemical mechanisms and neurocircuitry underlying the contribution of stress to cocaine seeking

Article

Full-text available

Mar 2021
J NEUROCHEM

In individuals with substance use disorders, stress is a critical determinant of relapse susceptibility. In some cases, stressors directly trigger cocaine use. In others, stressors interact with other stimuli to promote drug seeking, thereby setting the stage for relapse. Here, we review the mechanisms and neurocircuitry that mediate stress‐triggered and stress‐potentiated cocaine seeking. Stressors trigger cocaine seeking by activating noradrenergic projections originating in the lateral tegmentum that innervate the bed nucleus of the stria terminalis to produce beta adrenergic receptor‐dependent regulation of neurons that release corticotropin releasing factor (CRF) into the ventral tegmental area (VTA). CRF promotes the activation of VTA dopamine neurons that innervate the prelimbic prefrontal cortex resulting in D1 receptor‐dependent excitation of a pathway to the nucleus accumbens core that mediates cocaine seeking. The stage‐setting effects of stress require glucocorticoids, which exert rapid non‐canonical effects at several sites within the mesocorticolimbic system. In the nucleus accumbens, corticosterone attenuates dopamine clearance via the organic cation transporter 3 to promote dopamine signaling. In the prelimbic cortex, corticosterone mobilizes the endocannabinoid, 2‐arachidonoylglycerol (2‐AG), which produces CB1 receptor‐dependent reductions in inhibitory transmission, thereby increasing excitability of neurons which comprise output pathways responsible for cocaine seeking. Factors that influence the role of stress in cocaine seeking, including prior history of drug use, biological sex, chronic stress/co‐morbid stress‐related disorders, adolescence, social variables, and genetics are discussed. Better understanding when and how stress contributes to drug seeking should guide the development of more effective interventions, particularly for those whose drug use is stress related. image

Drug-Induced Conditioned Place Preference and Its Practical Use in Substance Use Disorder Research

Article

Full-text available

Sep 2020

The conditioned place preference (CPP) paradigm is a well-established model utilized to study the role of context associations in reward-related behaviors, including both natural rewards and drugs of abuse. In this review article, we discuss the basic history, various uses, and considerations that are tied to this technique. There are many potential takeaway implications of this model, including negative affective states, conditioned drug effects, memory, and motivation, which are all considered here. We also discuss the neurobiology of CPP including relevant brain regions, molecular signaling cascades, and neuromodulatory systems. We further examine some of our prior findings and how they integrate CPP with self-administration paradigms. Overall, by describing the fundamentals of CPP, findings from the past few decades, and implications of using CPP as a research paradigm, we have endeavored to support the case that the CPP method is specifically advantageous for studying the role of a form of Pavlovian learning that associates drug use with the surrounding environment.

Embarking on Discovering the Mechanisms of Resilience: Combining Language Use Analysis with Neuroscience

Article

Full-text available

Aug 2020

Novel treatments in mental health focus on one’s ability to recover and develop resilience. Current concepts are based on The Adaptations Level Theory, which describes the ability of resilient individuals to accustom to new and even downgraded conditions as the new standard, find meaning in trauma, and adapt to new social settings. However, it is not known which treatments specifically help to build up resilience in patients and how to reliably screen for it. We hypothesize that by analyzing mechanisms of behavior and physiology in resilient individuals, we will be able to strengthen these in people that are struggling to bounce back. Recent studies demonstrated that distinct patterns of language use correlated with various mental health conditions. Utilizing text samples from Holocaust survivors, we compared language use in resilient individuals to people with PTSD and the general population. The Holocaust survivors' language use was significantly different from PTSD sufferers, which suggests that we detected a possible resilience word use pattern. Next, we looked into the brain circuitry mechanisms that could be involved in resilience. We found that norepinephrine, the key neurotransmitter in stress response, modulated the activity of amygdala circuitry in a non-linear concentration-dependent manner. The shape and other characteristics of this dependency could be associated with the capacity for resilience.

Nalbuphine ameliorates morphine/tramadol-induced dependence and tolerance to analgesia through locus coereulus (LC) norepinephrine

Article

Jun 2020

The vagus nerve mediates the suppressing effects of peripherally administered oxytocin on methamphetamine self-administration and seeking in rats

Article

May 2020

The neuropeptide oxytocin has emerged as a promising pharmacotherapy for methamphetamine (METH) addiction, and clinical trials of intranasal oxytocin are underway. However, there is debate as to how peripherally administered oxytocin alters brain signalling to modulate addiction processes. Interestingly, there is evidence for functional interactions between peripheral oxytocin administration and the vagus nerve. Therefore, this study investigated whether the effects of peripherally administered oxytocin require vagal signalling to reduce METH self-administration and reinstatement of METH-seeking behaviours. Male and female Sprague-Dawley rats underwent surgery for jugular catheterisation and either subdiaphragmatic vagotomy (SDV) or a sham operation. Rats were trained to self-administer METH, and the effect of peripherally administered oxytocin on METH intake was assessed. Rats then underwent extinction, and effects of oxytocin were assessed on cue- and METH-induced reinstatement of METH-seeking. Oxytocin treatment robustly attenuated METH intake in both sexes, and SDV entirely prevented the suppressant effect of oxytocin (0.3 mg/kg) on METH intake, and partially prevented the effects of 1 mg/kg oxytocin in both sexes. After extinction, SDV decreased the suppressing effects of oxytocin on cue- and METH-primed reinstatement in males, but not females. SDV was functionally confirmed by measuring food intake following administration of the vagal dependent peptide, cholecyostokin-8. Our data suggest that vagus nerve signalling is required for the inhibitory effects of peripherally administered oxytocin on METH self-administration and reinstatement, and that this vagal dependency is partially mediated by sex and drug withdrawal. This study has implications for the use of oxytocin as a therapy for METH use disorder for both sexes.

Ketamine Blocks Morphine-Induced Conditioned Place Preference and Anxiety-Like Behaviors in Mice

Article

Full-text available

May 2020

Patients suffering from opioid use disorder often relapse during periods of abstinence, which is posited to be caused by negative affective states that drive motivated behaviors. Here, we explored whether conditioning mice with morphine in a conditioned place preference (CPP) training paradigm evoked anxiety-like behavior during morphine abstinence. To do this, mice were conditioned with morphine (10 mg/kg, i.p.) for 5 days. Twenty-four hours following conditioning, anxiety levels were tested by measuring time in the open arms of the elevated plus-maze. The next day, mice were placed in the three-compartment chamber to measure morphine-induced CPP. Our results show that following morphine conditioning, mice spent significantly less time in the open arm of the elevated plus-maze and expressed robust morphine CPP on CPP test day. Furthermore, we found that an acute treatment with (R,S)-ketamine (10 mg/kg, i.p.), a medication demonstrating promise for preventing anxiety-related phenotypes, 30 min before testing on post-conditioning day 1, increased time spent in the open arm of the elevated plus-maze in saline- and morphine-conditioned mice. Additionally, we found that the second injection of ketamine 30 min before CPP tests on post-conditioning day 2 prevented morphine-induced CPP, which lasted for up to 28 days post-conditioning. Furthermore, we found that conditioning mice with 10% (w/v) sucrose using an oral self-administration procedure did not evoke anxiety-like behavior, but elicited robust CPP, which was attenuated by ketamine treatment 30 min before CPP tests. Overall, our results suggest that the ketamine-induced block of morphine CPP may not be attributed solely to alleviating negative affective states, but potentially through impaired memory of morphine-context associations.

The effects of morphine withdrawal and conditioned withdrawal on memory consolidation and c‐Fos expression in the central amygdala

Article

May 2020

The current study tested the hypothesis that drug withdrawal contributes to the addiction cycle in part because of an action on memory consolidation. Hence, four experiments in male Sprague–Dawley rats compared the effects of precipitated morphine withdrawal and conditioned morphine withdrawal on the consolidation of object memory and on activation of c‐Fos in the central nucleus of the amygdala (CeA). It was found that immediate, but not 6 h delayed, post sample administration of 3 mg/kg of naltrexone significantly enhanced object memory in rats maintained, or previously maintained, on 10 mg/kg/day of morphine via osmotic minipumps. To establish whether conditioned withdrawal could also alter object memory, a contextual conditioning procedure was employed whereby morphine‐maintained (10 mg/kg/day) animals received naltrexone (3 mg/kg) in a distinctive context (CS+) and vehicle in a separate context (CS−) for 10 days. During conditioning in the CS+, naltrexone suppressed locomotor activity, caused a rapid body weight loss and increased frequency of wet dog shakes. Interestingly, confinement to this CS+ immediately, but not 6 h, after the sample phase, also enhanced object memory. Finally, posttraining naltrexone and exposure to the CS+ both induced significant expression of c‐Fos in the CeA. Therefore, this study reports for the first time that both acute precipitated withdrawal and conditioned withdrawal can facilitate memory consolidation, possibly through a common neural pathway that involves the central amygdala.

Timing of Morphine Administration Differentially Alters Paraventricular Thalamic Neuron Activity

Article

Full-text available

Dec 2019

The paraventricular thalamic nucleus (PVT) is a brain region involved in regulating arousal, goal-oriented behaviors, and drug seeking, all key factors playing a role in substance use disorder. Given this, we investigated the temporal effects of administering morphine, an opioid with strongly addictive properties, on PVT neuronal function in mice using acute brain slices. Here, we show that morphine administration and electrophysiological recordings that occur during periods of animal inactivity (light cycle) elicit increases in PVT neuronal function during a 24-h abstinence time point. Furthermore, we show that morphine-induced increases in PVT neuronal activity at 24-h abstinence are occluded when morphine administration and recordings are performed during an animals' active state (dark cycle). Based on our electrophysiological results combined with previous findings demonstrating that PVT neuronal activity regulates drug-seeking behaviors, we investigated whether timing morphine administration with periods of vigilance (dark cycle) would decrease drug-seeking behaviors in an animal model of substance use disorder. We found that context-induced morphine-seeking behaviors were intact regardless of the time morphine was administered (e.g., light cycle or dark cycle). Our electrophysiological results suggest that timing morphine with various states of arousal may impact the firing of PVT neurons during abstinence. Although, this may not impact context-induced drug-seeking behaviors.

Conditioned Aversion and Neuroplasticity Induced by a Superagonist of Extrasynaptic GABAA Receptors: Correlation With Activation of the Oval BNST Neurons and CRF Mechanisms

Article

Full-text available

May 2019

THIP (gaboxadol), a superagonist of the δ subunit-containing extrasynaptic GABAA receptors, produces persistent neuroplasticity in dopamine (DA) neurons of the ventral tegmental area (VTA), similarly to rewarding drugs of abuse. However, unlike them THIP lacks abuse potential and induces conditioned place aversion in mice. The mechanism underlying the aversive effects of THIP remains elusive. Here, we show that mild aversive effects of THIP were detected 2 h after administration likely reflecting an anxiety-like state with increased corticosterone release and with central recruitment of corticotropin-releasing factor corticotropin-releasing factor receptor 1 (CRF1) receptors. A detailed immunohistochemical c-Fos expression mapping for THIP-activated brain areas revealed a correlation between the activation of CRF-expressing neurons in the oval nucleus of the bed nuclei of stria terminalis and THIP-induced aversive effects. In addition, the neuroplasticity of mesolimbic DA system (24 h after administration) and conditioned place aversion by THIP after four daily acute sessions were dependent on extrasynaptic GABAA receptors (abolished in δ-GABAA receptor knockout mice) and activation of the CRF1 receptors (abolished in wildtype mice by a CRF1 receptor antagonist). A selective THIP-induced activation of CRF-expressing neurons in the oval part of the bed nucleus of stria terminalis may constitute a novel mechanism for inducing plasticity in a population of VTA DA neurons and aversive behavioral states.

Forging Neuroimaging Targets for Recovery in Opioid Use Disorder

Article

Full-text available

Mar 2019

The United States is in the midst of an opioid epidemic and lacks a range of successful interventions to reduce this public health burden. Many individuals with opioid use disorder (OUD) consume drugs to relieve physical and/or emotional pain, a pattern that may increasingly result in death. The field of addiction research lacks a comprehensive understanding of physiological and neural mechanisms instantiating this cycle of Negative Reinforcement in OUD, resulting in limited interventions that successfully promote abstinence and recovery. Given the urgency of the opioid crisis, the present review highlights faulty brain circuitry and processes associated with OUD within the context of the Three-Stage Model of Addiction (1). This model underscores Negative Reinforcement processes as crucial to the maintenance and exacerbation of chronic substance use together with Binge/Intoxication and Preoccupation/Anticipation processes. This review focuses on cross-sectional as well as longitudinal studies of relapse and treatment outcome that employ magnetic resonance imaging (MRI), functional near-infrared spectroscopy (fNIRs), brain stimulation methods, and/or electroencephalography (EEG) explored in frequency and time domains (the latter measured by event-related potentials, or ERPs). We discuss strengths and limitations of this neuroimaging work with respect to study design and individual differences that may influence interpretation of findings (e.g., opioid use chronicity/recency, comorbid symptoms, and biological sex). Lastly, we translate gaps in the OUD literature, particularly with respect to Negative Reinforcement processes, into future research directions involving operant and classical conditioning involving aversion/stress. Overall, opioid-related stimuli may lessen their hold on frontocingulate mechanisms implicated in Preoccupation/Anticipation as a function of prolonged abstinence and that degree of frontocingulate impairment may predict treatment outcome. In addition, longitudinal studies suggest that brain stimulation/drug treatments and prolonged abstinence can change brain responses during Negative Reinforcement and Preoccupation/Anticipation to reduce salience of drug cues, which may attenuate further craving and relapse. Incorporating this neuroscience-derived knowledge with the Three-Stage Model of Addiction may offer a useful plan for delineating specific neurobiological targets for OUD treatment.

Embarking on discovering the mechanisms of resilience: combining language use analysis with neuroscience.

Preprint

Full-text available

Dec 2018

Novel treatments in mental health focus on one’s ability to recover and develop resilience. Current concepts are based on The Adaptations Level Theory, which describes the ability of resilient individuals to accustom to new and even downgraded conditions as the new standard, find meaning in trauma, and adapt to new social settings. However, it is not known which treatments specifically help to build up resilience in patients and how to reliably screen for it. Recent studies demonstrated that distinct patterns of language use correlated with various mental health conditions. Utilizing text samples from the Holocaust survivors, we studied language use in resilient individuals compares to people with PTSD and general population. Holocaust survivors' language use was significantly different from PTSD sufferers, which suggests that we detected a possible resilience word use pattern. Next, we looked into the brain circuitry mechanisms that could be involved in resilience. We found that norepinephrine, the key neurotransmitter in stress response, modulated the activity of amygdala circuitry in a non-linear concentration-dependent manner. The shape and other characteristics of this dependency could be associated with the capacity for resilience.

Aldosterone-sensitive HSD2 neurons in mice

Article

Full-text available

Jan 2019
BRAIN STRUCT FUNCT

Sodium deficiency elevates aldosterone, which in addition to epithelial tissues acts on the brain to promote dysphoric symptoms and salt intake. Aldosterone boosts the activity of neurons that express 11-beta-hydroxysteroid dehydrogenase type 2 (HSD2), a hallmark of aldosterone-sensitive cells. To better characterize these neurons, we combine immunolabeling and in situ hybridization with fate mapping and Cre-conditional axon tracing in mice. Many cells throughout the brain have a developmental history of Hsd11b2 expression, but in the adult brain one small brainstem region with a leaky blood–brain barrier contains HSD2 neurons. These neurons express Hsd11b2, Nr3c2 (mineralocorticoid receptor), Agtr1a (angiotensin receptor), Slc17a6 (vesicular glutamate transporter 2), Phox2b, and Nxph4; many also express Cartpt or Lmx1b. No HSD2 neurons express cholinergic, monoaminergic, or several other neuropeptidergic markers. Their axons project to the parabrachial complex (PB), where they intermingle with AgRP-immunoreactive axons to form dense terminal fields overlapping FoxP2 neurons in the central lateral subnucleus (PBcL) and pre-locus coeruleus (pLC). Their axons also extend to the forebrain, intermingling with AgRP- and CGRP-immunoreactive axons to form dense terminals surrounding GABAergic neurons in the ventrolateral bed nucleus of the stria terminalis (BSTvL). Sparse axons target the periaqueductal gray, ventral tegmental area, lateral hypothalamic area, paraventricular hypothalamic nucleus, and central nucleus of the amygdala. Dual retrograde tracing revealed that largely separate HSD2 neurons project to pLC/PB or BSTvL. This projection pattern raises the possibility that a subset of HSD2 neurons promotes the dysphoric, anorexic, and anhedonic symptoms of hyperaldosteronism via AgRP-inhibited relay neurons in PB.

Relapse to opioid seeking in rat models: behavior, pharmacology and circuits

Article

Oct 2018
NEUROPSYCHOPHARMACOL

Lifetime relapse rates remain a major obstacle in addressing the current opioid crisis. Relapse to opioid use can be modeled in rodent studies where drug self-administration is followed by a period of abstinence and a subsequent test for drug seeking. Abstinence can be achieved through extinction training, forced abstinence, or voluntary abstinence. Voluntary abstinence can be accomplished by introducing adverse consequences of continued drug self-administration (e.g., punishment or electric barrier) or by introducing an alternative nondrug reward in a discrete choice procedure (drug versus palatable food or social interaction). In this review, we first discuss pharmacological and circuit mechanisms of opioid seeking, as assessed in the classical extinction-reinstatement model, where reinstatement is induced by reexposure to the self-administered drug (drug priming), discrete cues, discriminative cues, drug-associated contexts, different forms of stress, or withdrawal states. Next, we discuss pharmacological and circuit mechanisms of relapse after forced or voluntary abstinence, including the phenomenon of “incubation of heroin craving” (the time-dependent increases in heroin seeking during abstinence). We conclude by discussing the clinical implications of these preclinical relapse models.

What does the Fos say? Using Fos-based approaches to understand the contribution of stress to substance use disorders

Article

Jun 2018

Despite extensive research efforts, drug addiction persists as a largely unmet medical need. Perhaps the biggest challenge for treating addiction is the high rate of recidivism. While many factors can promote relapse in abstinent drug users, the contribution of stress is particularly problematic, as stress is uncontrollable and pervasive in the lives of those struggling with addiction. Thus, understanding the neurocircuitry that underlies the influence of stress on drug seeking is critical for guiding treatment. Preclinical research aimed at defining this neurocircuitry has, in part, relied upon the use of experimental approaches that allow visualization of cellular and circuit activity that corresponds to stressor-induced drug seeking in rodent relapse models. Much of what we have learned about the mechanisms that mediate stressor-induced relapse has been informed by studies that have used the expression of the immediate early gene, cfos, or its protein product, Fos, as post-mortem activity markers. In this review we provide an overview of the rodent models used to study stressor-induced relapse and briefly summarize what is known about the underlying neurocircuitry before describing the use of cfos/Fos-based approaches. In addition to reviewing findings obtained using this approach, its advantages and limitations are considered. Moreover, new techniques that leverage the expression profile of cfos to tag and manipulate cells based on their activity patterns are discussed. The intent of the review is to guide the interpretation of old and design of new studies that utilize cfos/Fos-based strategies to study the neurocircuitry that contributes to stress-related drug use.

The involvement of CRF1 receptor within the basolateral amygdala and dentate gyrus in the naloxone-induced conditioned place aversion in morphine-dependent mice

Article

Jan 2018

Drug withdrawal-associated aversive memories trigger relapse to drug-seeking behavior. Corticotrophin-releasing factor (CRF) is an important mediator of the reinforcing properties of drugs of abuse. However, the involvement of CRF1 receptor (CRF1R) in aversive memory induced by opiate withdrawal has yet to be elucidated. We used the conditioned-place aversion (CPA) paradigm to evaluate the role of CRF1R on opiate withdrawal memory acquisition, along with plasticity-related processes that occur after CPA within the basolateral amygdala (BLA) and dentate gyrus (DG). Male mice were rendered dependent on morphine and injected acutely with naloxone before paired to confinement in a naloxone-associated compartment. The CPA scores as well as the number of TH-positive neurons (in the NTS-A2 noradrenergic cell group), and the expression of the transcription factors Arc and pCREB (in the BLA and DG) were measured with and without CRF1R blockade. Mice subjected to conditioned naloxone-induced morphine withdrawal robustly expressed CPA. Pre-treatment with the selective CRF1R antagonist CP-154,526 before naloxone conditioning session impaired morphine withdrawal-induced aversive memory acquisition. CP-154,526 also antagonized the enhanced number of TH-positive neurons in the NTS-A2 that was seen after CPA. Increased Arc expression and Arc-pCREB co-localization were seen in the BLA after CPA, which was not modified by CP-154,526. In the DG, CPA was accompanied by a decrease of Arc expression and no changes in Arc-pCREB co-localization, whereas pre-treatment with CP-154,526 induced an increase in both parameters. These results indicate that CRF-CRF1R pathway could be a critical factor governing opiate withdrawal memory storage and retrieval and might suggest a role for TH-NA pathway in the effects of withdrawal on memory. Our results might indicate that the blockade of CRF1R could represent a promising pharmacological treatment strategy approach for the attenuation of the relapse to drug-seeking/taking behavior triggered by opiate withdrawal-associated aversive memories.

Spinal β-adrenergic receptors’ activation increases the blood glucose level in mice

Article

Full-text available

Jul 2017

We examined the role of spinally located β-adrenergic receptors in the regulation of the blood glucose level. The intrathecal (i.t.) injections with dobutamine (β1-adrenergic receptor agonist) or terbutaline (β2-adrenergic receptor agonist) caused an elevation of the blood glucose level, whereas metoprolol (β1-adrenergic receptor antagonist) or butoxamine (β2-adrenergic receptor antagonist) did not. In addition, i.t. pretreatment with pertussis toxin (PTX) attenuated the hyperglycemic effect induced by dobutamine or terbutaline. Moreover, plasma insulin level was increased by dobutamine but not by terbutaline, and PTX reduced dobutamine-induced up-regulation of the plasma insulin level. Terbutaline significantly increased plasma corticosterone level, and PTX further enhanced terbutaline-induced corticosterone level. Furthermore, intraperitoneal (i.p.) pretreatment with hexamethonium- (a preganglionic blocker) attenuated dobutamine- and terbutaline-induced hyperglycemic effects. Our results suggest that activation of spinal β1- and β2-adrenergic receptors produces hyperglycemic effects in a different manner. Spinally located PTX-sensitive G-proteins appear to be involved in hyperglycemic effect induced by terbutaline. Furthermore, dobutamine- or terbutaline-induced hyperglycemia appears to be mediated through the spinal nerves.

Pharmacology of the Bed Nucleus of the Stria Terminalis

Article

Full-text available

Dec 2016

The bed nucleus of the stria terminalis (BNST) regulates not only stress-related behaviors but also maternal behavior, pain-related behaviors, and reward-driven behavior. Dysfunction of the BNST leads to physiopathological states like anxiety disorder, post-traumatic syndrome disorder, anorexia, or addiction. Thus, a better understanding of the BNST emerges as an important challenge in order to develop innovative therapeutic strategies. Indeed, to improve our knowledge on the BNST, we first need to understand what shapes its activity. The BNST is strongly innervated by multiple inputs (glutamatergic, GABAergic, noradrenergic, dopaminergic, serotoninergic) giving rise to a part of its complexity. Importantly, under specific conditions (stress exposure, drug-withdrawal), endocannabinoid and neuropeptides can orchestrate the activity of the BNST. Here, we give a brief overview of the main pharmacological approaches targeting the BNST to assess the function of classical neurotransmitters and neuromodulators, from a pharmacological point of view through to behavior.

Neurobiology of Addiction

Chapter

Sep 2023

Bed Nucleus of Stria Terminalis (BNST) circuits

Chapter

Jan 2023

Inhibition of noradrenergic and corticotrophin-releasing factor systems: Effects on enhancement of memory consolidation by unconditioned and conditioned heroin withdrawal

Article

Feb 2022
NEUROPHARMACOLOGY

The aim of the current study was to test the hypothesis that unconditioned and conditioned opioid withdrawal enhance memory consolidation through overlapping neural systems. The reported experiments focussed on noradrenaline (NA) and corticotrophin-releasing factor (CRF) because of the known involvement of these neuromodulators in both opioid withdrawal and memory consolidation. Male Sprague-Dawley rats were implanted with subcutaneous osmotic mini-pumps releasing 3.5 mg/kg/day heroin and received injections of 3 mg/kg naloxone (NLX) to precipitate withdrawal. NLX was preceded by 0.1–0.6 mg/kg lofexidine (LOF) (alpha-2 adrenergic agonist) or 10–20 mg/kg antalarmin (ANT) (CRF1 receptor antagonist), and all injections were administered immediately after (i.e., post-training method) the sample phase of the spontaneous object recognition memory task. The same procedure was repeated 7 days after removal of the mini-pumps. To establish conditioned withdrawal, heroin-exposed rats were confined for 2 h in a context (CS+) following injections of 3 mg/kg NLX and in another context (CS-) following vehicle injections. Seven days after removal mini-pumps, the effects of immediate post-sample exposure to the CS+ (and CS-) preceded by 0.6 mg/kg LOF or 20 mg/kg ANT were assessed. It was found both LOF and ANT blocked the enhancement of object memory by post-sample NLX administration and by exposure to the CS+. These results suggest that pharmacological and psychological withdrawal impact memory storage by activating overlapping NA and CRF systems.

Differential involvement of nucleus tractus solitarius projections and locus coeruleus projections to the basolateral amygdala in morphine-associated memory destabilization

Article

Dec 2021
PROG NEURO-PSYCHOPH

Drug-related memory can be transiently destabilized by memory retrieval, after which memories are reconsolidated. Neurons in the basolateral amygdala (BLA) that are activated by emotional information may be one of the key mechanisms underlying this destabilization. However, the specific neural circuits underlying this destabilization process remain unknown. Because BLA receives noradrenergic inputs from the nucleus tractus solitarius (NTS) and locus coeruleus (LC), we studied the role of afferent projections into the BLA in the destabilization of morphine self-administration memory in rats. We first showed that morphine (unconditioned stimulus, US) + morphine-associated conditioned stimuli (CS) exposure, rather than CS exposure alone, destabilized morphine self-administration memory. Then, we measured projection-specific activation after the US + CS or CS retrieval test using c-fos (activity marker)-labeling in projection areas. Compared with CS exposure, we found that US + CS exposure induced more neuronal activation in the BLA and NTS but not in the LC. Next, we determined the effects of chemogenetic inactivation or activation of NTS or LC projections to BLA (NTS → BLA or LC → BLA) on this destabilization. We found that NTS → BLA, but not LC → BLA inactivation during memory retrieval, prevented memory destabilization induced by US + CS exposure. Furthermore, NTS → BLA, but not LC → BLA activation during CS retrieval induced destabilization. Thus, our results identify a specific neural circuit underlying the transformation of a stable opiate-associated memory into an unstable memory and subsequently guide reconsolidation.

Corticotropin releasing factor and norepinephrine related circuitry changes in the bed nucleus of the stria terminalis in stress and alcohol and substance use disorders

Article

Oct 2021
NEUROPHARMACOLOGY

Alcohol Use Disorder (AUD) affects around 14.5 million individuals in the United States, with Substance Use Disorder (SUD) affecting an additional 8.3 million individuals. Relapse is a major barrier to effective long-term treatment of this illness with stress often described as a key trigger for a person with AUD or SUD to relapse during a period of abstinence. Two signaling molecules, norepinephrine (NE) and corticotropin releasing factor (CRF), are released during the stress response, and also play important roles in reward behaviors and the addiction process. Within the addiction literature, one brain region in which there has been increasing research focus in recent years is the bed nucleus of the stria terminalis (BNST). The BNST is a limbic structure with numerous cytoarchitecturally and functionally different subregions that has been implicated in drug-seeking behaviors and stress responses. This review focuses on drug and stress-related neurocircuitry changes in the BNST, particularly within the CRF and NE systems, with an emphasis on differences and similarities between the major dorsal and ventral BNST subregions. This article is part of the special Issue on ‘Neurocircuitry Modulating Drug and Alcohol Abuse'.

Extended amygdala, conditioned withdrawal and memory consolidation

Article

Sep 2021
PROG NEURO-PSYCHOPH

Opioid withdrawal can be associated to environmental cues through classical conditioning. Exposure to these cues can precipitate a state of conditioned withdrawal in abstinent subjects, and there are suggestions that conditioned withdrawal can perpetuate the addiction cycle in part by promoting the storage of newly acquired memories. This review discusses evidence supporting the hypothesis that conditioned withdrawal facilitates memory consolidation by activating a neurocircuitry that involves the extended amygdala. Specifically, the central amygdala, the bed nucleus of the stria terminalis, and the nucleus accumbens shell interact functionally during withdrawal, mediate expression of conditioned responses, and are implicated in memory consolidation. From this perspective, the extended amygdala could be a neural pathway by which drug-seeking behaviour performed during a state of conditioned withdrawal is more likely to become habitual and persistent.

Nicotine, cocaine, amphetamine, morphine, and ethanol increase norepinephrine output in the bed nucleus of stria terminalis of freely moving rats

Article

Dec 2019

The bed nucleus of stria terminalis (BNST) is a complex limbic area involved in neuroendocrine and behavioural responses and, in particular, in the modulation of the stress response. BNST is innervated by dopamine and norepinephrine, which are known to be involved in drug addiction. It is also known that several drugs of abuse increase dopamine transmission in the BNST, but there has been less research regarding the effect on norepinephrine transmission. Here, we have used the microdialysis technique to investigate the effect of several drugs of abuse on norepinephrine transmission in the BNST of freely moving rats. We observed that nicotine (0.2‐0.4 mg/kg), cocaine (2.5‐5 mg/kg), amphetamine (0.25‐0.5 mg/kg), and ethanol (0.5‐1.0 g/kg), dose‐dependently increased norepinephrine output while the effect of morphine at 3.0 was lower than that of 1.0 mg/kg. These results suggest that many drugs of abuse, though possessing diverse mechanisms of action, share the property of increasing norepinephrine transmission in the BNST. Furthermore, we suggest that the recurring activation of NE transmission in the BNST, due to drug administration, contributes to the alteration of the function that BNST assumes in how the behavioural response to stress manifests, favouring the establishment of the stress‐induced drug seeking. The bed nucleus of stria terminalis (BNST) is acomplex limbic area involved in the modulation of the stress response. We report that several drugs of abuse, share the property of increasing norepinephrine transmission in the BNST. We suggest that the recurring activation of norepinephrine transmission in the BNST, due to drug administration, contributes to the alteration of the function that BNST assumesin how the behavioural response to stress manifests, favouring the establishment of the stress‐induced drug seeking.

Does Photoperiodism Involve a Seasonal and Non-Pathological Warburg Effect?

Article

Nov 2019
MED HYPOTHESES

Martin Norman Raitiere

The precise means whereby mammals recognize and respond to changing day length so as to adjust their physiology to the seasons (photoperiodism) remains enigmatic. We present a new hypothesis according to which aerobic glycolysis (AG) within selected astrocytic syncytia plays a central role in photoperiodism. We focus on the response of the mammal breeding in longer days (LD) to the shorter days (SD) of autumn. It is posited that AG in the brain of the SD organism is activated within a specified circuitry and temporal window. The circuitry involves regions targeted by the medullary norepinephrine (NE) system including but not limited to the anterior bed nucleus of the stria terminalis; the temporal window in question is defined by the autumnal extension of darkness into a segment of the organism's circadian activity cycle that was illuminated on the previous day. Lactate generated from glucose during SD serves primarily as a signaling entity as opposed to a fuel, instructing astrocytes, for example, gradually to replace the LD genome with one specific to SD. The requirement to provision glucose to the brain for AG through SD accounts for the frequent findings of mild autumnal hyperglycemia and elevated carbohydrate appetite across many different mammalian species including human beings. So long as the sidereal environment enveloping life on earth featured its extraordinarily predictable pattern of photoperiodic change, the dangers of exposing the organism to augmented glucose and lactate within a strictly delimited window were easily outweighed by the benefits of a precision mechanism ensuring the alignment of the animal's reproductive cycle with the seasonal one. With "light pollution," that delicate balance may now be at risk.

Maladaptive behavioral regulation in alcohol dependence: Role of kappa-opioid receptors in the bed nucleus of the stria terminalis

Article

Jul 2018
NEUROPHARMACOLOGY

There is an important emerging role for the endogenous opioid dynorphin (DYN) and the kappa-opioid receptor (KOR) in the treatment of alcohol dependence. Evidence suggests a role for the DYN/KOR system in the bed nucleus of the stria terminalis (BNST) in maladaptive behavioral regulation related to alcohol dependence and withdrawal. The current experiments were designed to assess dysregulation of the BNST DYN/KOR system by evaluating alcohol dependence-induced changes in DYN/KOR gene expression (Pdyn and Oprk1, respectively), and the sensitivity of alcohol self-administration, negative affective-like behavior and physiological withdrawal to intra-BNST KOR antagonism during acute withdrawal. Wistar rats trained to self-administer alcohol, or not trained, were subjected to an alcohol dependence induction procedure (14 h alcohol vapor/10 h air) or air-exposure. BNST micropunches from air- and vapor-exposed animals were analyzed using RT-qPCR to quantify dependence-induced changes in Pdyn and Oprk1 mRNA expression. In addition, vapor- and air-exposed groups received an intra-BNST infusion of a KOR antagonist or vehicle prior to measurement of alcohol self-administration. A separate cohort of vapor-exposed rats was assessed for physiological withdrawal and negative affective-like behavior signs following intra-BNST KOR antagonism. During acute withdrawal, following alcohol dependence induction, there was an upregulation in Oprk1 gene expression in alcohol self-administering animals, but not non-alcohol self-administering animals, that confirmed dysregulation of the KOR/DYN system within the BNST. Furthermore, intra-BNST KOR antagonism attenuated escalated alcohol self-administration and negative affective-like behavior during acute withdrawal without reliably impacting physiological symptoms of withdrawal. The results confirm KOR system dysregulation in the BNST in alcohol dependence, illustrating the therapeutic potential of targeting the KOR to treat alcohol dependence.

Social rank-Associated stress vulnerability predisposes individuals to cocaine attraction

Article

Full-text available

Jan 2018

Studies of personality have suggested that dissimilarities in ability to cope with stressful situations results in differing tendency to develop addictive behaviors. The present study used selectively bred stress-resilient, socially-dominant (Dom) and stress-vulnerable, socially-submissive (Sub) mice to investigate the interaction between environmental stress and inbred predisposition to develop addictive behavior to cocaine. In a Conditioned Place Preference (CPP) paradigm using cocaine, Sub mice displayed an aversion to drug, whereas Dom mice displayed drug attraction. Following a 4-week regimen of Chronic Mild Stress (CMS), Sub mice in CPP displayed a marked increase (>400%) in cocaine attraction, whereas Dom mice did not differ in attraction from their non-stressed state. Examination of hippocampal gene expression revealed in Sub mice, exposure to external stimuli, stress or cocaine, increased CRH expression (>100%), which was evoked in Dom mice only by cocaine exposure. Further, stress-induced decreases in DRD1 (>60%) and DRD2 (>50%) expression in Sub mice differed markedly from a complete lack of change in Dom mice. From our findings, we propose that social stratification dictates vulnerability to stress-induced attraction that may lead to addiction via differential regulation of hippocampal response to dopaminergic input, which in turn may influence differing tendency to develop addictive behaviors.

Neurobiological and Psychopathological mechanisms underlying addiction-like behaviors: An overview and thematic synthesis

Article

Full-text available

Aug 2017

The term dependency is increasingly being used also to explain symptoms resulting from the repetition of a behavior or legalized and socially accepted activities that do not involve substance assumption. These activities, although considered normal habits of daily life can become real addictions that may affect and disrupt socio-relational and working functioning. Growing evidence suggests to consider behavioral addictions similar to drug dependence for their common symptoms, the high frequency of poly-dependence conditions, and the correlation in risk (impulsivity, sensation seeking, early exposure, familiarity) and protective (parental control, adequate metacognitive skills) factors. The aim of this paper is to describe addiction in its general aspects, highlighting the underlying neurobiological and psychopathological mechanisms.

Role of Kappa Opioid Receptors in the Bed Nucleus of Stria Terminalis in Reinstatement of Alcohol Seeking

Article

Jun 2017
NEUROPSYCHOPHARMACOL

Kappa opioid receptors (KORs) and their endogenous ligand dynorphin are involved in stress-induced alcohol seeking but the mechanisms involved are largely unknown. We previously showed that systemic injections of the KOR agonist U50,488, which induce stress-like aversive states, reinstate alcohol seeking after extinction of the alcohol-reinforced responding. Here, we used the neuronal activity marker Fos and site-specific injections of the KOR antagonist nor-BNI and U50,488 to study brain mechanisms of U50,488-induced reinstatement of alcohol seeking. We trained male Long-Evans rats to self-administer alcohol (12% w/v) for 23-30 days. After extinction of the alcohol-reinforced responding, we tested the effect of U50,488 (0, 1.25, 2.5, 5 mg/kg) on reinstatement of alcohol seeking. Next, we correlated regional Fos expression with reinstatement induced by the most effective U50,488 dose (5 mg/kg). Based on the correlational Fos results, we determined the effect of bed nucleus of the stria terminalis (BNST) injections of nor-BNI (4 μg/side) on U50,488-induced reinstatement of alcohol seeking, and reinstatement induced by injections of U50,488 (0,.3, 1, 3 μg/side) into the BNST. U50,488-induced reinstatement of alcohol seeking was associated with increased Fos expression in multiple brain areas, including the BNST, where it was significantly correlated with lever-pressing. U50,488-induced reinstatement was blocked by BNST nor-BNI injections, and BNST U50,488 injections partially mimicked the drug's systemic effect on reinstatement. Our data indicate that the BNST is a critical site for U50,488-induced reinstatement of alcohol seeking and suggest that KOR/dynorphin mechanisms in this brain area play a key role in stress-induced alcohol seeking.Neuropsychopharmacology accepted article preview online, 07 June 2017. doi:10.1038/npp.2017.120.

The Suprachiasmatic Nucleus: The Mind's Clock

Book

Full-text available

Jan 1990

Orexin A activates locus coeruleus cell firing and increases arousal in the rat

Article

Full-text available

Sep 1999
P NATL ACAD SCI USA

The localization of orexin neuropeptides in the lateral hypothalamus has focused interest on their role in ingestion. The orexigenic neurones in the lateral hypothalamus, however, project widely in the brain, and thus the physiological role of orexins is likely to be complex. Here we describe an investigation of the action of orexin A in modulating the arousal state of rats by using a combination of tissue localization and electrophysiological and behavioral techniques. We show that the brain region receiving the densest innervation from orexinergic nerves is the locus coeruleus, a key modulator of attentional state, where application of orexin A increases cell firing of intrinsic noradrenergic neurones. Orexin A increases arousal and locomotor activity and modulates neuroendocrine function. The data suggest that orexin A plays an important role in orchestrating the sleep-wake cycle.

Effects of Locus Coeruleus Activation on Electroencephalographic Activity in Neocortex and Hippocampus

Article

Full-text available

Nov 1991

Experiments were conducted to examine the hypothesis that increased neuronal discharge activity of noradrenergic neurons of the locus coeruleus (LC) above resting discharge rates can alter forebrain electroencephalographic (EEG) activity. Small infusions (70-135 nl) of the cholinergic agonist bethanechol within 500 microns of the LC were used to activate this nucleus reversibly in halothane-anesthetized rats. A combined recording-infusion probe allowed verification of this electrophysiological activation. Simultaneously, EEG activity was recorded from sites in the frontal cortex and hippocampus and subjected to power-spectrum analyses. The findings were (1) LC activation was consistently followed, within 5 to 30 sec, by a shift from low-frequency, high-amplitude to high-frequency, low-amplitude EEG activity in frontal neocortex and by the appearance of intense theta-rhythm in the hippocampus; (2) forebrain EEG changes followed LC activation with similar latencies whether infusions were made lateral or medial to the LC; (3) infusions placed outside the immediate vicinity of the LC were not followed by these forebrain EEG effects; (4) following infusion-induced activation, forebrain EEG returned to preinfusion patterns with about the same time course as the recovery of LC activity (10-20 min for complete recovery). These infusion-induced effects on EEG activity were blocked or severely attenuated by pretreatment with the alpha 2-agonist clonidine, which inhibits LC discharge and norepinephrine release, or the beta-antagonist propranolol. These observations indicate that enhanced LC discharge activity is the crucial mediating event for the infusion-induced changes in forebrain EEG activity observed under these conditions and suggest that LC activation may be sufficient to induce EEG signs of cortical and hippocampal activation.

Lesions of the Nucleus Accumbens in Rats Reduce Opiate Reward but Do Not Alter Context-Specific Opiate Tolerance

Article

Full-text available

Dec 1989

Bilateral electrolytic lesions of the nucleus accumbens in rats eliminated the capacity of 10 mg/kg morphine to produce a conditioned place preference (Experiment 1). However, these lesions did not alter the capacity to establish context-specific tolerance to the analgesic effects of 5 mg/kg of morphine (Experiment 2). This latter finding indicates that rats with nucleus accumbens lesions are not impaired in associating the effects of morphine with a particular location. Thus, the failure of morphine to produce a conditioned place preference in these lesioned rats probably cannot be attributed to an inability to associate the effects of morphine with a particular chamber, i.e., the initially nonpreferred chamber. Rather, morphine may fail to establish a conditioned place preference in these rats because nucleus accumbens lesions disrupt a pathway that is critical in mediating the rewarding effects of opiates.

Activation of locus coeruleus from nucleus paragigantocellularis: A new excitatory amino acid pathway in brain

Article

Full-text available

Nov 1988

Recent anatomic and physiologic experiments revealed that a major afferent to the nucleus locus coeruleus (LC) is the nucleus paragigantocellularis (PGi) in the rostral ventrolateral medulla (Aston-Jones et al., 1986). In the present studies, responses of LC neurons to electrical activation of PGi were characterized in anesthetized rats. Low-intensity stimulation of PGi synaptically activated 73% of LC neurons at short latencies (mean onset, 11.3 msec), while a smaller population (16%) of LC neurons exhibited purely inhibitory responses. The excitatory transmission from PGi to LC was pharmacologically analyzed, revealing it to be resistant to cholinergic receptor antagonism, but completely abolished by the excitatory amino acid (EAA) antagonists kynurenic acid and gamma-D-glutamylglycine. The specific N-methyl-D-aspartate antagonist 2--amino-7-phosphonoheptanoic acid (AP7) and the preferential quisqualate receptor antagonist glutamate diethyl ester (GDEE) did not block LC responses to PGi stimulation, leading us to the tentative conclusion that EAAs may operate primarily at a kainate-type receptor on LC neurons to effect excitation from PGi. In addition to their blockade of PGi-evoked activity, kynurenic acid and DGG exerted a similar, simultaneous blockade of the characteristic excitation of LC neurons evoked by electrical stimulation of the hindpaw. These and other results indicate that the proposed EAA pathway from PGi may serve as a final link in a variety of sensory inputs to LC.

The Brain Nucleus Locus Coeruleus: Restricted Afferent Control of a Broad Efferent Network

Article

Full-text available

Dec 1986

Dense, focal injections of wheat germ agglutinin conjugated-horseradish peroxidase in the locus coeruleus of rats labeled afferent neurons in unexpectedly few brain regions. Major inputs emanate from only two nuclei--the paragigantocellularis and the prepositus hypoglossi, both in the rostral medulla. The dorsal cap of the paraventricular hypothalamic nucleus and the spinal intermediate gray are possible minor afferents to locus coeruleus. Other areas reported to project to locus coeruleus (for example, amygdala, nucleus tractus solitarius, and spinal dorsal horn) did not exhibit consistent retrograde labeling. Anterograde tracing and electrophysiologic experiments confirmed the absence of input to locus coeruleus from these areas, which instead terminate in targets adjacent to locus coeruleus. These findings redefine the anatomic organization of the locus coeruleus, and have implications for hypotheses concerning the functions of this noradrenergic brain nucleus.

Paraventricular Nucleus:A Site for the Integration of Neuroendocrine and Autonomic Mechanisms

Article

Full-text available

Jan 1981

We have summarized here recent evidence that clarifies the cellular organization and connections of the paraventricular nucleus of the hypothalamus (PVH) in the rat. The nucleus consists of a magnocellular division, with three distinct parts, and a parvocellular division with five distinct parts. Most neurons in the magnocellular division contain either oxytocin or vasopressin, and project to the posterior lobe of the pituitary gland. Separate cell populations centered in the parvocellular division give rise to projections to the median eminence, or to the brain stem and spinal cord including the intermediolateral column; some cells project both to the dorsal vagal complex and to the spinal cord. Cells with long descending projections may contain either oxytocin, vasopressin, somatostatin, or dopamine, although the biochemical specificity of most such neurons has not been determined. Noradrenergic fibers are found preferentially within those parts of the magnocellular division that are predominantly vasopressinergic. The parvocellular division is innervated by adrenergic as well as noradrenergic fibers from the brain stem, and by fibers from the dorsal vagal complex and the parabrachial nucleus. The bed nucleus of the stria terminalis and adjacent parts of the hypothalamus also innervate the PVH. The evidence indicates that subpopulations of neurons in the PVH are directly related to autonomic and neuroendocrine effector mechanisms, and suggest that the nucleus plays an important role in the regulation of visceral responses in the periphery and in the CNS itself.

Twenty-Four Hour Rhythms of Norepinephrine and Serotonin in Nucleus Suprachiasmaticus, Raphe Nuclei, and Locus Coeruleus in the Rat

Article

Full-text available

Feb 1984

Twenty-four hour rhythms, at 4 h intervals, of norepinephrine (NE) and serotonin (5-HT) contents were investigated in the rat brain regions where sleep-wakefulness regulation is believed to occur: Nucleus suprachiasmaticus (SC), n. raphe dorsalis (RD) and medialis (RM), and locus coeruleus. Cosinor method of Halberg was applied to evaluate sinusoidal rhythmicity of the measured values. In the SC only NE showed a significant rhythm with a peak value at the beginning of the light period, which suggests that a NE mechanism may be involved in oscillating biological rhythms in rats. In the RD and RM, 5-HT and 5-hydroxyindoleacetic acid increased significantly during the light period. Moreover, 5-HT rhythm in the RD was maintained even under constant dark conditions, which suggests that 5-HT rhythm in the RD may be endogenous.

Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle

Article

Full-text available

Sep 1981

Spontaneous discharge of norepinephrine-containing locus coeruleus (NE-LC) neurons was examined during the sleep-walking cycle (S-WC) in behaving rats. Single unit and multiple unit extracellular recordings yielded a consistent set of characteristic discharge properties. (1) Tonic discharge co-varied with stages of the S-WC, being highest during waking, lower during slow wave sleep, and virtually absent during paradoxical sleep. (2) Discharge anticipated S-WC stages as well as phasic cortical activity, such as spindles, during slow wave sleep. (3) Discharge decreased within active waking during grooming and sweet water consumption. (4) Bursts of impulses accompanied spontaneous or sensory-evoked interruptions of sleep, grooming, consumption, or other such ongoing behavior. (5) These characteristic discharge properties were topographically homogeneous for recordings throughout the NE-LC. (6) Phasic robust activity was synchronized markedly among neurons in multiple unit populations. (7) Field potentials occurred spontaneously in the NE-LC and were synchronized with bursts of unit activity from the same electrodes. (8) Field potentials became dissociated from unit activity during paradoxical sleep, exhibiting their highest rates in the virtual absence of impulses. These results are generally consistent with previous proposals that the NE-LC system is involved in regulating cortical and behavioral arousal. On the basis of the present data and those described in the following report (Aston-Jones, G., and F. E. Bloom (1981) J. Neurosci.1: 887-900), we conclude that these neurons may mediate a specific function within the general arousal framework. In brief, the NE-LC system may globally bias the responsiveness of target neurons and thereby influence overall behavioral orientation.

State-Dependent Respiratory and Cardiac Relationships with Neuronal Discharge in the Bed Nucleus of the Stria Terminalis

Article

Full-text available

May 1995

Discharge patterns of 63 neurons in the bed nucleus of the stria terminalis (BNST) were cross-correlated with inspiratory onsets of the respiratory cycle and the R wave of the cardiac cycle in seven unrestrained, drug-free cats during waking (AW), quiet sleep (QS) and rapid eye movement (REM) sleep. BNST neurons fired slowly, with half having rates of less than 1/second; rates were higher in AW and REM states than in QS. Approximately one-quarter of cells showed a phasic discharge timing relationship with the respiratory cycle, and one-fifth with the cardiac cycle, in at least one sleep-waking state. Respiratory-cell correlations occurred more frequently during AW (18 cells) and QS (15) than REM (6), while cardiac-neuronal correlations preferentially developed during QS (13 cells) or REM sleep (11), with a smaller proportion during waking (7). Cardiac-cell discharge correlations were weaker than respiratory-cell correlations and much weaker during REM than during either AW or QS. The data suggest that sleep states modulate a respiratory-dependent neuronal discharge in this rostral site classically associated with affective functions, with the relationship being reduced during REM.

Lesions of the dorsomedial amygdala, but not the nucleus accumbens, reduce the aversiveness of morphine withdrawal in rats

Article

Full-text available

Jan 1995

Small lesions of the dorsomedial amygdala reduced the magnitude of the conditioned place aversion produced by naltrexone-precipitated morphine withdrawal, whereas large lesions of the ventral nucleus accumbens had no effect. This finding that the dorsomedial amygdala, which has not been implicated in opiate reward, is involved in mediating the aversiveness of opiate withdrawal is consistent with data indicating that amygdala lesions reduce the aversiveness of a variety of aversive events. In contrast, the nucleus accumbens, which is involved in mediating the rewarding effects of opiates, does not appear to be critically involved in mediating the aversive effects of opiate withdrawal. Together, these findings suggest that the neural structures that mediate the rewarding effects of opiates may be at least partially distinct from the structures that mediate the aversive effects of opiate withdrawal.

Simulation of daytime vigilance by the additive interaction of a homeostatic and a circadian process

Article

Jun 1994

The two-process model of sleep regulation postulates that a homeostatic and a circadian process underlie sleep regulation. The timing of sleep and waking is accounted for by the interaction of these two processes. The assumptions of two separate processes or of a single process resulting from their additive interaction are mathematically equivalent but conceptually different. Based on an additive interaction, subjective alertness ratings in a forced desynchrony protocol and subjective sleepiness ratings in a photoperiod experiment were simulated. The correspondence between empirical and simulated data supports the basic assumption of the model.

Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior (vol 92, pg 573, 1998)

Article

Jan 1998
CELL

T. Sakurai

Catecholamines, serotonin, acetylcholine, and γ-aminobutyric acid in the rat brain: Biochemical studies

Article

Jan 1984

IN MORPHINE-DEPENDENT RATS, THE NALOXONE-INDUCED PLACE AVERSION AND SOMATIC SYNDROME AND HE PROTECTIVE EFFECTS OF CLONIDINE ARE NOT IMPAIRED BY A TOTAL LESION OF LOCUS COERULEUS NORADRENERGIC NEURONS

Article

May 1996
BEHAV PHARMACOL

Role of β-adrenoceptors in the expression of morphine withdrawal signs

Article

Dec 1994
LIFE SCI

The effects of intracerebroventricular (i.c.v.) pretreatment with the noradrenergic neurotoxin DSP-4 and β1- and β2-adrenoceptor antagonists on the expression of morphine withdrawal signs were investigated in mice. Mice were chronically treated with morphine (8–45 mg/kg, s.c.). Several withdrawal signs were observed following naloxone challenge in morphine-dependent mice which had been pretreated with vehicle. Treatment with DSP-4 before the naloxene chalenge suppressed the expression of morphine withdrawal signs, including jumping and “wet dog” shakes. Similarly, pretreatment with the β1-antagonist atenolol significantly reduced the incidence of naloxene-precipitated jumping and “wet dog” shakes. However, pretreatment with the β2-antagonist ICI118,551 suppressed the expression of “wet dog” shakes, but not that of jumping. These findings suggest that the central noradrenergic system may mediate the expression of withdrawal signs. The blocking effects of β-antagonists indicate that naloxone-precipitated jumping may be mediated predominantly by β1-adrenoceptors, while naloxone-precipitated “wet dog” shakes may be mediated by both β1- and β2-adrenoceptors.

Brain maps: structure of the rat brain (2nd edn)

Article

Jan 1992

L. W. Swanson

The Sky, A User's Guide

Article

Jan 1991

David H. Levy

This is an ideal book for starting astronomy. It stirs the imagination, and puts observation of the sky into the framework of leisure activity as well as a personal adventure. Written by an award winning astronomer, it is a non-technical guide to the night sky, full of practical hints. The author's lively style enthuses, entertains and informs. * know the constellations, even if you live in a large city * observe the Sun safely * find out how comets are discovered * watch a star vary in brightness from week to week * explore star clusters and remote galaxies. Author David Levy is one of the world's foremost amateur astronomers. He has discovered 17 comets. Minor Planet 3673 Levy is named in his honour. An English graduate, Levy has written a beautiful introduction to the glories of the observable universe of constellations, stars and galaxies.

Catecholamin innervation of the basal forebrain. I. The septal area

Article

Feb 1978
J COMP NEUROL

Robert Y. Moore

The septal area of the rat is known to receive a rich innervation by axons of catecholamine (CA) neurons. In the present study this innervatic was studied using biochemical assay of CA content and fluorescence histochemical analysis of the distribution of CA‐producing axons to determine the nuclei origin of the septal CA innervation and the effects of lesions on these parameters. The autoradiographic tracing technique and the horseradish peroxidase (HRP)‐retrograde transport technique also were used for this purpose. The norepinephrine (NE) content of the normal septal area is 1,162 ± 127 ng/g and the dopamine (DA) content is 522 ± 106 ng/g. Hemisection of the brainstem caudal to the locus coeruleus results in a 47% decrease in septal NE content and a unilateral locus coeruleus lesion produces a 48% decrease in septal NE content. These observations suggest that the NE innervation of the septal area arises approximately equally from the locus coeruleus and nuclei in the caudal brain stem. This is confirmed, at least in part, by the anterograde and retrograde transport studies. The DA innervation of the septal area is shown by all of the techniques employed to arise almost exclusively from cells of the ventral tegmental area. NE axons arising from the locus coeruleus distribute in the septal area to the hippocampal rudiment, the nucleus of the diagonal band, the interstitial nucleus of the stria terminalis, the medial septal nucleus, the lateral septal nucleus and the nucleus septofimbrialis. In each area the innervation is sparse to moderate in density and has the plexiform organization typical of locus coeruleus innervation. The brainstem NE innervation is very dense in the interstitial nucleus of the stria terminalis, moderately dense in the lateral septal nucleus and sparse in the nucleus of the diagonal band. The DA axons innervating the septum terminate in two distinct patterns. The first is identical to that seen in the neostriatum. Preterminal axons are very fine and non‐varicose. As they reach a terminal area they branch markedly and give rise to extremely numerous, closely‐packed, fine varicosities. This type of DA innervation is found in the medial part of the lateral septal nucleus in a dense band and about some scattered lateral septal nucleus neurons, in the nucleus accumbens and in the interstitial nucleus of the stria terminalis. The second pattern is for non‐varicose preterminal axons to branch and terminate in pericellular baskets about lateral septal nucleus neurons or simply terminate in the lateral septal nucleus neuropil. In each case the terminal branches give off distinct varicosities which are larger than those formed in the first pattern of DA innervation. Thus, the septal area has a complex organization of CA innervation with NE axons arising from caudal brainstem nuclei and the locus coeruleus and DA axons arising from the ventral tegmental area.

Hypocretin (Orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system

Article

Dec 1999
J COMP NEUROL

Hypocretin has been identified as a regulator of metabolic and endocrine systems. Several brain regions involved in the central regulation of autonomic and endocrine processes or attention are targets of extensive hypocretin projections. The most dense arborization of hypocretin axons in the brainstem was detected in the locus coeruleus (LC). Multiple labeling immunocytochemistry revealed a massive synaptic innervation of catecholaminergic LC cells by hypocretin axon terminals in rats and monkeys. In both species, all tyrosine hydroxylase-immunopositive cells in the LC examined by electron microscopy were found to receive asymmetrical (excitatory) synaptic contacts from multiple axons containing hypocretin. In parallel electrophysiological studies with slices of rat brain, all LC cells showed excitatory responses to the hypocretin-2 peptide. Hypocretin-2 uniformly increased the frequency of action potentials in these cells, even in the presence of tetrodotoxin, indicating that receptors responding to hypocretin were expressed in LC neurons. Two mechanisms for the increased firing rate appeared to be a reduction in the slow component of the afterhyperpolarization (AHP) and a modest depolarization. Catecholamine systems in other parts of the brain, including those found in the medulla, zona incerta, substantia nigra or olfactory bulb, received significantly less hypocretin input. Comparative analysis of lateral hypothalamic input to the LC revealed that hypocretin-containing axon terminals were substantially more abundant than those containing melanin-concentrating hormone. The present results provide evidence for direct action of hypothalamic hypocretin cells on the LC noradrenergic system in rats and monkeys. Our observations suggest a signaling pathway via which signals acting on the lateral hypothalamus may influence the activity of the LC and thereby a variety of CNSfunctions related to noradrenergic innervation, including vigilance, attention, learning, and memory. Thus, the hypocretin innervation of the LC may serve to focus cognitive processes to compliment hypocretin-mediated activation of autonomic centers already described. J. Comp. Neurol. 415:145–159, 1999. © 1999 Wiley-Liss, Inc.

The patterns of afferent innervation of the core and shell in the “Accumbens” part of the rat ventral striatum: Immunohistochemical detection of retrogradely transported fluoro-gold

Article

Dec 1993
J COMP NEUROL

Recent data have emphasized the neurochemically distinct nature of subterritories in the accumbens part of the rat ventral striatum termed the core, shell, and rostral pole. In order to gain a more comprehensive understanding of how afferents are distributed relative to these subterritories, immunohistochemical detection of retrogradely transported Fluoro-Gold was carried out following iontophoretic injections intended to involve selectively one of the subterritories. The data revealed that a number of cortical afferents of the medial shell and core originate in separate areas, i.e., the dorsal peduncular, infralimbic, and posterior piriform cortices (to medial shell) and the dorsal prelimbic, anterior agranular insular, anterior cingulate, and perirhinal cortices (to core). The lateral shell and rostral pole are innervated by cortical structures that also project either to the medial shell or core. The orbital, posterior agranular insular, and entorhinal cortices, hippocampus, and basal amygdala were observed to innervate the accumbens in a topographic manner. Following core injections, strong bilateral cortical labeling was observed. Few labeled cortical cells were observed contralaterally following injections in the medial shell. Intermediate numbers of labeled neurons were observed in contralateral cortices following lateral shell injections. Robust subcortical labeling in a variety of structures in the ventral forebrain, lateral hypothalamus, deep temporal lobe, and brainstem was observed after shell injections, particularly those that involved the caudal dorsomedial extremity of the shell, i.e., its “septal pole.” Selective ipsilateral labeling of subcortical structures in the basal ganglia circuitry was observed following injections in the core and, to a lesser extent, lateral shell. It was concluded that a number of afferent systems exhibit varying degrees of segregation with respect to the accumbal subterritories.

Dopamine microdialysis in the nucleus accumbens during acute and chronic morphine, naloxone-precipitated withdrawal and clonidine treatment

Article

Jan 1992
BRAIN RES

This study shows the effect of opiate withdrawal on dopamine (DA) in the nucleus accumbens (NAC). Microdialysis was used to detect variations in extracellular DA, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the NAC of freely moving rats during acute and chronic morphine treatment followed by naloxone-precipitated withdrawal with and without clonidine. Basal levels of extracellular DA did not change between sessions, but morphine (20 mg/kg, i.p.) caused a significant and identical increase in extracellular DA and metabolites in both the acute phase (day 1) and the chronic phase (day 7). On day 8, naloxone (20 mg/kg i.p.) caused a significant decrease in DA levels accompanied by typical withdrawal symptoms such as wet dog shakes and teeth-chattering. Clonidine pretreatment (200 μg/kg i.p.) eliminated both the withdrawal symptoms and the DA decrease. These results support the view that morphine increases extracellular DA at times when the drug is rewarding and also suggest that the converse may be true; morphine withdrawal decreases DA release in association with the aversive state.

Contribution of bed nucleus of the stria terminalis to the cardiovascular responses elicited by stimulation of the amygdala

Article

Nov 1993
J Auton Nerv Syst

Anatomical and physiological studies were done in the rat to investigate the possibility that the cardiovascular responses elicited by stimulation of central nucleus of the amygdala (ACe) were mediated via projections to bed nucleus of the stria terminalis (BST). In the first series, to determine the distribution of neurons in ACe that projected to the cardiovascular region of BST, the retrograde tracer Fluorogold (FG) or rhodamine latex micro-beads (Rd) were injected into BST. FG and Rd injections that overlapped the cardiovascular region of BST resulted in retrogradely labelled neurons throughout the amygdala. In ACe, retrogradely labelled neurons were observed primarily in the lateral subdivision of the rostral ACe compared to the caudal ACe. The medial subdivision of ACe was found to have very few retrogradely labelled neurons. In the second series, the effect of either blocking synaptic transmission in BST with CoCl2, chemical lesions of BST with ibotenic acid (IBO), or electrolytic lesions of BST on the depressor response elicited by either electrical or chemical stimulation of ACe was investigated in the chloralose-anesthetized, artificially ventilated and paralysed rat. Microinjections of CoCl2 into BST significantly attenuated the depressor responses to stimulation of the rostral components of the lateral subnucleus of ACe, but not those to stimulation of the caudal and medial components of ACe. Microinjections of IBO into BST or electrolytic lesions of BST resulted in similar effects on the depressor responses to ACe stimulation. Taken together, these data indicate that neurons within the rostral components of the lateral subnucleus of ACe project to the cardiovascular region of BST and mediate in part the depressor responses to stimulation of the rostral ACe. On the other hand, the depressor responses elicited from the caudal ACe are not mediated through BST. These results suggest that at least two independent pathways originate in the ACe that influence the circulation.

Short-term memory, alterness and performance: A reappraisal of their relationship to body temperature

Article

Mar 1992

Previous studies have led to the beliefs: (1) that short-term memory is best during the night when the body temperature is at its nadir, and (2) that the circadian rhythms of short-term memory and subjective alertness are driven by oscillators independent from each other and from the body temperature cycle. Unfortunately, these conclusions, which would have major implications for understanding the organization of the human circadian timing system, are largely based on field and laboratory studies, which in many cases sampled data infrequently and/or limited data collection to normal waking hours. In order to investigate these points further, we have monitored behavioural variables in two different protocols under controlled laboratory conditions: (1) during a period of 36-60 h of sustained wakefulness; and (2) during forced desynchrony between the body temperature and sleep/wake cycles, allowing testing of non-sleep-deprived subjects at all circadian phases. Contrary to earlier findings, we report here that the circadian rhythm of short-term memory varies in parallel with the circadian rhythms of subjective alertness, calculation performance, and core body temperature under both these experimental conditions. These results challenge the notion that short-term memory is inversely linked to the body temperature cycle and suggest that the human circadian pacemaker, which drives the body temperature cycle, is the primary determinant of endogenous circadian variations in subjective alertness and calculation performance as well as in the immediate recall of meaningful material.

Stereotaxic Mapping of the Monoamine Pathways in the Rat Brain*

Article

Dec 1971
Acta Physiol Scand Suppl

Urban Ungerstedt

The ascending monoamine pathways in the rat brain are demonstrated by the pile up of fluorescent material occurring in the axons after various types of lesions. The anatomy of the pathways is outlined in drawings of frontal sections of the brain and the origin and termination of several pathways is determined by studying the anterograde and retrograde degeneration occurring after well localised lesions. It is possible to separate the ascending NA pathways into a dorsal and a ventral bundle of axons. The dorsal bundle innervates the cortex and the hippocampus and the ventral bundle supplies NA nerve terminals to the medulla, the pons, the mesencephalon and the diencephalon. The dorsal bundle is found to originate in the locus coeruleus. Lesions of this nucleus abolish the nerve terminals in all cortical areas and in several other areas of the brain indicating a unique role for the locus coeruleus in influencing the activity of the entire brain. The 5-HT pathways have a distribution similar to the ventral NA pathyway. The course of the nigro-striatal and the meso-limbic DA pathways is presented in detail.

Origin of serotonergic nerves terminating in the cerebral ventricles

Article

Jun 1975
BRAIN RES

The dorsal and median raphe nuclei of the midbrain are known to contain the perikarya of origin of the major serotonergic (indoleamine) neurons projecting to the parenchyma of the forebrain. Lesions were placed in these nuclei to determine whether serotonin-containing nerve terminals in the cerebral ventricular system are also derived from the raphe nuclei. Brain tissue from control rats and rats 2-7 days after placement of raphe lesions was examined by fluorescence and electron microscopy. By the third day after lesion there was a marked reduction in the formaldehyde-induced fluorescence of supra-ependymal terminals. By the same time virtually all supra-ependymal terminals showed advanced degenerative changes as visualized by electron microscopy. There was a degeneration of supra-ependymal terminals in all parts of the cerebral ventricular system examined, including the epithalamic region (e.g., habenula and pineal recess; serotonin-containing terminals in the latter areas had previously been thought to arise from modified pinealocytes in the pineal recess). We conclude that most, if not all, supra-ependymal nerve terminals are derived from serotonergic cells of origin in the raphe nuclei.

Hobson JA, McCarley RW, Wyzinski PW. Sleep cycle oscillation: reciprocal discharge by two brainstem neuronal groups. Science 189: 55-58

Article

Jul 1975

During the sleep cycle in cats, neurons localized to the posterolateral pole of the nucleus locus coeruleus and the nucleus subcoeruleus undergo discharge rate changes that are the opposite of those of the pontine reticular giant cells. The inverse rate ratios and activity curves of these two interconnected populations are compatible with reciprocal interaction as a physiological basis of sleep cycle oscillation.

The central adrenergic system. An immunofluorescence study of the location of cell bodies and their efferent connections in the rat utilizing dopamine-B-hydroxylase as a marker

Article

Oct 1975

A sensitive immunofluorescence technique was used to describe systematically the distrubution of dopamine-beta-hydroxylase (DBH)-containing cell bodies, non-terminal fiber pathways, and terminal fields in the brain of the male albino rat. DBH is the enzyme that catalyzes the conversion of dopamine to noradrenaline, and as such is useful as an anatomical marker for noradrenaline and possibly adrenaline neurons. The enzyme is not present in dopamine- or indolamine-containing neurons. Ten micron frozen sections (1-in 20 series) were prepared in the frontal, sagittal, and horizontal planes from the olfactory bulb to the upper cervical segments of the spinal cord; adjacent sections in each plane were stained for DBH and for cells (toluidine blue=azure II). An atlas consisting of 40 projection drawings of selected frontal sections illustrates the results of the investigation. DBH perikarya are confined to three groups in the pons and medulla: the well defined locus coeruleus, a more diffuse but continuous subcoeruleus group that arches through the pons and ventral medulla, and a third dorsal medullary group centered in the dorsal motor nucleus of the vagus. A single principal adrenergic fiber system distributes a great many of the axons from these neuron groups to a majority of nuclear areas in the brain. In the pons and medulla two components of the fiber system may be distinguished. A medullary branch may be followed from the posterior aspect of the subcoeruleus group dorsally and then anteriorly through the lateral tegmental field and ventral aspect of the vestibular complex to a position subjacent to the locus coeruleus, where it is joined by a subcoeruleus branch consisting of a large number of fibers coursing among cells along the length of the subcoeruleus group, and by fibers arising from the locus coeruleus. Anterior to the locus coeruleus the principal adrenergic bundle courses as a single fiber tract immediately ventrolateral to the central gray in the mesencephalon and in the zona incerta and substantia innominata in the diencephalon. At the level of the septal area separate bundles reach the cortex dorsally over the genu of the corpus calosum via the medial septal-diagonal band nuclei and the lateral septum and ventrally between the olfactory tubercle and caudate-putamen. In the medulla and pons adrenergic fibers undoubtedly course in both directions. Anterior to the most rostral pontine cell bodies, however, all fibers presumably ascend. Along the course of the bundle distinct branches emerge to innervate circumscribed terminal fields. In addition, certain regions of the brain such as the reticular formation and pontine gray receive diffuse DBH innervation derived from less clearly defined pathways. A small number of areas in the brain contain little or no detectable DBH. These include the caudate-putamen, nucleus accumbens, globus pallidus, olfactory tubercle, subthalamic nucleus, substantia nigra, pretectal area, third, fourth and sixth cranial verve nuclei, and the trapezoid body nucleus.

Monoamine innervation of bed nucleus of stria terminalis: An electron microscopic investigation

Article

Jul 1992
BRAIN RES BULL

Immunocytochemical studies showed distinctive monoamine input to the bed nucleus of the stria terminalis (BST). A comparison of axons immunoreactive (IR) for a catecholamine synthetic enzyme [tyrosine hydroxylase (TH) or dopamine beta-hydroxylase (DBH) or phenylethanolamine-N-methyl transferase (PNMT)] or serotonin (5-HT) was performed. TH-IR axons had a greater density in the lateral BST, but DBH-IR and 5-HT-IR axons had a greater density in the medial BST. PNMT-IR axons were dense in the intermediate BST. TH-IR axons had a greater density than DBH- and PNMT-IR axons in the dorsolateral BST, but DBH-IR axons had the greatest density in the ventrolateral BST. Ultrastructural studies revealed that TH-IR terminals formed synapses with soma, dendrites, spines, and axons in the dorsolateral BST. DBH-IR terminals formed synapses with dendritic shafts and spines, and 5-HT-IR terminals formed synapses with dendrites in the ventrolateral BST. Only some 5-HT-IR axons were myelinated. The medial vs. lateral organization of the noradrenergic and dopaminergic afferents in the BST of the rat brain is now evident and is similar to the human brain. The medial-lateral functional subdivision of the BST is supported by the pattern of dopaminergic, noradrenergic, and serotonergic afferents. This demonstration of epinephrine-producing afferents in the BST is the first detailed description of adrenergic input to the BST and aided the determination that catecholaminergic innervation of the ventrolateral BST is predominantly noradrenergic as has been proposed for many years. However, the additional demonstration of rich dopaminergic innervation of the dorsolateral subnucleus suggests further division of the BST into dorsal and ventral functional subgroups.

Marked inhibition of mesolimbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats

Article

Nov 1992
EUR J PHARMACOL

Withdrawal of rats from chronic ethanol, morphine, cocaine and amphetamine resulted in a marked reduction in extracellular dopamine (DA) concentration in the ventral striatum as measured by microdialysis. Following ethanol and naloxone-precipitated morphine withdrawal, the time course of DA reduction paralleled that of the withdrawal symptomatology. On the other hand, following discontinuation of chronic cocaine, DA reduction was delayed by over 24 h but persisted for several days. After amphetamine withdrawal the fall in DA occurred more rapidly but the reduction also persisted for several days. The administration of the NMDA receptor antagonist, MK-801, to rats withdrawn from chronic ethanol, morphine or amphetamine, but not from chronic cocaine, readily reversed the fall in DA output. The reduction in extracellular DA during ethanol withdrawal was also reversed by SL 82.0715, another NMDA receptor antagonist.

Noradrenergic-induced expression of c-fos in rat cortex: Neuronal localization

Article

Jul 1992
NEUROSCI LETT

beta Adrenoceptors in the rat forebrain have been shown to exist predominantly on astrocytes. Studies were undertaken to determine whether the cellular localization of c-fos expression caused by the activation of brain beta receptors would have a similar cellular localization. Double label light and electron microscopic immunohistochemical experiments with a glial (glial fibrillary acidic protein, GFAP) and neuronal marker (neurofilament protein, NFP) were undertaken in rats treated with the adrenergic drug, yohimbine. These studies revealed a predominantly neuronal localization of Fos protein in the cerebral cortex. The latter results indicate that neurons are the postsynaptic noradrenergic target cells in which this immediate early gene is expressed in response to the stimulation of beta adrenoceptors. The possible relation of these findings to the glial localization of these receptors is discussed.

Evidence for two different afferent pathways carrying stress-related information (noxious and amygdala stimulation) to the bed nucleus of the stria terminalis

Article

Jun 1992
BRAIN RES

The bed nucleus of the stria terminalis (BNST) is an important nucleus involved in mediating amygdala-regulated endocrine effects. Since the amygdala is important in mediating the endocrine response to noxious somatosensory stimuli and olfactory stimulation, this experiment studies whether noxious input (tail pinch, TP) and stress-related input (amygdala stimulation, AmygS) will modulate BNST neuronal activity. One hundred and fifty-eight BNST neurons were studied following AmygS, TP and cutaneous stroke. AmygS was effective in 66% of BNST neurons and produced one of the following five responses: oligosynaptic excitation (43%), polysynaptic excitation (5%), time-locked inhibition (4%), generalized increase in firing rate (8%), or generalized decrease in firing rate (6%). TP produced an increase in firing rate in 27% of BNST neurons tested. Analysis of a contingency table constructed to determine the degree of correspondence between neurons responsive to AmygS and neurons responsive to TP showed that the distributions of reactivity to these stimuli in BNST neurons are independent of each other. This suggests that although AmygS and TP are both capable of altering the firing rate of BNST neurons, the pathways by which they reach BNST differ.

Memory retrieval enhancement by locus coeruleus stimulation: evidence for mediation by ??-receptors

Article

May 1991
BEHAV BRAIN RES

Rats were trained in a complex food-motivated maze task, then implanted with indwelling stimulating electrodes in the noradrenergic nucleus locus coeruleus (LC). When tested 4 weeks later, they showed significant forgetting. Electrical stimulation of the LC alleviated forgetting in that stimulated rats made no more errors during the test than they did on the last learning trial. Systemic treatment with the beta noradrenergic antagonist propranolol blocked the effect of stimulation, suggesting that the memory facilitation is mediated through a beta-receptor.

Forebrain nuclei involved in autonomic control (Review)

Article

Feb 1991
Progr Brain Res

A.D. Loewy

Several key regions of the forebrain are involved in regulation of autonomic functions. These areas include the several areas within the hypothalamus (viz., paraventricular hypothalamic nucleus, lateral hypothalamic area, posterior periventricular area, and zona incerta), the basal forebrain (viz., central nucleus of the amygdala and bed nucleus of the stria terminalis), and the cerebral cortex (viz., insular and medial prefrontal cortex). All these areas have been implicated on anatomical grounds to be part of a central autonomic network involving multiple interconnecting circuits. Apart from these complex interconnections, most of these areas project to the lower brain stem where they are capable of influencing the cell groups which innervate the vagal and sympathetic preganglionic neurons or in some cases, like the paraventricular hypothalamic nucleus and the lateral hypothalamic area, provide direct projections to these neurons.

Nucleus accumbens and amygdala are possible substrates for the aversive stimulus effects of opiate withdrawal

Article

Feb 1990
NEUROSCIENCE

Specific brain sites for the opiate abstinence syndrome syndrome have been elusive to delineate, and the classic overt signs of withdrawal such as wet dog shakes, ptosis and teeth chattering appear to be widely represented in the brain. Using a more general motivational test involving a disruption of operant behavior in dependent rats, the brain site most sensitive to the response disruptive effects of intracerebral administration of the opiate antagonist, methylnaloxonium, was the region of the nucleus accumbens, a site also implicated in the acute reinforcing properties of opiates. This disruption of operant responding was hypothesized to reflect the aversive properties of opiate withdrawal. The present study directly tested that hypothesis by exploring whether intercerebral administration of methylnaloxonium produced aversive stimulus effects as measured by the formation of place aversions. Rats implanted intracerebroventricularly or with bilateral cannulae aimed at the medial dorsal thalamus, periaqueductal gray, ventral tegmental area, amygdala or nucleus accumbens were made dependent on morphine by subcutaneous implantation of two 75-mg morphine pellets. The animals were then subjected to place aversion training by pairing of a distinct environment (one of three arms of a three-armed box with distinct texture, markings and smell) with a single injection of methylnaloxonium intracerebroventricularly or intracerebrally. Results showed that at high doses of methylnaloxonium (1000-2000 ng) all sites produced a place aversion. However, lower doses (250-500 ng) produced a significant brain site selectivity with the region of the nucleus accumbens the most sensitive. Observational measurements taken during the postinjection period with the high dose of methylnaloxonium showed that agitation was particularly observed following methylnaloxonium administration into the nucleus accumbens and periaqueductal gray.(ABSTRACT TRUNCATED AT 250 WORDS)

Nucleus accumbens as a substrate for the aversive stimulus effects of opiate withdrawal

Article

Feb 1989

Previous studies from our laboratory using methylnaloxonium, a hydrophilic antagonist, showed that opiate receptors in the region of the nucleus accumbens are important for the acute reinforcing effects of heroin in non-dependent rats. A similar increased sensitivity to the response disruptive effects of intracerebrally injected methylnaloxonium in opiate dependent rats was observed in a fixed-ratio (FR) baseline of operant behaviors. These results suggest that the same opiate receptors in the region of the nucleus accumbens important for the positive reinforcing stimulus properties of opiates may also be responsible for the response disruptive, aversive stimulus properties of opiate withdrawal. These results also suggest that the neural substrates of some aspects of dependence may be partly related to those of the reinforcing effects of opiates. In particular, it is hypothesized that "euphoria" and "dysphoria" induced by opiates may reflect opponent motivational processes operating at a cellular level within the nucleus accumbens.

Ventromedial and dorsomedial hypothalamic syndromes in the weanling rat: Is the "center" concept really outmoded?

Article

Jul 1985
BRAIN RES BULL

Lee L. Bernardis

This report juxtaposes findings from weanling rats with precise lesions in the ventromedial (VMNL rats) to data of weanling rats with lesions in the dorsomedial (DMNL) hypothalamic nuclei. Despite the proximity of the two nuclei their destruction produces opposite effects in most cases but similar responses in other parameters. Absolute and relative food intake are normal in VMNL rats yet they become obese in the face of normal body weight gains. DMNL rats show both reduced absolute food intake and body weight but normal relative food intake and body composition. Both VMNL and DMNL cause reduced linear growth and running wheel activity. DMNL rats defend their lower body weight set point against various challenges and maintain normal body composition. Organ growth in both absolute and relative terms is reduced in VMNL rats. In DMNL rats relative organ growth is normal. Pancreatic growth, protein/pancreas and content and concentrations of several pancreatic enzymes are normal in DMNL but reduced in VMNL rats. Mean 24-hour plasma growth hormone (GH) and corticosterone (B) levels are reduced and insulin levels are greatly elevated in VMNL rats; prolactin (PRL) levels are normal. In DMNL rats, GH, B, insulin and somatomedin activity are normal but PRL is elevated. Circadian rhythms of GH, insulin and triiodothyronine are normal in DMNL rats but B levels are disrupted, as they are in VMNL rats. Glucose incorporation and oxidation in adipose tissue of VMNL rats are enhanced in VMNL rats but normal in DMNL rats. Gluconeogenesis in VMNL rats is enhanced as early as 4 hours post-operatively; in DMNL rats it is normal at this time and several weeks thereafter. Basal lipolysis in epididymal fat pads is elevated in both VMNL and DMNL rats but epinephrine-stimulated lipolysis is elevated in VMNL and decreased in DMNL rats. Both VMNL and DMNL rats show normal basal and epinephrine-stimulated lipolysis in interscapular brown adipose tissue. Several hepatic enzymes are normal in DMNL and depressed in VMNL rats. The above data suggest that the DMN and its circuitry are part of an "organismic" set point system with a "true" body weight and no fat set point, as seems to be the case in the VMNL rat.

Blockade of nucleus accumbens opiate receptors attenuates intravenous heroin reward in rats

Article

Feb 1985

A quaternary derivative of naloxone, methyl naloxonium chloride (MN), was administered intracerebrally to rats trained to self-administer heroin intravenously. Increases in intravenous (IV) heroin self-administration rates were found following injections of low doses of MN into the nucleus accumbens (N.Acc), but not following injections of low doses of MN into the ventral tegmental area (VTA). These results were interpreted to suggest that the rewarding properties of IV heroin were decreased following N.Acc opiate receptor blockade. The relative insensitivity of the VTA to MN treatment was taken to suggest that VTA opiate receptors are either not essential or play a secondary role in mediating IV heroin self-administration. The present data support the notion that post-synaptic N.Acc opiate receptors play a crucial role in maintaining IV heroin self-administration.

Neurochemical substrates for opiate reinforcement

Article

Feb 1986

The studies reported herein summarize our work to date aimed at determining the neurochemical substrates for the reinforcing properties of opiates. Rats were trained to self-administer heroin intravenously in daily 3-hour sessions, and pharmacological blockade and neurotoxin-induced lesions were used to define the neurochemical substrates for this reinforcing action. Low-dose DA receptor blockade failed to alter heroin self-administration but significantly increased cocaine self-administration, presumably reflecting a decrease in the reinforcing effectiveness of cocaine. Destruction of presynaptic DA terminals within the N.Acc. produced extinction of cocaine, but not heroin, self-administration. Opiate receptor blockade with systemic naloxone increased heroin, but not cocaine, self-administration. Methylnaloxonium injections into the N.Acc. were effective in increasing heroin self-administration at doses one-eighth those observed for intracerebroventricular injections. Reinforcement has been explored using a place-preference procedure and a self-administration drug-substitution paradigm. Mu/delta agonists such as B-END readily produce a naloxone-reversible place preference. Fentanyl derivatives also produce place preference and substitute for heroin during self-administration. The kappa agonist U50-488 produces place aversion, not place preference, and does not readily substitute for heroin. Altogether, these results suggest that mu/delta receptor subtypes in the region of the N.Acc. may be an important neurochemical substrate for opiate reinforcement.

New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: The striatopallidal, amygdaloid, and corticopetal components of substantia innominata

Article

Nov 1988
NEUROSCIENCE

The basal forebrain is critically involved in functions representing the highest levels of integration. Only recently has a relatively clear anatomical picture of this important area begun to emerge. The territory that has generally been referred to as the "substantia innominata" appears to be composed of portions of three recognizable forebrain structures: the ventral striatopallidal system, the extended amygdala and the magnocellular corticopetal system. (1) Rostrally, the striatopallidal system reaches ventrally to the base of the brain. (2) Caudal to the ventral extension of the striatopallidal system elements of the centromedial amygdala and bed nucleus of the stria terminalis are merged so that these two areas together with this subpallidal corridor form a large forebrain unit that might be described as an "extended amygdala". (3) Large cholinergic and non-cholinergic corticopetal neurons form a more or less continuous aggregate that is interwoven with the striatopallidal and extended amygdala systems in basal forebrain. Consideration of morphological and connectional characteristics of basal forebrain suggests that the corticopetal cell groups, together with magnocellular elements of the striatum, serve similar functional roles for the striatopallidal system, the extended amygdala, and the septal-diagonal band complex. Specifically, the output of medium spiny neurons in striatum, extended amygdala, and lateral septum are directed toward somewhat larger sparsely or moderately spiny neurons with radiating dendrites which in turn project to diencephalon and brainstem or provide either local feedback (e.g. in striatum) or distal feedback to cortex. The functional implications of this parallel processing of descending forebrain afferents are discussed.

Efferent projections of the suprachiasmatic nucleus: I. Studies using anterograde transport of Phaseolus vulgaris leucoagglutinin in the rat

Article

Apr 1987

The efferent projections of the suprachiasmatic nucleus (SCh) in the rat hypothalamus have been reexamined with the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L), which displays labeled axons with the clarity of a Golgi impregnation. Fibers from the SCh can be divided into six pathways for descriptive purposes. By far the densest terminal field arising from cells in the SCh ends in a roughly comma-shaped zone between the SCh and paravontricular nucleus on the one hand and the periventricular nucleus and anterior hypothalamic area on the other. A few axons continue dorsally from this “subparaventricular zone” to pass through parvicellular parts of the paraventricular nucleus and the overlying midline thalamic nuclei to end in midrostrocaudal parts of the paraventricular nucleus of the thalamus, and a larger number continue caudally to end in the dorsomedial nucleus, dorsal parts of the cell-sparse zone surrounding the ventromedial nucleus, and the posterior hypothalamic area. The other five pathways all consist of relatively small numbers of fibers and give rise to relatively sparse terminal fields. The second pathway consists of rostrally directed fibers that end in ventral parts of the medial preoptic area and anteroventral periventricular nucleus. The third consists of anterodorsally oriented fibers that pass through the medial preoptic nucleus and adjacent regions to end ventrally in the intermediate lateral septal nucleus. The fourth consists of fibers just caudal to the third group that end in the preoptic continuation of the bed nucleus of the stria terminalis, as well as in the parataenial nucleus and rostral part of the paraventricular nucleus of the thalamus. The fifth consists of laterally directed fibers that course over the optic tract to end in the ventral lateral geniculate nucleus. And the sixth consists of fibers that course posteriorally through the anterior hypothalamic and retrochiasmatic areas to end in the cell-sparse zone between the arcuate nucleus and ventral parts of the ventromedial nucleus, as well as in adjacent parts of the lateral hypothalamic area. The distribution of projections labeled following PHA-L injections centered in the subparaventricular zone was also examined and was confirmed with retrograde tracer experiments (Watts and Swanson: J. Comp. Neurol. 258:230–252, '87). The results indicate that the subparaventricular zone projects to essentially the same regions as the SCh, only much more densely, and also sends fibers back to the SCh. In addition, the subparaventricular zone innervates a much larger extent of the lateral septal nucleus than the SCh and also sends fibers throughout the length of the periaqueductal gray. The results of this study indicate that the output of the SCh may be viewed best as a two-stage process in concert with the subparaventricular zone. Unfortunately, it is still not entirely clear how the SCh effects all manner of circadian and diurnal rhythms since it does not appear to innervate in a significant way cell groups that are known to play a direct role in somatomotor, autonomic, and neuroendocrine responses. Nevertheless, the possible functional role of cell groups innervated directly by the SCh and subparaventricular zone is discussed.

Nucleus Locus Ceruleus: New Evidence of Anatomical and Physiological Specificity

Article

Aug 1983

Rainbow TC, Parsons B, Wolfe BB. Quantitative autoradiography of 1- and 2-adrenergic receptors in rat brain. Proc Natl Acad Sci USA 81: 1585-1589

Article

Apr 1984

We have used quantitative autoradiography to localize in rat brain beta 1- and beta 2-adrenergic receptors. These receptors were labeled in vitro with 125I-labeled pindolol, an antagonist of beta-adrenergic receptors that binds nonselectively to both beta 1 and beta 2 subtypes. The selective inhibition of 125I-labeled pindolol binding with specific antagonists of beta 1 and beta 2 receptors allowed the visualization of beta-adrenergic receptor subtypes. High levels of beta 1 receptors were observed in the cingulate cortex, layers I and II of the cerebral cortex, the hippocampus, the Islands of Calleja, and the gelatinosus, mediodorsal, and ventral nuclei of the thalamus. High levels of beta 2 receptors were found in the molecular layer of the cerebellum, over pia mater, and in the central, paraventricular, and caudal lateral posterior thalamic nuclei. Approximately equal levels of beta 1 and beta 2 receptors occurred in the substantia nigra, the olfactory tubercle, layer IV of the cerebral cortex, the medial preoptic nucleus, and all nuclei of the medulla. The pronounced differences in the ratio of beta 1 to beta 2 receptors among brain regions suggests that the subtypes of beta-adrenergic receptors may play different roles in neuronal function.

Dorsal noradrenergic bundle lesions fail to alter suppression of opiate withrawal by clonidine

Article

Feb 1984
LIFE SCI

Previous work has shown that clonidine effectively suppresses many of the signs of opiate withdrawal. The present study was designed to test the hypothesis that the suppression of opiate withdrawal by clonidine is mediated by forebrain noradrenergic projections of the locus coeruleus. Two groups of 24 rats each were subjected to either a 6-hydroxydopamine lesion of the dorsal noradrenergic bundle (Lesion group) or a sham, vehicle injection (Sham group). All rats were made dependent on morphine by subcutaneous implantation of one 75 mg silastic morphine pellet for three days followed by 3 more days with two additional 75 mg pellets. Following removal of the morphine pellet, withdrawal was precipitated in all rats by subcutaneous injection of 4 mg/kg of naloxone. Pretreatment 10 min. before withdrawal with clonidine (0.1 or 0.2 mg/kg) produced a significant attenuation of withdrawal signs as compared to saline injected rats; this effect was equally significant in both sham and lesion groups. Lesions of the locus coeruleus had no effect on withdrawal, nor did they affect the ameliorating action of clonidine. These results substantiate the observation that clonidine can effectively attenuate signs of opiate withdrawal in the rat, but fail to support the hypothesis that these effects are mediated by the forebrain projections of the locus coeruleus.

Sleep and its Disorders

Article

Feb 1981

Elliot D. Weitzman

The advances in research on sleep an biological rhythms have recently been applied to the diagnosis and treatment of sleep disorders. A new clinical specialty has developed with the establishment of sleep disorder centers and a diagnostic classification of sleep and arousal disorders. This new nosological approach has evolved from an extensive base of new scientific information concerning descriptive polygraphic and analysis of clinical case series. Four major categories have been defined: (a) disorders of initiating and maintaining sleep (insomnias), (b) disorders of excessive somnolence, (c) disorders of the sleep-wake schedule, and (d) dysfunctions associated with sleep. Within this comprehensive classification certain major pathophysiological advances are described for the "insomnias." These include polysomnographic identification of altered sleep stage patterns in the major effective illnesses, insomnias related to hypnotic drugs and alcohol, sleep disturbances associated with sleep-induced respiratory impairment, and sleep-related periodic movements during sleep (nocturnal myoclonus). Excessive daytime somnolence is primarily associated with the hypersomnia sleep-apnea syndrome and with narcolepsy. The relationship between biological rhythms (chronobiology) and disorders of the human sleep-wake schedules is very actively investigated. The recognition that sleep length, internal organization, and timing within neurophysiological circadian time-keeping systems has lead to better diagnosis of these sleep-wake disorders and new chronotherapeutic regimens. Finally, increasing identification and description of "parasomnias," i.e. dysfunctions associated with sleep, has led sleep research into important new areas that are of general physiological interest. It is now clear that sleep disorders medicine has become a new scientific and clinical discipline in its own right.

Projections of the suprachiasmatic nuclei, subparaventricular zone and retrochiasmatic area in the golden hamster

Article

Aug 1994
NEUROSCIENCE

The patterns of projections from the hamster suprachiasmatic nucleus, retrochiasmatic area and subpraventricular hypothalamic zone were examined using anterograde tracing with the plant lectin, Phaseolus vulgaris leucoagglutinin. Suprachiasmatic nucleus efferents comprise four major fiber groups: (i) an anterior projection to the ventral lateral septum, the bed nucleus of the stria terminalis and anterior paraventricular thalmus; (ii) a periventricular hypothalamic projection extending from the preoptic region to the premammillary area; (iii) a lateral thalamic projection to the intergeniculate leaflet and ventral lateral geniculate; and (iv) a posterior projection to the posterior paraventricular thalamus, precommissural nucleus and olivary pretectal nucleus. The retrochiasmatic area showed a similar projection pattern with several major exceptions. There are projections to endopiriform cortex, fundus striati, ventral pallidum, horizontal limb of the nucleus of the diagonal band and three separate routes to the amygdala. There are also projections laterally with fibers of the supraoptic commissures, which enter the superior thalamic radiation and innervate the caudal dorsomedial thalamic nuclei. Other fibers traveling with the commissures terminate in the ventral zona incerta. The subparaventricular zone projects to most targets of the suprachiasmatic nucleus, but not to the intergeniculate leaflet. There is a substantial input to both the subparaventricular zone and retrochiasmatic area from the suprachiasmatic nucleus, but little apparent reciprocity. There is extensive overlap of suprachiasmatic nuclei and retrochiasmatic efferents, and between retrochiasmatic and known medial amygdaloid efferents. The anatomical information is discussed in the context of circadian rhythm regulation, photoperiodism and chemosensory pathways controlling male hamster reproductive behavior.

Lesion to terminals of noradrenergic locus coeruleus neurons do not inhibit opiate withdrawal behaviour in rats

Article

Mar 1995
NEUROSCI LETT

The involvement of neurones of the locus coeruleus (LC) in expression of opiate withdrawal behaviour was tested in morphine-dependent rats using N-2-chloroethyl-N-ethyl-2-bromobenzylamine (DSP4), a neurotoxin selective for noradrenergic terminals arising from LC. Lesions were validated by determination of cortical noradrenaline concentrations using gas chromatography-mass spectrometry, inhibition of the post-decapitation hindpaw reflex and dopamine-beta-hydroxylase immunohistochemistry. Lesions did not inhibit the expression of any naloxone-precipitated withdrawal signs. These results suggest no involvement of noradrenergic LC neurones in expression of the overt signs of opiate withdrawal, and raise the possibility that previous microinjection and electrolytic lesion studies were confounded by effects on nearby brain regions.

Changes in arterial blood pressure alter activity of electrophysiologically identified single units of the bed nucleus of the stria terminalis

Article

Mar 1995
NEUROSCIENCE

The bed nucleus of the stria terminalis may play a role in cardiovascular function by way of its connectivity to the diagonal band of Broca/ventral septal area. The present study sought to determine whether changes in systemic blood pressure affect the electrical activity of single units within the bed nucleus of the stria terminalis. Extracellular voltage recordings from neurons in the bed nucleus were performed in urethane-anaesthetized rats catheterized for arterial blood pressure measurements and for the intravenous administration of pressor and depressor drugs. Afferent or efferent connectivity of each recorded neuron was determined following electrical stimulation of nearby nuclei with and without known barosensitive regions. Of neurons demonstrating efferent connectivity (antidromically evoked potentials) with the diagonal band of Broca/ventral septal area or habenular nuclei, 24 and 20%, respectively, responded to changes in blood pressure with either increases or decreases in firing frequency. Paraventricular nucleus-projecting neurons were not affected by alterations in arterial blood pressure. Orthodromic potentials (inhibitory and/or excitatory) in the bed nucleus were also observed following stimulation of these nearby nuclei. Of these orthodromically activated neurons, changes in arterial pressure affected 31% of neurons receiving input from the diagonal band of Broca/ventral septal area, 33% of neurons with connectivity to the habenular nuclei and 60% of neurons with connectivity to the paraventricular nucleus.

Afferent projections to the rat locus coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and PHA-L

Article

Apr 1995
NEUROSCIENCE

The aim of this study was to examine the afferents to the rat locus coeruleus by means of retrograde and anterograde tracing experiments using cholera-toxin B subunit and phaseolus leucoagglutinin. To obtain reliable injections of cholera-toxin B in the locus coeruleus, electrophysiological recordings were made through glass micropipettes containing the tracer and the noradrenergic neurons of the locus coeruleus were identified by their characteristic discharge properties. After iontophoretic injections of cholera-toxin B into the nuclear core of the locus coeruleus, we observed a substantial number of retrogradely labeled cells in the lateral paragigantocellular nucleus and the dorsomedial rostral medulla (ventromedial prepositus hypoglossi and dorsal paragigantocellular nuclei) as previously described. We also saw a substantial number of retrogradely labeled neurons in (1) the preoptic area dorsal to the supraoptic nucleus, (2) areas of the posterior hypothalamus, (3) the Kölliker-Fuse nucleus, (4) mesencephalic reticular formation. Fewer labeled cells were also observed in other regions including the hypothalamic paraventricular nucleus, dorsal raphe nucleus, median raphe nucleus, dorsal part of the periaqueductal gray, the area of the noradrenergic A5 group, the lateral parabrachial nucleus and the caudoventrolateral reticular nucleus. No or only occasional cells were found in the cortex, the central nucleus of the amygdala, the lateral part of the bed nucleus of the stria terminalis, the vestibular nuclei, the nucleus of the solitary tract or the spinal cord, structures which were previously reported as inputs to the locus coeruleus. Control injections of cholera-toxin B were made in areas surrounding the locus coeruleus, including (1) Barrington's nucleus, (2) the mesencephalic trigeminal nucleus, (3) a previously undefined area immediately rostral to the locus coeruleus and medial to the mesencephalic trigeminal nucleus that we named the peri-mesencephalic trigeminal nucleus, and (4) the medial vestibular nucleus lateral to the caudal tip of the locus coeruleus. These injections yielded patterns of retrograde labeling that differed from one another and also from that obtained with cholera-toxin B injection sites in the locus coeruleus. These results indicate that the area surrounding the locus coeruleus is divided into individual nuclei with distinct afferents. These results were confirmed and extended with anterograde transport of cholera-toxin B or phaseolus leucoagglutinin. Injections of these tracers in the lateral paragigantocellular nucleus, preoptic area dorsal to the supraoptic nucleus, the ventrolateral part of the periaqueductal gray, the Kölliker-Fuse nucleus yielded a substantial to large number of labeled fibers in the nuclear core of the locus coeruleus.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of glutamate stimulation of bed nucleus of the stria terminalis on arterial pressure and heart rate

Article

Dec 1993
Am J Physiol

Experiments were done in the chloralose-anesthetized, paralyzed, and artificially ventilated rat to determine the cardiovascular responses elicited during chemical stimulation of bed nucleus of the stria terminalis (BST) and to investigate the components of the peripheral autonomic nervous system that mediate these responses. Neurons in BST were selectively stimulated by the microinjection (10-20 nl) of the excitatory amino acid L-glutamate (1 M). Stimulation of BST elicited decreases in mean arterial pressure (n = 105) of -6 to -55 mmHg. These depressor responses were on occasion (n = 60) accompanied by decreases in heart rate ranging between -10 and -40 beats/min. The largest depressor responses were consistently elicited from a crescent-shaped region of BST around the dorsolateral, lateral, and ventrolateral surfaces of the anterior commissure. Intravenous administration of the muscarinic receptor blocker, atropine methylbromide, had no affect on the magnitude of the mean arterial pressure and heart rate responses. On the other hand, administration (intravenous) of the nicotinic receptor blocker, hexamethonium bromide or arfonad, abolished both the depressor response and cardiac slowing during stimulation of BST. These data suggest that the BST depressor and the bradycardia responses are mediated by inhibition of both sympathetic vasoconstrictor fibers to the vasculature and cardioacceleratory fibers to the heart, respectively.

The Bed Nucleus of the Stria Terminalis: A Target Site for Noradrenergic Actions in Opiate Withdrawal

Abstract

No full-text available

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