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Clonidine blocks stress-induced reinstatement of heroin seeking in rats: An effect independent of locus coeruleus noradrenergic neurons
Abstract
Using a reinstatement procedure, it has been shown that intermittent footshock stress reliably reinstates extinguished drug-taking behaviour in rats. Here we studied the role of noradrenaline (NE), one of the main brain neurotransmitters involved in responses to stress, in reinstatement of heroin seeking. We first determined the effect of clonidine, an alpha-2 adrenergic receptor agonist that decreases NE cell firing and release, on stress-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin (0.1 mg/kg per infusion, IV, three 3-h sessions per day) for 9–10 days. Extinction sessions were given for up to 11 days during which saline was substituted for the drug. Tests for reinstatement were then conducted after exposure to intermittent footshock (5, 15 and 30 min, 0.5 mA). During testing, clonidine was injected systemically (10–40 μg/kg, i.p.) or directly into the lateral or fourth ventricles (1–3 μg). Clonidine (1–2 μg per site) or its charged analogue, 2-[2,6-diethylphenylamino]-2-imidazole (ST-91, 0.5–1 μg per site), was also injected bilaterally into the locus coeruleus (LC), the main noradrenergic cell group in the brain. Clonidine blocked stress-induced reinstatement of drug seeking when injected systemically or into the cerebral ventricles. In contrast, neither clonidine nor ST-91 consistently altered stress-induced reinstatement when injected into the locus coeruleus. We therefore studied the effect of lesions of the lateral tegmental NE neurons on stress-induced reinstatement. 6-Hydroxydopamine (6-OHDA) lesions performed after training for heroin self-administration had no effect on extinction of heroin-taking behaviour, but significantly attenuated reinstatement induced by intermittent footshock. These data suggest that: (i) clonidine prevents stress-induced relapse to heroin seeking by its action on neurons other than those of the locus coeruleus; and (ii) activation of the lateral tegmental NE neurons contributes to stress-induced reinstatement of heroin seeking.
... However, the prospective predictive validity of opioid relapse models has yet to be established. The alpha-2 adrenoceptor agonist clonidine decreases footshock stress-induced reinstatement of heroin seeking in rats [82]. These observations led to human studies showing that clonidine modestly decreases heroin craving and heroin relapse in a double-blind human clinical study [179]. ...
... Regarding NE, systemic or ventricular injections of the alpha-2 adrenoceptor agonist clonidine decrease footshock-induced reinstatement of heroin seeking [82]. Repeated injections of the alpha-2 adrenoceptor agonist lofexidine during the extinction and reinstatement phases decrease footshock-induced reinstatement of speedball (heroin-cocaine mixture) seeking [83]. ...
... The critical NE projection involved in footshock-induced reinstatement is the ventral NE bundle that originates in the lateral tegmental nuclei (A1, A2, and A4) and innervates the BNST, CeA, NAc, and other subcortical areas; in contrast, the dorsal NE bundle that originates from the locus coeruleus (LC, A6 area) and innervates mPFC and other cortical areas [84,85] does not play a role in footshockinduced reinstatement. Shaham et al. [82] found that 6hydroxydopamine (6-OHDA) lesions of the ventral NE bundle decrease footshock-induced reinstatement; in contrast, inhibition of NE cell firing and release by injections of clonidine (or its charged analogue ST-91) into the LC has no effect on this reinstatement. The likely lateral tegmental nuclei projection areas that play a role in footshock stress-induced reinstatement are the BNST and CeA: reversible inactivation of these brain areas with TTX decreases this reinstatement (see Fig. 7 in [77]). ...
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.
... However, pharmacologic manipulations that increase CRF are also sufficient to reinstate drug seeking to nicotine (Zislis et al., 2007), alcohol (Lê et al., 2000), heroin (Shaham et al., 1997), cocaine (Brown et al., 2009;Erb & Stewart, 1999), and methamphetamine (Nawata et al., 2012). Likewise, manipulations to increase NE reinstate drug seeking to nicotine (Feltenstein et al., 2012), alcohol (Lê et al., 2005), heroin (Shaham et al., 2000b), cocaine (Erb et al., 2000), and methamphetamine (Shepard et al., 2004). 5 Moreover, CRF receptor antagonists potently reduce stress-induced reinstatement to nicotine (Bruijnzeel et al., 2009;Plaza-Zabala et al., 2010), alcohol (Gehlert et al., 2007;Lê et al., 2000), heroin (Shaham et al., 1997), cocaine (Erb et al., 2001;Shaham et al., 1998), and methamphetamine (Nawata et al., 2012). ...
... 5 Moreover, CRF receptor antagonists potently reduce stress-induced reinstatement to nicotine (Bruijnzeel et al., 2009;Plaza-Zabala et al., 2010), alcohol (Gehlert et al., 2007;Lê et al., 2000), heroin (Shaham et al., 1997), cocaine (Erb et al., 2001;Shaham et al., 1998), and methamphetamine (Nawata et al., 2012). Comparable evidence suggests blocking NE neurotransmission reduces stress-induced reinstatement to nicotine (Zislis et al., 2007), alcohol Lê et al., 2005Lê et al., , 2011, heroin (Shaham et al., 2000b), and cocaine (Erb et al., 2000). Although much of the research on stress-induced reinstatement has used nonspecific central CRF/NE manipulations (e.g., i.c.v. ...
... Although much of the research on stress-induced reinstatement has used nonspecific central CRF/NE manipulations (e.g., i.c.v. injections), evidence suggests that these effects are mediated in part by CeA to BNST pathways (Erb & Stewart, 1999;Shaham et al., 2000b; for reviews, see Silberman & Winder, 2013;Smith & Aston-Jones, 2008). ...
Stressors clearly contribute to addiction etiology and relapse in humans, but our understanding of specific mechanisms remains limited. Rodent models of addiction offer the power, flexibility, and precision necessary to delineate the causal role and specific mechanisms through which stressors influence alcohol and other drug use. This review describes a program of research using startle potentiation to unpredictable stressors that is well positioned to translate between animal models and clinical research with humans on stress neuroadaptations in addiction. This research rests on a solid foundation provided by three separate pillars of evidence from (a) rodent behavioral neuroscience on stress neuroadaptations in addiction, (b) rodent affective neuroscience on startle potentiation, and (c) human addiction and affective science with startle potentiation. Rodent stress neuroadaptation models implicate adaptations in corticotropin-releasing factor and norepinephrine circuits within the central extended amygdala following chronic alcohol and other drug use that mediate anxious behaviors and stress-induced reinstatement among drug-dependent rodents. Basic affective neuroscience indicates that these same neural mechanisms are involved in startle potentiation to unpredictable stressors in particular (vs. predictable stressors). We believe that synthesis of these evidence bases should focus us on the role of unpredictable stressors in addiction etiology and relapse. Startle potentiation in unpredictable stressor tasks is proposed to provide an attractive and flexible test bed to encourage tight translation and reverse translation between animal models and human clinical research on stress neuroadaptations. Experimental therapeutics approaches focused on unpredictable stressors hold high promise to identify, repurpose, or refine pharmacological and psychosocial interventions for addiction.
... The pharmacological stressor yo- himbine, an α2-AR antagonist that blocks autoreceptors and promotes NA signalling, produces withdrawal symptoms and increases craving in opiate addicts and alcoholics (Stine et al., 2002;Umhau et al., 2011). Presynaptic regulation of NA signalling with α2-AR agonists buffered withdrawal-induced anxiety ( Buffalari et al., 2012), attenuated alcohol self-administration and stress-induced reinstatement of alcohol seeking ( Le et al., 2005), heroin seeking ( Shaham et al., 2000), and cocaine seeking ( Erb et al., 2000;Mantsch et al., 2010;Buffalari et al., 2012). Human addicts treated with α2-AR agonists experience diminished stress-related drug cravings and demonstrate improved relapse out- comes ( Sinha and Li, 2007;Jobes et al., 2011;Fox et al., 2012). ...
... Both acute and chronic morphine were associated with augmented extracellular NA levels in the vBNST during naloxone- precipitated withdrawal ( Fuentealba et al., 2000;Fox et al., 2017). Lesions of the ventral noradrenergic bundle in rats abolished stress- induced reinstatement of morphine CPP ( Wang et al., 2001) and heroin seeking ( Shaham et al., 2000). ICV delivery of NA increased Fos ex- pression in the BNST and reinstated cocaine seeking (Brown et al., 2011). ...
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.
... Another issue to consider in the interpretation of our data within the context of the general phenomenon of stressinduced reinstatement (Mantsch et al, 2016;Shaham et al, 2000b) is whether the effect of U50,488 on reinstatement of alcohol seeking is due to the instigation of a stress-like state that promotes drug seeking. In support of this notion, we found that, as with exposure to environmental stressors like footshock or restraint (Kant et al, 1985;Shaham et al, 1997), U50,488 injections increased plasma levels of the stress hormone corticosterone (Selye, 1936). ...
... κ-Opioid receptors and reinstatement AD Lê et al (Wang et al, 2001(Wang et al, , 2006. In addition, 6-OHDA lesions of the ventral noradrenergic bundle, which innervates the BNST (Aston-Jones et al, 1999), decrease footshock-induced reinstatement of heroin seeking (Shaham et al, 2000b) and morphine CPP (Wang et al, 2001). Furthermore, reversible inactivation of the BNST with tetrodotoxin decreases footshock-induced reinstatement of heroin seeking (Shaham et al, 2000a), and reversible inactivation of the BNST with lidocaine decreases swim stress-induced reinstatement of cocaine CPP (Briand et al, 2010). ...
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 first involves the VTA and its projections to the hypothalamus, NAcc, amygdala, and bed nucleus of the stria terminalis, predominately via noradrenaline. The second involves the central nucleus of the amygdala and projections to the bed nucleus of the stria terminalis using CRH as its major neurotransmitter (Shaham et al., 2000). ...
Substance use disorder (SUD) is a chronic condition characterized by pathological drug-taking and seeking behaviors. remarkably different between males and females, suggesting that drug addiction is a sexually differentiated disorder. The neurobiological bases of sex differences in SUD include sex-specific reward system activation, influenced by interactions between gonadal hormone level changes, dopaminergic reward circuits, and epigenetic modifications of key reward system genes. This systematic review, adhering to PICOS and PRISMA-P 2015 guidelines, highlights the sex-dependent roles of estrogens, progesterone, and testosterone in SUD. In particular, estradiol elevates and progesterone reduces dopaminergic activity in SUD females, whilst testosterone and progesterone augment SUD behavior in males. Finally, SUD is associated with a sex-specific increase in the rate of opioid and monoaminergic gene methylation. The study reveals the need for detailed research on gonadal hormone levels, dopaminergic or reward system activity, and epigenetic landscapes in both sexes for efficient SUD therapy development.
... The BNST is heavily innervated by noradrenergic projections. Specifically, projections from the A1 and A2 lateral tegmental medullary cell groups via the ventral noradrenergic bundle to the BNST appear to mediate stressor-induced drug seeking, as 6-OHDA lesions of these cell groups attenuate shock-induced drug seeking while pharmacological inhibition of locus coeruleus noradrenergic neurons has no effect [78]. In particular, noradrenergic signaling via beta-adrenergic receptors appears to be critical for stressor-induced drug seeking [79,80]. ...
The neuropeptide, corticotropin releasing factor (CRF), has been an enigmatic target for the development of medications aimed at treating stress-related disorders. Despite a large body of evidence from preclinical studies in rodents demonstrating that CRF receptor antagonists prevent stressor-induced drug seeking, medications targeting the CRF-R1 have failed in clinical trials. Here, we provide an overview of the abundant findings from preclinical rodent studies suggesting that CRF signaling is involved in stressor-induced relapse. The scientific literature that has defined the receptors, mechanisms and neurocircuits through which CRF contributes to stressor-induced reinstatement of drug seeking following self-administration and conditioned place preference in rodents is reviewed. Evidence that CRF signaling is recruited with repeated drug use in a manner that heightens susceptibility to stressor-induced drug seeking in rodents is presented. Factors that may determine the influence of CRF signaling in substance use disorders, including developmental windows, biological sex, and genetics are examined. Finally, we discuss the translational failure of medications targeting CRF signaling as interventions for substance use disorders and other stress-related conditions. We conclude that new perspectives and research directions are needed to unravel the mysterious role of CRF in substance use disorders.
... Together, these changes might indicate that stressors occurring during abstinence impact male and female mice differently. We know that stress is often a driving force behind relapse to drug taking behavior and preclinical data implicates noradrenergic signaling in the extended amygdala in reinstatement [42,53,54]. Sleep, stress, and opioid signaling overlap in these extended amygdala circuits, and all utilize noradrenergic signaling. ...
Opioid misuse has dramatically increased over the last few decades resulting in many people suffering from opioid use disorder (OUD). The prevalence of opioid overdose has been driven by the development of new synthetic opioids, increased availability of prescription opioids, and more recently, the COVID-19 pandemic. Coinciding with increases in exposure to opioids, the United States has also observed increases in multiple Narcan (naloxone) administrations as life-saving measures for respiratory depression, and, thus, consequently, naloxone-precipitated withdrawal. Sleep dysregulation is a main symptom of OUD and opioid withdrawal syndrome, and therefore, should be a key facet of animal models of OUD. Here we examine the effect of precipitated and spontaneous morphine withdrawal on sleep behaviors in C57BL/6J mice. We find that morphine administration and withdrawal dysregulate sleep, but not equally across morphine exposure paradigms. Furthermore, many environmental triggers promote relapse to drug-seeking/taking behavior, and the stress of disrupted sleep may fall into that category. We find that sleep deprivation dysregulates sleep in mice that had previous opioid withdrawal experience. Our data suggest that the 3-day precipitated withdrawal paradigm has the most profound effects on opioid-induced sleep dysregulation and further validates the construct of this model for opioid dependence and OUD.
Highlights
Morphine withdrawal differentially dysregulates the sleep of male and female mice
3-day precipitated withdrawal results in larger changes than spontaneous withdrawal
Opioid withdrawal affects responses to future sleep deprivation differently between sexes
... Lorcaserin decreased reinstatement of drug "seeking" in both rodents and nonhuman primates (Gerak et al., 2016;Harvey-Lewis et al., 2016;Neelakantan et al., 2017), but increased subjective reports of drug craving in humans (Brandt et al., 2020;Pirtle et al., 2019). However, when preclinical and clinical endpoints of relapse are more homologous, successful translation of candidate medication outcomes is possible (Kowalczyk et al., 2015;Shaham et al., 2000). In this example, successful translation resulted from both endpoints and independent variables (e.g. ...
Substance use disorders (SUDs) are heterogeneous and complex, making the development of translationally predictive rodent and non-human primate models to uncover their neurobehavioral underpinnings difficult. Neuroscience-focused outcomes have become highly prevalent, and with this, the notion that SUDs are disorders of the brain embraced as a dominant theoretical orientation to understand SUD etiology and treatment. These efforts, however, have led to few efficacious pharmacotherapies, and in some cases (as with cocaine or methamphetamine), no pharmacotherapies have translated from preclinical models for clinical use. In this theoretical commentary, we first describe the development of animal models of substance use behaviors from a historical perspective. We then define and discuss three logical fallacies including 1) circular explanation, 2) affirming the consequent, and 3) reification that can apply to developed models. We then provide three case examples in which conceptual or logical issues exist in common methods (i.e., behavioral economic demand, escalation, and reinstatement). Alternative strategies to refocus behavioral models are suggested for the field to better bridge the translational divide between animal models, the clinical condition of SUDs, and current and future regulatory pathways for intervention development.
... Priming stimuli-specific circuitry underlying stress-, drug-, and cueinduced reinstatement of cocaine seeking is also comprised of nonpallidal nuclei. Stress-induced reinstatement uniquely involves activation of noradrenergic projections from the nucleus of the solitary tract (NTS) to the BNST and the central nucleus of the amygdala (CeA) (Leri et al., 2002;Shaham et al., 2000) and corticotropin-releasing hormone (CRH) projections from the CeA to the BNST (Erb et al., 2001) and from the BNST to the VTA (Mantsch et al., 2016;Vranjkovic et al., 2014). CRH signalling modulates glutamate transmission in the VTA after cocaine experience, which subsequently activates mesocortical dopamine neurons (Wang et al., 2005). ...
Women are more sensitive to cocaine craving elicited by stimuli associated with relapse. Ovarian hormones modulate cocaine craving and may therefore function as risk factors or therapeutic agents for the development and treatment of cocaine use disorder, respectively. We review herein the neuropharmacological effects of the steroid hormones 17ß-estradiol, progesterone, and allopregnanolone, a progesterone metabolite, in relation to their effects on cocaine-induced locomotion, behavioural sensitization, conditioned place preference, and reinstatement of cocaine seeking. In general, the literature suggests that female rats are more sensitive to these cocaine-induced behaviours than males and that 17ß-estradiol facilitates the expression of these sex differences. Alternatively, in females, exogenous progesterone attenuates cocaine conditioned place preference, reinstatement, and possibly behavioural sensitization, either on its own or after conversion to allopregnanolone. These opposing effects of 17ß-estradiol and progesterone/allopregnanolone involve endocannabinoid, γ-aminobutyric acid, dopamine, and glutamate transmission in the medial prefrontal cortex and striatum. We conclude that 17ß-estradiol may be a risk factor for various components of cocaine use disorder in women, whereas progesterone and allopregnanolone may be potential treatment options.
... Lorcaserin decreased reinstatement of drug "seeking" in both rodents and nonhuman primates(Gerak et al., 2016; Harvey-Lewis et al., 2016; Neelakantan et al., 2017), but increased subjective reports of drug craving in humans(Brandt et al., 2020;Pirtle et al., 2019). However, when preclinical and clinical endpoints of relapse are more homologous, successful translation is possible(Kowalczyk et al., 2015;Shaham et al., 2000). ...
Substance use disorders (SUDs) are heterogenous and complex, making the development of translationally predictive rodent and non-human primate models to uncover their neurobehavioral underpinnings difficult. Neuroscience-focused outcomes have become highly prevalent, and with this, the notion that SUDs are disorders of the brain embraced as a dominant theoretical orientation to understand SUD etiology and treatment. These efforts, however, have led to few efficacious pharmacotherapies, and in some cases (as with cocaine or methamphetamine), no pharmacotherapies have translated from preclinical models for clinical use. In this review and theoretical commentary, we first describe the development of animal models of SUDs from a historical perspective. We then define and discuss three logical fallacies including 1) circular explanation, 2) affirming the consequent, and 3) reification that can apply to developed models. We then provide three case examples in which conceptual or logical issues exist in common methods (i.e., behavioral economic demand, escalation, and reinstatement). Alternative strategies to refocus behavioral models are suggested for the field in an attempt to better bridge the translational divide between animal models and the clinical condition of SUDs.
... For example, intermittent footshock has been shown to reinstate drug seeking following cocaine (Ahmed & Koob, 1997;Erb et al., 1996), heroin (Shaham & Stewart, 1995), alcohol (Lê et al., 1998), and nicotine (Buczek et al., 1999), self-administration. In each case, shockinduced drug seeking is prevented by CRF receptor antagonism Lê et al., 2000;Shaham et al., 1997;Zislis et al., 2007) or administration of an alpha-2 adrenergic receptor agonist (Erb et al., 2000;Lê et al., 2005;Shaham et al., 2000;Zislis et al., 2007). ...
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.
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... Norepinephrine signaling has also been implicated in relapse, particularly in response to stress. Agonists of the α 2 -receptor reduced stress-induced reinstatement for cocaine (Erb et al., 2000), heroin (Shaham, Highfield, Delfs, Leung, & Stewart, 2000), a heroin-cocaine mixture (Highfield, Yap, Grimm, Shalev, & Shaham, 2001), and alcohol (Le et al., 2011;Le, Harding, Juzytsch, Funk, & Shaham, 2005) in rats. Atomoxetine, a NE uptake inhibitor, reduced cue-induced reinstatement of heroin and cocaine seeking after abstinence in rats (Economidou, Dalley, & Everitt, 2011). ...
Addiction is a chronic disorder that consists of a three-stage cycle of binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These stages involve, respectively, neuroadaptations in brain circuits involved in incentive salience and habit formation, stress surfeit and reward deficit, and executive function. Much research on addiction focuses on the neurobiology underlying single drug use. However, alcohol use disorder (AUD) can be co-morbid with substance use disorder (SUD), called dual dependence. The limited epidemiological data on dual dependence indicates that there is a large population of individuals suffering from addiction who are dependent on more than one drug and/or alcohol, yet dual dependence remains understudied in addiction research. Here, we review neurobiological data on neurotransmitter and neuropeptide systems that are known to contribute to addiction pathology and how the involvement of these systems is consistent or divergent across drug classes. In particular, we highlight the dopamine, opioid, corticotropin-releasing factor, norepinephrine, hypocretin/orexin, glucocorticoid, neuroimmune signaling, endocannabinoid, glutamate, and GABA systems. We also discuss the limited research on these systems in dual dependence. Collectively, these studies demonstrate that the use of multiple drugs can produce neuroadaptations that are distinct from single drug use. Further investigation into the neurobiology of dual dependence is necessary to develop effective treatments for addiction to multiple drugs.
... In addition to connectivity with midbrain dopaminergic neurons, amygdala connectivity to other monoaminergic nuclei within the brainstem contribute to pathological behavior. For example, the pharmacological blockade of the ventral noradrenergic bundle, which connects the amygdala to noradrenergic nuclei within the brainstem, leads to significant attenuation of heroin seeking behavior (Shaham et al., 2000;Leri et al., 2002). Connectivity of the amygdala with these structures likely influences addictive and reward-related behaviors through combined influences on reinforcement learning, reward valuation, and the subjective emotional experience associated with reward consumption. ...
Introduction: The amygdala is known to play a role in mediating emotion and possibly addiction. We used probabilistic tractography (PT) to evaluate whether structural connectivity of the amygdala to the brain reward network is associated with impulsive choice and tobacco smoking.
Methods: Diffusion and structural MRI scans were obtained from 197 healthy subjects (45 with a history of tobacco smoking) randomly sampled from the Human Connectome database. PT was performed to assess amygdala connectivity with several brain regions. Seed masks were generated, and statistical maps of amygdala connectivity were derived. Connectivity results were correlated with a subject performance both on a delayed discounting task and whether they met specified criteria for difficulty quitting smoking.
Results: Amygdala connectivity was spatially segregated, with the strongest connectivity to the hippocampus, orbitofrontal cortex (OFC), and brainstem. Connectivity with the hippocampus was associated with preference for larger delayed rewards, whereas connectivity with the OFC, rostral anterior cingulate cortex (rACC), and insula were associated with preference for smaller immediate rewards. Greater nicotine dependence with difficulty quitting was associated with less hippocampal and greater brainstem connectivity. Scores on the Fagerstrom Test for Nicotine Dependence (FTND) correlated with rACC connectivity.
Discussion: These findings highlight the importance of the amygdala-hippocampal-ACC network in the valuation of future rewards and substance dependence. These results will help to identify potential targets for neuromodulatory therapies for addiction and related disorders.
... Stress is a precipitating factor for craving and relapse in cocaine use disorder (CUD) [1][2][3]; however, there are no FDA-approved medications for the treatment of relapse in CUD. α 2a -adrenergic receptor (α 2a -AR) agonists inhibit stress-induced reinstatement of operant drug-seeking and conditioned place preference (CPP), animal models useful in the study of stress-induced relapse [4][5][6][7]. In clinical laboratory studies, these compounds have been investigated for stress-induced cocaine craving [8,9], but the application of full α 2a -AR agonists for the treatment of CUD has been limited due to adverse effects such as sedation and hypotension [10,11]. ...
The α2a-adrenergic receptor (α2a-AR) agonist guanfacine has been investigated as a potential treatment for substance use disorders. While decreasing stress-induced reinstatement of cocaine seeking in animal models and stress-induced craving in human studies, guanfacine has not been reported to decrease relapse rates. Although guanfacine engages α2a-AR autoreceptors, it also activates excitatory Gi-coupled heteroreceptors in the bed nucleus of the stria terminalis (BNST), a key brain region in driving stress-induced relapse. Thus, BNST α2a-AR heteroreceptor signaling might decrease the beneficial efficacy of guanfacine. We aimed to determine the role of α2a-AR heteroreceptors and BNST Gi-GPCR signaling in stress-induced reinstatement of cocaine conditioned place preference (CPP) and the effects of low dose guanfacine on BNST activity and stress-induced reinstatement. We used a genetic deletion strategy and the cocaine CPP procedure to first define the contributions of α2a-AR heteroreceptors to stress-induced reinstatement. Next, we mimicked BNST Gi-coupled α2a-AR heteroreceptor signaling using a Gi-coupled designer receptor exclusively activated by designer drug (Gi-DREADD) approach. Finally, we evaluated the effects of low-dose guanfacine on BNST cFOS immunoreactivity and stress-induced reinstatement. We show that α2a-AR heteroreceptor deletion disrupts stress-induced reinstatement and that BNST Gi-DREADD activation is sufficient to induce reinstatement. Importantly, we found that low-dose guanfacine does not increase BNST activity, but prevents stress-induced reinstatement. Our findings demonstrate a role for α2a-AR heteroreceptors and BNST Gi-GPCR signaling in stress-induced reinstatement of cocaine CPP and provide insight into the impact of dose on the efficacy of guanfacine as a treatment for stress-induced relapse of cocaine use.
... Exposure to stress strongly activates the firing of NA neurons and increases the release of NA from their terminals. This release of NA in the forebrain underlies stress-induced reinstatement of drug seeking (Erb et al., 2000;Shaham et al., 2000b;Mantsch et al., 2016). The alpha-1 adrenoceptor plays an important role in stress-induced relapse. ...
Background:
Stress is associated with relapse to alcohol seeking during abstinence, but the processes underlying this relationship are poorly understood. Noradrenaline is a key transmitter in stress responses and in stress-induced drug seeking. The alpha-1 adrenoceptor antagonist prazosin has been investigated as a treatment for alcoholism and for chronic stress disorders that are frequently comorbid with alcoholism. In rats, we previously showed that prazosin blocks reinstatement of alcohol seeking induced by footshock and yohimbine stressors, and reduces yohimbine-induced brain activation. The role of alpha-1 adrenoceptors in reinstatement induced by other stressors is not known. Our most recent work is on the role of kappa opioid receptors (KOR) in stress-induced reinstatement of alcohol seeking and have reported that the selective KOR agonist U50,488 induces reinstatement and neuronal activation in stress- and relapse-related brain regions. Here we determine the involvement of alpha-1 receptors in reinstatement and brain activation induced by U50,488.
Methods:
We trained male Long-Evans rats to self-administer alcohol (12% w/v), extinguished alcohol-reinforced responding and then determined the effects of prazosin (1 mg/kg) on U50,488 (2.5 mg/kg)-induced reinstatement and regional Fos expression.
Results:
Prazosin blocked U50,488-induced reinstatement and decreased U50,488-induced Fos expression in the OFC, NAC core, ventral BNST, CeA, BLA and VTA.
Conclusions:
These findings suggest that prazosin may reduce U50,488-induced relapse by inhibiting activity in one or more of these brain areas.
... 75,76 For example, the noradrenergic system is a potential substrate for these distinct mechanisms, and studies with morphine and heroin have shown that the locus coeruleus and medullary noradrenergic nuclei are differentially involved in withdrawal and stress-induced reinstatement. 33,75,77 Also of interest are how these mechanisms interact with sex. Even something as seemingly fundamental as dopamine release in response to nicotine has been shown to differ in nuanced ways between male and female rats, 78 such that exogenous estrogen differentially affects males and females, and men and women who smoke, 79 whereas smoking-induced dopamine release is observed in a discrete region of the right ventral striatum in men but not women, and in the right dorsal putamen in women but not men. ...
Relapse to smoking occurs at higher rates in women compared to men, especially when triggered by stress. Studies suggest that sex-specific interactions between nicotine reward and stress contribute to these sex differences. Accordingly, novel treatment options targeting stress pathways, such as guanfacine, an α2-adrenergic receptor agonist, may provide sex-sensitive therapeutic effects. Preclinical studies are critical for elucidating neurobiological mechanisms of stress-induced relapse and potential therapies, but rodent models of nicotine addiction are often hindered by large behavioral variability. In this study, we used nicotine conditioned place preference to investigate stress-induced reinstatement of nicotine preference in male and female mice, and the effects of guanfacine on this behavior. Our results showed that overall, nicotine induced significant place preference acquisition and swim stress-induced reinstatement in both male and female mice, but with different nicotine dose-response patterns. In addition, we explored the variability in nicotine-dependent behaviors with median split analyses and found that initial chamber preference in each sex differentially accounted for variability in stress-induced reinstatement. In groups that showed significant stress-induced reinstatement, pretreatment with guanfacine attenuated this behavior. Finally, we evaluated neuronal activation by Arc immunoreactivity in the infralimbic cortex, prelimbic cortex, anterior insula, basolateral amygdala, lateral central amygdala, and nucleus accumbens core and shell. Guanfacine induced sex-dependent changes in Arc immunoreactivity in the infralimbic cortex and anterior insula. This study demonstrates sex-dependent relationships between initial chamber preference and stress-induced reinstatement of nicotine conditioned place preference, and the effects of guanfacine on both behavior and neurobiological mechanisms. This article is protected by copyright. All rights reserved.
... Alpha-2 adrenoceptor agonists block stress-induced drug-seeking behavior in the rat reinstatement model (1)(2)(3) and reduce drug craving in human laboratory stu- dies (4-6). Therefore, we undertook a clinical trial in which we showed that opioid-dependent participants ran- domized to receive the alpha-2 agonist clonidine as an adjuvant to buprenorphine had longer periods of contin- uous abstinence and maintained a longer time to initial lapse (7). ...
Background:
In a recent clinical trial (NCT00295308), we demonstrated that clonidine decreased the association between opioid craving and moderate levels of stress and affect in patients receiving buprenorphine-based opioid agonist therapy.
Objectives:
To examine the relationship between illicit opioid use and craving and affect during the evaluation of clonidine as an adjunct medication in buprenorphine treatment for opioid use disorder. Secondarily, to examine whether those relationships are driven by within- or between-participant factors.
Methods:
This was a secondary data analysis from our original trial. Participants (N = 108, female: n = 23, male n = 85) receiving buprenorphine were randomized to receive adjunct clonidine or placebo. Participants used portable electronic devices to rate stress, mood, and craving via ecological momentary assessment (EMA) four times randomly each day. To associate the EMA data with illicit opioid use, each EMA report was linked to participants' next urine drug screen (thrice weekly). We used generalized linear mixed models to examine the interaction between treatment group and illicit opioid use, as well as to decompose the analysis into within- and between-participant effects.
Results:
Craving for opioids and cocaine was increased when participants were using illicit opioids; this effect was greater in the clonidine group. For affect, mood was poorer during periods preceding opioid-positive urines than opioid-negative urines for clonidine-treated participants, whereas there was no difference for placebo participants.
Conclusion:
This secondary analysis provides evidence that for participants maintained on opioid agonist therapy, clonidine minimized the behavioral impact of moderate levels of negative affect and craving.
... Noradrenergic contributions to stress-related drug seeking have been studied predominantly in male rats, even though female rats have higher expression of adrenergic receptors in brain regions that modulate motivation and drug seeking behaviors (Ferris et al., 2007;Espana et al., 2016). Systemic a1and b-adrenergic receptor antagonists, or autoreceptor agonists such as clonidine that decrease NE release, block stress-induced reinstatement of drug seeking in male rats Brown et al., 1977;Erb et al. 2000;Weinshenker et al., 2000;Shaham et al., 2000;Leri and Stewart, 2002;Ventura et al., 2005;Lê et al., 2005Lê et al., , 2011Smith and Aston-Jones, 2011). In clinical studies, administration of betablockers, such as carvedilol or propranolol, reduced cocaine self-administration, increased treatment retention, and promoted periods of abstinence in cocaine-dependent individuals (Kampman et al., 1999(Kampman et al., , 2001Sofuoglu et al., 2000;Kampman 2005). ...
Responses to stress may be important in understanding gender differences in substance use disorders and may also be a target for development of treatment interventions. A growing body of both preclinical and clinical research supports important underlying gender differences in the corticotropin-releasing factor (CRF) and noradrenergic systems, which may contribute to drug use. Preclinical models have demonstrated increased sensitivity of females to CRF and noradrenergic-induced drug reinstatement compared with males, and, consistent with these findings, human laboratory studies have demonstrated greater sensitivity to corticotropin-releasing hormone (CRH) and noradrenergic stimulation in cocaine-dependent women compared with men. Furthermore, neuroimaging studies have demonstrated increased neural response to stressful stimuli in cocaine-dependent women compared with men as well as showing significant sex differences in the sensitivity of brain regions responsible for regulating the response to CRH. Development of interventions targeting the noradrenergic system and stress response in drug-dependent individuals could have important clinical implications for both women and men.
... Cue-induced reinstatement also involves a glutamatergic projection from the prelimbic prefrontal cortex, basolateral amygdala, and ventral subiculum to the nucleus accumbens, and dopamine modulation in the basolateral amygdala and dorsal striatum (tables 1, 2, circuits 14 and 15). 51,52,95 By contrast, the stress-induced reinstatement of drug-related responding in animal models appears to depend on the activation of both CRF and norepinephrine in elements of the extended amygdala (ie, central nucleus of the amygdala and bed nucleus of the stria terminalis; tables 1, 2, circuits 16 and 17) 22,33,53,[96][97][98] and the ventral tegmental area (tables 1, 2, circuit 9). Protracted abstinence, largely described in alcohol dependence models, appears to involve overactive glutamatergic and CRF systems. ...
Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages. The rewarding effects of drugs of abuse, development of incentive salience, and development of drug-seeking habits in the binge/intoxication stage involve changes in dopamine and opioid peptides in the basal ganglia. The increases in negative emotional states and dysphoric and stress-like responses in the withdrawal/negative affect stage involve decreases in the function of the dopamine component of the reward system and recruitment of brain stress neurotransmitters, such as corticotropin-releasing factor and dynorphin, in the neurocircuitry of the extended amygdala. The craving and deficits in executive function in the so-called preoccupation/anticipation stage involve the dysregulation of key afferent projections from the prefrontal cortex and insula, including glutamate, to the basal ganglia and extended amygdala. Molecular genetic studies have identified transduction and transcription factors that act in neurocircuitry associated with the development and maintenance of addiction that might mediate initial vulnerability, maintenance, and relapse associated with addiction.
... Norepinephrine signaling also plays a role in drug reward (Olson et al, 2006) and withdrawal aversion . Suppression of noradrenergic signaling blocks stressinduced reinstatement (Erb et al, 2000;Leri et al, 2002;Shaham et al, 2000), and treatment with the adrenergic agonist clonidine promotes heroin-abstinence in human addicts (Kowalczyk et al, 2015). Although few studies emphasize the noradrenergic component of drug use, norepinephrine in the bed nucleus of the stria terminalis (BNST) has been clearly implicated in drug withdrawal (Aston-Jones et al, 1999). ...
Dysregulated catecholamine signaling has long been implicated in drug abuse. Although much is known about adaptations following chronic drug administration, little work has investigated how a single drug exposure paired with withdrawal influences catecholamine signaling in vivo. We used fast-scan cyclic voltammetry in freely moving rats to measure real-time catecholamine overflow during acute morphine exposure and naloxone-precipitated withdrawal in two regions associated with the addiction cycle: the dopamine-dense nucleus accumbens (NAc) and norepinephrine-rich ventral bed nucleus of the stria terminalis (vBNST). We compared dopamine transients in the NAc with norepinephrine concentration changes in the vBNST, and correlated release with specific withdrawal-related behaviors. Morphine increased dopamine transients in the NAc, but did not elicit norepinephrine responses in the vBNST. Conversely, dopamine output was decreased during withdrawal, while norepinephrine was released in the vBNST during specific withdrawal symptoms. Both norepinephrine and withdrawal symptoms could be elicited in the absence of morphine by administering naloxone with an α2 antagonist. The data support reciprocal roles for dopamine and norepinephrine signaling during drug exposure and withdrawal. The data also support the allostasis model and show that negative-reinforcement may begin working after a single exposure/withdrawal episode.Neuropsychopharmacology accepted article preview online, 27 July 2016. doi:10.1038/npp.2016.135.
... In animal models, stress drives reinstatement of drug seeking in a CRF-dependent manner [5][6][7][8], and females show greater stress-induced reinstatement compared to males [9,10]. Notably, several studies link stress and the central NE system in relapse to drug seeking [11][12][13][14][15]. ...
Locus coeruleus norepinephrine (LC-NE) and corticotropin releasing factor (CRF) neurons are involved in stress responses, including stress's ability to drive drug relapse. Previous animal studies indicate that female rats exhibit greater drug seeking than male rats during initial drug abstinence. Moreover, females are more sensitive to the effect of stress to drive drug seeking than males. Finally, LC-NE neurons are more sensitive to CRF in females compared to males. We hypothesized that increased drug seeking in females on extinction day one (ED1) is due to increased response to the stress of early withdrawal and is dependent upon the increased response of LC in females to CRF. We predicted that LC-NE neurons would exhibit Fos activation on ED1, and that blocking CRF1 signaling would decrease drug seeking on ED1 measured by responding on an active lever previously associated with cocaine self- administration. After chronic cocaine self-administration, female and male rats underwent a test for initial extinction responding by measuring lever pressing in the absence of cocaine. Prior to this Extinction Day 1 (ED1) session, rats were injected with vehicle or the selective CRF1 antagonist (CP) to measure effects of CRF antagonism on drug seeking during early abstinence. ED1 increased corticosterone in female rats, in proportion to lever responding in male and female, indicating that ED1 was stressful. Pretreatment with CP decreased cocaine seeking on ED1 more effectively in female compared to male rats. This increase in responding was associated with an increase in activation of LC NE neurons. Together, these findings indicate that stress, and signaling at CRF receptors in LC, may be involved in the increased drug seeking during initial abstinence.
... Previous studies have shown that 1.0 mg/kg ATO did not alter physical effort discounting, but did increase response latency and omissions (Hosking et al., 2015). It is possible that drug-induced elevations of extracellular NE are mimicking features of the stress response (Cole and Robbins, 1987; Shaham et al., 2000), and exposure to stress has been reported to lower selection of high-effort options (Shafiei et al., 2012; Bryce and Floresco, 2016). This reduced exertion of effort induced by NET inhibition could represent a stress-related mechanism of energy conservation. ...
Deficits in behavioral activation, exertion of effort, and other psychomotor/motivational symptoms are frequently seen in people with depression and other disorders. Depressed people show a decision bias towards selection of low effort activities, and animal tests of effort-related decision making are being used as models of motivational dysfunctions seen in psychopathology. The present studies investigated the ability of drugs that block dopamine transport (DAT), norepinephrine transport (NET), and serotonin transport (SERT) to modulate work output in rats responding on a test of effort-related decision making (i.e., a progressive ratio (PROG)/chow feeding choice task). With this task, rats choose between working for a preferred food (high carbohydrate pellets) by lever pressing on a PROG schedule vs. obtaining a less preferred lab chow that is freely available in the chamber. The present studies focused on the effects of the selective DAT inhibitor GBR12909, the selective SERT inhibitor fluoxetine, and the selective NET inhibitors desipramine and atomoxetine. Acute and repeated administration of GBR12909 shifted choice behavior, increasing measures of PROG lever pressing but decreasing chow intake. In contrast, fluoxetine, desipramine and atomoxetine failed to increase lever pressing output, and actually decreased it at higher doses. In the behaviorally effective dose range, GBR12909 elevated extracellular dopamine levels in accumbens core as measured by microdialysis, but fluoxetine, desipramine and atomoxetine decreased extracellular dopamine. Thus, blockade of DAT increases selection of the high effort instrumental activity, while inhibition of SERT or NET does not. These results have implications for the use of monoamine uptake inhibitors for the treatment of effort-related psychiatric symptoms in humans.
... Chronic opioid use and chronic non-cancer pain may render the brain extended amygdala system hypersensitive to the negative emotional lows, such as dysphoria, anxiety, irritability, and hyperalgesia occurring following extended opioid use and during withdrawal (1), a psychological-distress state that heightens vulnerability to opioid-use relapse. In a reinstatement model of drug relapse, alpha-2 adrenergic receptor agonists (for example, clonidine or lofexidine) that inhibit noradrenaline/ norepinephrine activity in the extended amygdala block stressinduced relapse to opioid and cocaine seeking (3,4). Clonidine, an alpha-2 receptor agonist, has been used off-label for years in an opioid-using population to ameliorate symptoms of opioid withdrawal. ...
Over the past two decades, a steeply growing number of persons with chronic non-cancer pain have been using opioid analgesics chronically to treat it, accompanied by a markedly increased prevalence of individuals with opioid-related misuse, opioid use disorders, emergency department visits, hospitalizations, admissions to drug treatment programs, and drug overdose deaths. This opioid misuse and overdose epidemic calls for well-designed randomized-controlled clinical trials into more skillful and appropriate pain management and for developing effective analgesics that have lower abuse liability and are protective against stress induced by chronic non-cancer pain. However, incomplete knowledge regarding effective approaches to treat various types of pain has been worsened by an under-appreciation of overlapping neurobiological mechanisms of stress, stress-induced relapse to opioid use, and chronic non-cancer pain in patients presenting for care for these conditions. This insufficient knowledge base has unfortunately encouraged common prescription of conveniently available opioid pain-relieving drugs with abuse liability, as opposed to treating underlying problems using team-based multidisciplinary, patient-centered, collaborative-care approaches for addressing pain and co-occurring stress and risk for opioid use disorder. This paper reviews recent neurobiological findings regarding overlapping mechanisms of stress-induced relapse to opioid misuse and chronic non-cancer pain, and then discusses these in the context of key outstanding evidence gaps and clinical-treatment research directions that may be pursued to fill these gaps. Such research directions, if conducted through well-designed randomized-controlled trials, may substantively inform clinical practice in general medical settings on how to effectively care for patients presenting with pain-related distress and these common co-occurring conditions.
... Regarding mechanisms, studies in the late 1990s and early 2000s showed a critical role of extrahypothalamic CRF (Erb et al., 1998;Le et al., 2000;Shaham et al., 1997b) and noradrenaline originating from the lateral tegmental nuclei but not locus coeruleus (Erb et al., 2000;Shaham et al., 2000b) in footshock stress-induced reinstatement of drug seeking. Subsequent studies demonstrated a role of dopamine transmission in VTA, NAc, dorsal mPFC, orbitofrontal, and the glutamatergic projections from dorsal mPFC to NAc core (Capriles et al., 2003;McFarland et al., 2004;Xi et al., 2004), as well as a role of VTA CRF and glutamate in this reinstatement (Blacktop et al., 2011;Wang et al., 2005). ...
High rates of relapse to drug use during abstinence is a defining feature of drug addiction. In abstinent drug users, drug relapse is often precipitated by acute exposure to the self-administered drug, drug-associated cues, stress, as well as by short-term and protracted withdrawal symptoms. In this review, we discuss different animal models that have been used to study behavioral and neuropharmacological mechanisms of these relapse-related phenomena. In the first part, we discuss relapse models in which abstinence is achieved through extinction training, including the established reinstatement model, as well as the reacquisition and resurgence models. In the second part, we discuss recent animal models in which drug relapse is assessed after either forced abstinence (e.g., the incubation of drug craving model) or voluntary (self-imposed) abstinence achieved either by introducing adverse consequences to ongoing drug self-administration (e.g., punishment) or by an alternative nondrug reward using a discrete choice (drug vs. palatable food) procedure. We conclude by briefly discussing the potential implications of the recent developments of animal models of drug relapse after voluntary abstinence to the development of medications for relapse prevention.
... Evidence for a noradrenergic contribution to stress-related reinstatement includes the ability of pharmacological suppression of NE release (α 2 -agonists), α 1 -or β-receptor blockade, or inhibition of NE synthesis to attenuate stressor-induced reinstatement of psychostimulant- (Erb et al., 2000;Schroeder et al., 2013), alcohol- (Lê et al., 2005;Lê et al., 2011) and opiate-seeking in rats (Shaham et al., 2000b;Leri et al., 2002;Ventura et al., 2005) in both CPP and self-administration paradigms. Similar observations have been made in human psychostimulant and opioid addicts (Sinha et al., 2007;Jobes et al., 2011). ...
Arousal plays a critical role in cognitive, affective and motivational processes. Consistent with this, the dysregulation of arousal-related neural systems is implicated in a variety of psychiatric disorders, including addiction. Noradrenergic systems exert potent arousal-enhancing actions that involve signaling at α1- and β-noradrenergic receptors within a distributed network of subcortical regions. The majority of research into noradrenergic modulation of arousal has focused on the nucleus locus coeruleus. Nevertheless, anatomical studies demonstrate that multiple noradrenergic nuclei innervate subcortical arousal-related regions, providing a substrate for differential regulation of arousal across these distinct noradrenergic nuclei. The arousal-promoting actions of psychostimulants and other drugs of abuse contribute to their widespread abuse. Moreover, relapse can be triggered by a variety of arousal-promoting events, including stress and re-exposure to drugs of abuse. Evidence has long-indicated that norepinephrine plays an important role in relapse. Recent observations suggest that noradrenergic signaling elicits affectively-neutral arousal that is sufficient to reinstate drug seeking. Collectively, these observations indicate that norepinephrine plays a key role in the interaction between arousal, motivation, and relapse.
This article is part of a Special Issue entitled SI: Noradrenergic System.
Conditioned place preference (CPP) paradigm in zebrafish has been used to measure drug reward, but there is limited research on CPP reinstatement to determine relapse vulnerability. The present study aimed to investigate extinction and reinstatement of methamphetamine (MA)‐induced CPP in zebrafish and evaluate the model's predictive validity. Zebrafish received different doses of MA (0–60 mg/kg) during CPP training. The preferred dose of MA at 40 mg/kg was used for extinction via either confined or nonconfined procedures. The extinguished CPP was reinstated by administering a priming dose of MA (20 mg/kg) or various stressors. To assess persistent susceptibility to reinstatement, MA CPP and reinstatement were retested following 14 days of abstinence. In addition, the effects of SCH23390, naltrexone, and clonidine on MA CPP during acquisition, expression, or reinstatement phases were monitored. MA induced CPP in a dose‐dependent manner. Both nonconfined and confined extinction procedures time‐dependently reduced the time spent on the MA‐paired side. A priming dose of MA, chasing stress, or yohimbine reinstated the extinguished CPP. After 14 days of abstinence, the MA CPP remained extinguished and was significantly reinstated by MA priming or chasing stress. Similar to the observations in rodents, SCH23390 suppressed the acquisition of MA CPP, naltrexone reduced the expression and MA priming‐induced reinstatement, while clonidine prevented stress‐induced reinstatement of MA CPP. This work expanded the zebrafish CPP paradigm to include extinction and reinstatement phases, demonstrating predictive validity and highlighting its potential as a valuable tool for exploring drug relapse.
Opioid misuse has dramatically increased over the last few decades resulting in many people suffering from opioid use disorder (OUD). The prevalence of opioid overdose has been driven by the development of new synthetic opioids, increased availability of prescription opioids, and more recently, the COVID-19 pandemic. Coinciding with increases in exposure to opioids, the United States has also observed increases in multiple Narcan (naloxone) administrations as a life-saving measures for respiratory depression, and, thus, consequently, naloxone-precipitated withdrawal. Sleep dysregulation is a main symptom of OUD and opioid withdrawal syndrome, and therefore, should be a key facet of animal models of OUD. Here we examine the effect of precipitated and spontaneous morphine withdrawal on sleep behaviors in C57BL/6J mice. We find that morphine administration and withdrawal dysregulate sleep, but not equally across morphine exposure paradigms. Furthermore, many environmental triggers promote relapse to drug-seeking/taking behavior, and the stress of disrupted sleep may fall into that category. We find that sleep deprivation dysregulates sleep in mice that had previous opioid withdrawal experience. Our data suggest that the 3-day precipitated withdrawal paradigm has the most profound effects on opioid-induced sleep dysregulation and further validates the construct of this model for opioid dependence and OUD.
The central noradrenergic system innervates almost all regions of the brain and, as such, is well positioned to modulate many neural circuits implicated in behaviors and physiology underlying substance use disorders. Ample pharmacological evidence demonstrates that α1, α2, and β adrenergic receptors may serve as therapeutic targets to reduce drug –seeking behavior and drug withdrawal symptoms. Further, norepinephrine is a key modulator of the stress response, and stress has been heavily implicated in reinstatement of drug taking. In this review, we discuss recent advances in our understanding of noradrenergic circuitry and noradrenergic receptor signaling in the context of opioid, alcohol, and psychostimulant use disorders.
Rationale: Stress plays a dual role in substance use disorders as a precursor to drug intake and a relapse precipitant. With heroin use at epidemic proportions in the United States, understanding interactions between stress disorders and opioid use disorder is vital and will aid in treatment of these frequently comorbid conditions.
Objectives: Here, we combine assays of stress and contingent heroin self-administration (SA) to study behavioral adaptations in response to stress and heroin associated cues in male and female rats.
Methods: Rats underwent acute restraint stress paired with an odor stimulus and heroin SA for subsequent analysis of stress and heroin cue reactivity. Lofexidine was administered during heroin SA and reinstatement testing to evaluate its therapeutic potential. Rats also underwent tests on the elevated plus maze, locomotor activity in a novel environment, and object recognition memory following stress and/or heroin.
Results: A history of stress and heroin resulted in disrupted behavior on multiple levels. Stress rats avoided the stress conditioned stimulus and reinstated heroin seeking in response to it, with males reinstating to a greater extent than females. Lofexidine decreased heroin intake, reinstatement, and motor activity. Previous heroin exposure increased time spent in the closed arms of an elevated plus maze, activity in a round novel field, and resulted in object recognition memory deficits.
Discussion: These studies report that a history of stress and heroin results in maladaptive coping strategies and suggests a need for future studies seeking to understand circuits recruited in this pathology and eventually help develop therapeutic approaches.
Opioid Use Disorders (OUDs) and drug overdose deaths are increasing at alarmingly high rates in the United States. Stress and dysregulation in biologic stress response systems such as the hypothalamic-pituitary-adrenal axis and noradrenergic system appear to play an important role in the pathophysiology of substance use disorders and relapse to drug use, particularly for women. Alpha-2 adrenergic agonist medications effectively decrease noradrenergic activity and have demonstrated benefit in preventing relapse to substance use and decreasing stress-reactivity and craving in cocaine- and nicotine-dependent women, compared to men. Alpha-2 adrenergic agonists may help decrease stress reactivity in individuals with OUDs and prevent relapse to drug use, but gender differences have yet to be systematically explored. We describe the rationale, study design and methodology of a randomized, double-blind, placebo-controlled clinical trial examining gender differences in stress, craving and drug use among adult men and women with OUD taking methadone or buprenorphine and randomly assigned to an alpha-2 adrenergic agonist, lofexidine, compared to placebo. In addition, we describe methods for measuring daily stress, craving and drug use in participant's natural environment as well as participant's physiological (i.e., heart rate, cortisol) and psychological (i.e., stress, craving) response to laboratory social and drug cue stressors. Lastly, we detail methods adopted to sustain research activity while following guidelines for the COVID-19 pandemic.
ClinicalTrials.gov Registration Number: NCT03718065
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.
This second edition volume expands on the previous edition with updates to chapters and new chapters discussing the latest research in neuropsychiatric diseases. The chapters in this book are organized into eleven sections and cover the diversity and utility of animal models of psychiatric disorders, their development, modeling, and pathophysiological and molecular profiles. Part One looks at experimental modeling of neuropsychiatric studies and the usefulness and need of animal models. Parts Two and Three focus on experimental models of neuropsychiatric illnesses, including self-injurious behavior, bipolar disorder, anxiety, and learning and decision-making testing. Parts Four and Five discuss animal models of substance abuse. Part Six describes protocols to examine animal models related to maladaptive eating habits and behaviors. Parts Seven and Eight cover neurodegenerative diseases stemming from natural causes (aging), abnormal genetic backgrounds, or those brought on by trauma. Part Nine talks about inflammatory and metabolic alteration profiles relevant to autism spectrum disorders and depression. Parts Ten and Eleven conclude the book with a discussion on genetics, epigenetics, and system biology in the field of psychiatric disorders. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls.
Cutting-edge and thorough, Psychiatric Disorders: Methods and Protocols, Second Edition is a useful resource for graduates, postdoctoral workers, and established scientists working in the fields of behavioral and molecular neuropsychiatric research.
Drug addiction is a chronic relapsing disorder, and a significant amount of research has been devoted to understand the factors that contribute to the development, loss of control, and persistence of compulsive addictive behaviors. In this review, we provide an overview of various theories of addiction to drugs of abuse and the neurobiology involved in elements of the addiction cycle. Specific focus is devoted to the role of the mesolimbic pathway in acute drug reinforcement and occasional drug use, the role of the mesocortical pathway and associated areas (e.g., the dorsal striatum) in escalation/dependence, and the contribution of these pathways and associated circuits to conditioned responses, drug craving, and loss of behavioral control that may underlie drug relapse. By enhancing the understanding of the neurobiological factors that mediate drug addiction, continued preclinical and clinical research will aid in the development of novel therapeutic interventions that can serve as effective long-term treatment strategies for drug-dependent individuals.
Addiction is an international public health problem. It is a polygenic disorder best understood by accounting for the interplay between genetic and environmental factors. A recent way of perceiving this interaction is through epigenetics, which help grasp the neurobiological changes that occur in addiction and explain its relapsing-remitting nature. It is now known that every cell has a different way of expressing its phenotype, despite a universal DNA sequence. This is particularly true in the central nervous system where environmental factors influence this expression. Three major epigenetic processes have been found to participate in the perpetuation of addiction by changing the state of the chromatin and the degree of gene transcription: histone acetylation and methylation, DNA methylation, and noncoding RNAs. In the animal model literature, substantial evidence exists about the role of these epigenetic changes in the different phases of substance use disorders. This book chapter is a non-systematic literature review of the recent publications tackling the topic of epigenetics in addiction. Even though this evidence remains scarce and relatively poorly systematized, it is a promising foundation for future research of molecules that target specific brain regions and their functions to address core behavioral changes seen in addiction.
Stress contributes to numerous psychiatric disorders. Corticotropin releasing factor (CRF) signaling and CRF neurons in the bed nucleus of the stria terminalis (BNST) drive negative affective behaviors, thus agents that decrease activity of these cells may be of therapeutic interest. Here, we show that acute restraint stress increases cFos expression in CRF neurons in the mouse dorsal BNST, consistent with a role for these neurons in stress-related behaviors. We find that activation of α2A-adrenergic receptors (ARs) by the agonist guanfacine reduced cFos expression in these neurons both in stressed and unstressed conditions. Further, we find that α- and β-ARs differentially regulate excitatory drive onto these neurons. Pharmacological and channelrhodopsin-assisted mapping experiments suggest that α2A-ARs specifically reduce excitatory drive from parabrachial nucleus (PBN) afferents onto CRF neurons. Given that the α2A-AR is a Gi-linked GPCR, we assessed the impact of activating the Gi-coupled DREADD hM4Di in the PBN on restraint stress regulation of BNST CRF neurons. CNO activation of PBN hM4Di reduced stress-induced Fos in BNST Crh neurons. Further, using Prkcd as an additional marker of BNST neuronal identity, we uncovered a female-specific upregulation of the coexpression of Prkcd/Crh in BNST neurons following stress, which was prevented by ovariectomy. These findings show that stress activates BNST CRF neurons, and that α2A-AR activation suppresses the in vivo activity of these cells, at least in part by suppressing excitatory drive from PBN inputs onto CRF neurons.SIGNIFICANCE STATEMENT Stress is a major variable contributing to mood disorders. Here, we show that stress increases activation of BNST CRF neurons that drive negative affective behavior. We find that the clinically well tolerated α2A-AR agonist guanfacine reduces activity of these cells in vivo, and reduces excitatory PBN inputs onto these cells ex vivo Additionally, we uncover a novel sex-dependent coexpression of Prkcd with Crh in female BNST neurons after stress, an effect abolished by ovariectomy. These results demonstrate input-specific interactions between norepinephrine and CRF, and point to an action by which guanfacine may reduce negative affective responses.
Stress is a precipitating agent in neuropsychiatric disease and initiates relapse to drug-seeking behavior in addicted patients. Targeting the stress system in protracted abstinence from drugs of abuse with anxiolytics may be an effective treatment modality for substance use disorders. α2A-adrenergic receptors (α2A-ARs) in extended amygdala structures play key roles in dampening stress responses. Contrary to early thinking, α2A-ARs are expressed at non-noradrenergic sites in the brain. These non-noradrenergic α2A-ARs play important roles in stress responses, but their cellular mechanisms of action are unclear. In humans, the α2A-AR agonist guanfacine reduces overall craving and uncouples craving from stress, yet minimally affects relapse, potentially due to competing actions in the brain. Here, we show that heteroceptor α2A-ARs postsynaptically enhance dorsal bed nucleus of the stria terminalis (dBNST) neuronal activity in mice of both sexes. This effect is mediated by hyperpolarization-activated cyclic nucleotide-gated cation channels because inhibition of these channels is necessary and sufficient for excitatory actions. Finally, this excitatory action is mimicked by clozapine-N-oxide activation of the Gi-coupled DREADD hM4Di in dBNST neurons and its activation elicits anxiety-like behavior in the elevated plus maze. Together, these data provide a framework for elucidating cell-specific actions of GPCR signaling and provide a potential mechanism whereby competing anxiogenic and anxiolytic actions of guanfacine may affect its clinical utility in the treatment of addiction.
Stress-related substance use is a major challenge for treating substance use disorders. This selective review focuses on emerging pharmacotherapies with potential for reducing stress-potentiated seeking and consumption of nicotine, alcohol, marijuana, cocaine, and opioids (i.e., key phenotypes for the most commonly abused substances). I evaluate neuropharmacological mechanisms in experimental models of drug-maintenance and relapse, which translate more readily to individuals presenting for treatment (who have initiated and progressed). An affective/motivational systems model (three dimensions: valence, arousal, control) is mapped onto a systems biology of addiction approach for addressing this problem. Based on quality of evidence to date, promising first-tier neurochemical receptor targets include: noradrenergic (α1 and β antagonist, α2 agonist), kappa-opioid antagonist, nociceptin antagonist, orexin-1 antagonist, and endocannabinoid modulation (e.g., cannabidiol, FAAH inhibition); second-tier candidates may include corticotropin releasing factor-1 antagonists, serotonergic agents (e.g., 5-HT reuptake inhibitors, 5-HT3 antagonists), glutamatergic agents (e.g., mGluR2/3 agonist/positive allosteric modulator, mGluR5 antagonist/negative allosteric modulator), GABA-promoters (e.g., pregabalin, tiagabine), vasopressin 1b antagonist, NK-1 antagonist, and PPAR-γ agonist (e.g., pioglitazone). To address affective/motivational mechanisms of stress-related substance use, it may be advisable to combine agents with actions at complementary targets for greater efficacy but systematic studies are lacking except for interactions with the noradrenergic system. I note clinically-relevant factors that could mediate/moderate the efficacy of anti-stress therapeutics and identify research gaps that should be pursued. Finally, progress in developing anti-stress medications will depend on use of reliable CNS biomarkers to validate exposure-response relationships.
Neurons in the lateral hypothalamic area that express hypocretin (Hcrt) neuropeptides help regulate many behaviors including wakefulness and reward seeking. These neurons project throughout the brain, including to neural populations that regulate wakefulness, such as the locus coeruleus (LC) and tuberomammilary nucleus (TMN), as well as to populations that regulate reward, such as the nucleus accumbens (NAc) and ventral tegmental area (VTA). To address the roles of Hcrt neurons in seemingly disparate behaviors, it has been proposed that Hcrt neurons can be anatomically subdivided into at least two distinct subpopulations: a “medial group” that projects to the LC and TMN, and a “lateral group” that projects to the NAc and VTA. Here, we use a dual retrograde tracer strategy to test the hypotheses that Hcrt neurons can be classified based on their downstream projections and medial/lateral location within the hypothalamus. We found that individual Hcrt neurons were significantly more likely to project to both the LC and TMN or to both the VTA and NAc than would be predicted by chance. In contrast, we found that Hcrt neurons that projected to the LC or TMN were mostly distinct from Hcrt neurons that projected to the VTA or NAc. Interestingly, these two populations of Hcrt neurons are intermingled within the hypothalamus and cannot be classified into medial or lateral groups. These results suggest that Hcrt neurons can be distinguished based on their downstream projections but are intermingled within the hypothalamus.
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The bed nucleus of the stria terminalis (BNST) is a component of the extended amygdala that shows significant changes in activity and plasticity through chronic exposure to drugs and stress. The region is critical for stress- and cue-induced reinstatement of drug-seeking behaviors and is thus a candidate region for the plastic changes that occur in abstinence that prime addicted patients for reinstatement behaviors. Here, we discuss the various forms of long-term potentiation (LTP) and long-term depression (LTD) in the rodent BNST, and highlight the way that these changes in excitatory transmission interact with exposure to alcohol and other drugs of abuse, as well as other stressors. In addition, we highlight potential areas for future research in this area, including investigating input- and cell-specific bidirectional changes in activity. As we continue to accrue foundational knowledge in the mechanisms and effects of plasticity in the BNST, molecular targets and treatment strategies that are relevant to reinstatement behaviors will also begin to emerge. Here we briefly discuss the effects of catecholamine receptor modulators on synaptic plasticity in the BNST due to the role of norepinephrine in LTD and dopamine on the short-term component of LTP, as well as the role that signaling at these receptors play in reinstatement of drug- and alcohol-seeking behaviors. We hope that insights gained on the specific changes in plasticity that occur within the BNST during abstinence from alcohol and other drugs of abuse will provide insight into the biological underpinnings of relapse behavior in human addicts and inform future treatment modalities for addiction that tackle this complex biological problem.
Introduction: In Colombia, the prevalence of problems associated with heroin dependence has increased since the nineties. Method: After contextualize this issue, the article focuses on the scientific findings, indications, and pharmacotherapeutic limitations of the range of existing medications to treat acute withdrawal syndrome, commonly known as detoxification. Results: The pharmacological options available include opioid agonists, opioid partial agonists, antagonists and alpha-2 adrenergic agonists. Conclusion: Although the comprehensive treatment of heroin dependence include psychotherapeutic interventions, this review indicates that the approach, perhaps more successful in controlling acute withdrawal syndrome after abrupt discontinuation of heroin is methadone or buprenorphine followed by a gradual reductionin dose, while promoting lifestyle changes sustainable and relapse prevention.
Opioid drugs are potent modulators of many physiological and psychological processes. When given acutely, they can elicit the signature responses of euphoria and analgesia that societies have coveted for centuries. Repeated, or chronic, use of opioids induces adaptive or allostatic changes that modify neuronal circuitry and create an altered normality — the “drug-dependent” state. This state, at least that exhibited by those maintained continuously on long-acting opioid drugs such as methadone or buprenorphine, is generally indistinguishable from the drug-naïve state for most overt behaviors. The consequences of the allostatic changes (cellular, circuit, and system adaptations) that accompany the drug-dependent state are revealed during drug withdrawal. Drug cessation triggers a temporally orchestrated allostatic re-establishment of neuronal systems, which is manifested as opposing physiological and psychological effects to those exhibited by acute drug intoxication. Some withdrawal symptoms, such as physical symptoms (sweating, shaking, and diarrhea) resolve within days, whilst others, such as dysphoria, insomnia, and anxiety, can linger for months, and some adaptations, such as learned associations, may be established for life. We will briefly discuss the cellular mechanisms and neural circuitry that contribute to the opioid drug-dependent state, inferring an emerging role for neuroinflammation. We will argue that opioid addictive behaviors result from a learned relationship between opioids and relief from an existing or withdrawal-induced anxiogenic and/or dysphoric state. Furthermore, a future stressful life event can recall the memory that opioid drugs alleviate negative affect (despair, sadness, and anxiety) and thereby precipitate craving, resulting in relapse. A learned association of relief of aversive states would fuel drug craving in vulnerable people living in an increasingly stressful society. We suggest that this route to addiction is contributive to the current opioid epidemic in the USA.
Sustained exposure to various psychological stressors can exacerbate neuropsychiatric disorders, including drug addiction. Addiction is a chronic brain disease in which individuals cannot control their need for drugs, despite negative health and social consequences. The brains of addicted individuals are altered and respond very differently to stress than those of individuals who are not addicted. In this Review, we highlight some of the common effects of stress and drugs of abuse throughout the addiction cycle. We also discuss both animal and human studies that suggest treating the stress-related aspects of drug addiction is likely to be an important contributing factor to a long-lasting recovery from this disorder.
Pharmacotherapies for heroin addiction may target opiate withdrawal symptoms, facilitate initiation of abstinence and/or reduce relapse to heroin use either by maintenance on an agonist or antagonist agent. Available agents include opioid agonists, partial opioid agonists, opioid antagonists and alpha(2)-agonists for use during managed withdrawal and long-term maintenance. Experimental approaches combine alpha(2)-agonists with naltrexone to reduce the time of opiate withdrawal and to accelerate the transition to abstinence. Recently, buprenorphine has been introduced in the US for off ice-based maintenance, with the hope of replicating the success of this treatment in Europe and Australia. Naloxone has been added to buprenorphine in order to reduce its potential diversion to intravenous use, whilst facilitating the expansion of treatment. Although comprehensive substance abuse treatment is not limited to pharmacotherapy, this review will focus on the rationale, indications and limitations of the range of existing medications for detoxification and relapse prevention treatments. The two major goals of pharmacotherapy are to relieve the severity of opiate withdrawal symptoms during the managed withdrawal of the opioid and to prevent relapse to heroin use either after abstinence initiation or after being stabilised on a long-acting opiate agonist, such as methadone.
Relapse to drug use is one of the most debilitating long-term effects of addiction and one of the greatest challenges for treatment. There are many correlational studies implicating life stress as an important factor contributing to increased rates of drug and alcohol use, and as a trigger for relapse in individuals with substance abuse disorders. This chapter focuses on experiments conducted in laboratory animals to study the effects of exposure to environmental stressors on relapse to psychostimulant, opiate, and alcohol seeking, and on the neurobiological mechanisms mediating those effects. Two commonly used animal models of relapse, so-called reinstatement procedures, are described, and a summary of the types of stressors that have been found to effectively induce relapse to drug seeking using procedures based on these models is provided. In addition, studies aimed at uncovering the neurobiological underpinnings of stress-induced relapse are reviewed. Furthermore, recent work demonstrating that a history of drug exposure can produce long-lasting changes in the responsivity of the central nervous system to stressors is discussed with respect to its potential implications for understanding the relationship between stress and relapse to drug seeking.
Brain science is at the core of future understanding of how drugs affect behavior and their consequent impact the society. Extraordinary advances in the past three decades have meant that now much is understood about the connectivity of the brain and how its functionality depends on chemical messages passing among nerve cells, or neurons, in the form of neurotransmitters they release that bind to receptors. Psychoactive substances exert their effects by affecting the regulation of neurotransmitters or simulating their actions at their receptors, and subsequently within the nerve cell itself, often in highly specific ways. It is now understood that many drugs work in molecular terms and they may work, at least initially, in the brain. Moreover, one now knows in broad terms how different parts of the brain work at a systems level to produce behavioral and cognitive output. A complementary advance is the application of some aspects of neural decision making theory to the explanation of the behavior of individual substance abusers. Vulnerability or susceptibility to some actions of psychoactive substances, including both cognitive enhancement and dependence, depends on individual differences based on genetic or environmental, including developmental factors. Although in the society drug abuse is viewed as a social or moral problem best handled through the criminal justice system, the growing scientific evidence suggests instead that addiction is a chronic, relapsing, and treatable brain disorder that can result from prolonged effects of drugs on the brain.
The locus coeruleus noradrenergic (LC-NE) system is one of the first systems engaged following a stressful event. While numerous groups have demonstrated that LC-NE neurons are activated by many different stressors, the underlying neural circuitry and the role of this activity in generating stress-induced anxiety has not been elucidated. Using a combination of in vivo chemogenetics, optogenetics, and retrograde tracing, we determine that increased tonic activity of the LC-NE system is necessary and sufficient for stress-induced anxiety and aversion. Selective inhibition of LC-NE neurons during stress prevents subsequent anxiety-like behavior. Exogenously increasing tonic, but not phasic, activity of LC-NE neurons is alone sufficient for anxiety-like and aversive behavior. Furthermore, endogenous corticotropin-releasing hormone(+) (CRH(+)) LC inputs from the amygdala increase tonic LC activity, inducing anxiety-like behaviors. These studies position the LC-NE system as a critical mediator of acute stress-induced anxiety and offer a potential intervention for preventing stress-related affective disorders.
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Noncontingent “priming” presentations of positive reinforcers (or incentive events) can enhance and reinstate previously acquired instrumental responding for these reinforcers. We describe how this phenomenon may be used to study the motivational control of drug-taking behavior and the relapse to drug-taking in drug-free individuals.
Corticotropin-releasing factor (CRF) and norepinephrine (NE) mediate many hormonal, autonomic, and behavioral effects of acute stress, and it is possible that an interaction between these neurotransmitters could underlie neuronal adaptations in response to chronic stress. To test this hypothesis, the influence of chronically administered CRF and a specific CRF antagonist, alpha-helical CRF, on the induction of tyrosine hydroxylase, the rate-limiting enzyme in NE biosynthesis, was examined in the rat locus coeruleus (LC). We now report that administration of alpha-helical CRF specifically blocks the induction of tyrosine hydroxylase in response to a repeated intermittent stress paradigm involving foot shock and noise stress but has no effect on steady-state levels of the enzyme in nonstressed animals or on the induction of the enzyme in response to reserpine treatment. In addition, repeated administration of CRF alone for 5 days, like chronic stress, increases levels of tyrosine hydroxylase in LC. The results demonstrate that endogenous CRF is necessary for the induction of tyrosine hydroxylase in response to this stress paradigm and that exogenously administered CRF is sufficient for the regulation of this enzyme in nonstressed rats. These findings may prove important in elucidating mechanisms by which chronic stress triggers and sustains the biochemical alterations associated with some stress-related psychiatric disorders.
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.
This paper presents a biopsychological theory of drug addiction, the 'Incentive-Sensitization Theory'. The theory addresses three fundamental questions. The first is: why do addicts crave drugs? That is, what is the psychological and neurobiological basis of drug craving? The second is: why does drug craving persist even after long periods of abstinence? The third is whether 'wanting' drugs (drug craving) is attributable to 'liking' drugs (to the subjective pleasurable effects of drugs)? The theory posits the following. (1) Addictive drugs share the ability to enhance mesotelencephalic dopamine neurotransmission. (2) One psychological function of this neural system is to attribute 'incentive salience' to the perception and mental representation of events associated with activation of the system. Incentive salience is a psychological process that transforms the perception of stimuli, imbuing them with salience, making them attractive, 'wanted', incentive stimuli. (3) In some individuals the repeated use of addictive drugs produces incremental neuroadaptations in this neural system, rendering it increasingly and perhaps permanently, hypersensitive ('sensitized') to drugs and drug-associated stimuli. The sensitization of dopamine systems is gated by associative learning, which causes excessive incentive salience to be attributed to the act of drug taking and to stimuli associated with drug taking. It is specifically the sensitization of incentive salience, therefore, that transforms ordinary 'wanting' into excessive drug craving. (4) It is further proposed that sensitization of the neural systems responsible for incentive salience ('for wanting') can occur independently of changes in neural systems that mediate the subjective pleasurable effects of drugs (drug 'liking') and of neural systems that mediate withdrawal. Thus, sensitization of incentive salience can produce addictive behavior (compulsive drug seeking and drug taking) even if the expectation of drug pleasure or the aversive properties of withdrawal are diminished and even in the face of strong disincentives, including the loss of reputation, job, home and family. We review evidence for this view of addiction and discuss its implications for understanding the psychology and neurobiology of addiction.
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.
Neuroanatomical, neurophysiological, and behavioral studies suggest that brain stem nucleus locus coeruleus (LC) plays an important role in stress response. The present study was designed to clarify, whether infusion of CRF antagonist, αhCRF, into LC could attenuate or block stress-induced changes in norepinephrine (NE) concentrations in microdialysates collected from the medial prefrontal cortex (PFM). Rats were implanted with a bilateral cannulae assembly aimed in the LC and a microdialysis probe (4 mm active membrane length) into the LC. Immobilization of animals significantly increased the concentration of NE in microdialysates from PFM to a maximum of 170.8 ± 12.8% of the baseline ten minutes after the onset of stressor. Concentration of NE in dialysates remained significantly elevated for the next 40 min. Infusion of αhCRF into the LC significantly attenuated stress-induced increase in PFM NE concentration in samples collected at 10, 20, 30, and 50 min after the onset of immobilization. Infusion of αhCRF alone (no immobilization) did not change concentrations at any time during sample collection. These results are consistent with other studies and suggest that stress can facilitate NE release in the PFM through the activation of the CRF system in the brain.
Central and systemic morphine analgesia as well as both opioid and nonopioid forms of swim analgesia display gender differences with male rats showing greater magnitudes of analgesia than female rats. Since nonopioid swim analgesia is dependent upon muscarinic cholinergic and alpha2-noradrenergic mechanisms, the present study evaluated in rats whether gender, adult gonadectomy or estrous phase altered analgesia induced by either the muscarinic cholinergic receptor agonist, pilocarpine or the alpha2-noradrenergic receptor agonist, clonidine. Pilocarpine (1–10 mg/kg) analgesia was significantly greater in male rats. Female rats displayed 7-fold and 3-fold rightward shifts in peak analgesia on the tail-flick and jump tests respectively. Clonidine (100–500 μg/kg) analgesia was significantly greater on both nocipeptive tests in males, but only produced a 2-fold rightward shift in peak analgesia in females on the jump test. Whereas castration failed to shift either dose-response curve, ovariectomy mitigated the gender differences in pilocarpine and clonidine analgesia. Both pilocarpine and clonidine analgesia were not altered by estrous phase changes. These data indicate that gender differences in analgesia are not specific to opioid systems.
These studies examined how pharmacological stimulation and blockade of alpha receptors would affect active motor behavior in rats. In experiment I, alpha-2 receptor antagonists (piperoxane, yohimbine) and agonists [clonidine, norepinephrine (NE)] were infused into various locations in the ventricular system of the brain, including the locus coeruleus region, and motor activity was measured. Activity was measured principally in a swim test but spontaneous (ambulatory) activity was also recorded while drugs were being infused. When infused into the locus coeruleus region, small doses of the antagonists piperoxane and yohimbine depressed activity in the swim test while infusion of the agonists clonidine and NE had the opposite effect of stimulating activity. These effects were highly specific to the region of the locus coeruleus, since infusions of these drugs into other nearby locations in the ventricular system or use of larger doses had different, often opposite effects. This was especially true of clonidine and NE which profoundly depressed activity when infused posterior to the locus coeruleus, particularly over the dorsal vagal complex. Infusion of small doses of these drugs into the lateral ventricle had effects similar to infusion into the locus coeruleus region, though less pronounced. Changes in spontaneous motor activity were also observed, but this measure differentiated the groups less well than did the swim test. In experiment II, the predominantly postsynaptic receptor agonists isoproterenol (beta agonist) and phenylephrine (alpha-1 agonist) were infused into the ventricular system. Since infusions of piperoxane and yohimbine into the locus coeruleus that decreased activity in experiment I increase the release of NE by blocking alpha-2 inhibitory receptors on cell bodies and dendrites of the locus coeruleus, experiment II tested whether ventricular infusion of predominantly postsynaptic receptor agonists would also decrease activity in the swim test. Both isoproterenol and phenylephrine produced this effect, but did so selectively with respect to dose and location of infusion in the ventricular system. These findings are consistent with recent results relating to the mechanism that underlies stress-induced depression of active behavior.
The serotonergic dorsal raphe nucleus is innervated by corticotropin-releasing factor (CRF) and expresses CRF receptors, suggesting that endogenous CRF impacts on this system. The present study characterized interactions between CRF and the dorsal raphe serotonin (5-HT) system. The effects of intracerebroventricularly (i.c.v.) administered CRF on microdialysate concentrations of 5-HT in the lateral striatum of freely moving rats were determined. CRF had biphasic effects, with 0.1 and 0.3 μg decreasing, and 3.0 μg increasing 5-HT dialysate concentrations. I.C.V. administration of CRF inhibited neuronal activity of the majority of dorsal raphe neurons at both low (0.3 μg) and high (3 μg) doses. Likewise, intraraphe administration of CRF (0.3 and 1.0 ng) had predominantly inhibitory effects on discharge rate. Together, these results suggest that CRF is positioned to regulate the function of the dorsal raphe serotonergic system via actions within the cell body region. This regulation may play a role in stress-related psychiatric disorders in which 5-HT has been implicated.
Noradrenaline release in rat medial prefrontal cortex (PFC) was measured using a brain microdialysis technique. Immobilization stress increased noradrenaline release to a maximum level of 248.7 ± 12.8% of the basal release, which was significantly attenuated by preinjection of α-helical CRF9–41 (50 μg/rat) into the lateral cerebroventricle. Intracerebroventricular injection of CRF also increased noradrenaline release in the medial PFC. These results suggest that immobilization-stress facilitates noradrenaline release in the medial PFC through activation of the CRF system in the brain.
The hypothesis that brain noradrenergic systems have a broad biological function which is related to human fear or anxiety is reviewed. Data from studies of the function of the nucleus locus coereleus in non-human primates are presented in the context of recent anatomical, physiological, pharmacological, and animal behavioral experiments. Implications are suggested for the treatment of anxiety, drug addictions, pain, and psychosomatic diseases.
This paper presents a biopsychological theory of drug addiction, the ‘Incentive-Sensitization Theory’. The theory addresses three fundamental questions. The first is: why do addicts crave drugs? That is, what is the psychological and neurobiological basis of drug craving? The second is: why does drug craving persist even after long periods of abstinence? The third is whether ‘wanting’ drugs (drug craving) is attributable to ‘liking’ drugs (to the subjective pleasurable effects of drugs)? The theory posits the following.
St-91, 2(2,6-diethylphenylamino)-2-imidazoline, is a clonidine derivative which does not penetrate the blood-brain barrier. In spontaneously hypertensive (SH) rats is acutely increased arterial pressure and reduced heart rate while at 8 to 12 h after oral administration, it slightly lowered arterial pressure. In contrast, clonidine had acute antihypertensive activity at all doses used. By intracerebroventricular administration to SH rats, both drugs (St-91 and clonidine) reduced arterial pressure and heart rate; in this respect, clonidine was more potent then St-91. Cardiac acceleration induced by low frequency electrical stimulation of right cardiac sympathetic nerves in anesthetized and vagotomized dogs was reduced by St-91 at the same doses by clonidine. Phenoxybenzamine, phentolamine and desipramine antagonized the inhibitory effects of St-91 on electrically induced cardiac acceleration. It was concluded that St-91, like clonidine, stimulates inhibitory alpha-adrenergic receptors at the sympathetic nerve endings but, unlike clonidine, is substantially devoid of acute antihypertensive activity. This suggests that stimulation of peripheral presynaptic inhibitory alpha-adrenergic receptors is not likely to represent the sole mechanism of antihypertensive action of clonidine.
By means of single unit recording techniques it was found that a small systemically administered (intravenous) dose of the alpha-adrenergic agonist clonidine inhibited the spontaneous firing of brain norepinephrine (NE)-containing neurons in the locus coeruleus. In addition, the NE neurons were consistently inhibited by the direct (microiontophoretic) application of minute amounts of NE or clonidine. Intravenous clonidine also inhibited the firing of the great majority of (5-HT) neurons in the midbrain dorsal raphe nucleus. However, this action does not appearto be a direct one since clonidine (and NE) had relatively weak or variable effects when applied microiontophoretically to raphe neurons. The clonidine-induced depression of raphe firing may be secondary to an impairment in adrenergic transmission since (1) the depression could be reversed by the NE-releasing agents D- and L-amphetamine, (2) high doses of clonidine itself (which have been reported to have postsynaptic alpha-agonistic activity) reversed the depression produced by a low dose of clonidine and (3) prior destruction of NE neurons by 6-hydroxydopamine (7-12 days) rendered raphe neurons insensitive to the depressant effect of i.v. clonidine. Dopaminergic (substantia nigra, zona compacta) neurons did not respond to either low or high doses of clonidine. These results are consistent with previous data showing that clonidine decreases NE and 5-HT but not dopamine turnover. We conclude that systemically administered clonidine inhibits the firing of brain NE neurons by acting directly upon adrenergic receptors located on or near the soma of these neurons but that the concomitant inhibition of 5-HT neurons is an indirect effect (possibly secondary to an impairment in noracrenergic transmission).
Intracerebroventricularly administered alpha-helical CRF9-41, a corticotropin-releasing factor (CRF) receptor antagonist, is known to reduce a variety of stress-induced behavioral responses. This study examined in rats whether antagonism of CRF receptors in the region of locus coeruleus (LC) plays a role in reducing freezing induced by electric foot shock. Freezing is a well-characterized defensive response to stress and has been demonstrated to index an animal's degree of fear. A CRF-receptor antagonist, alpha-helical CRF9-41, bilaterally infused into the LC significantly reduced the duration of freezing at a dose as low as 0.20 micrograms. Additional experiments confirmed that 0.20 micrograms of alpha-helical CRF9-41 significantly reduced the duration of freezing only when cannulae were within the LC or in regions bordering the nucleus. Antagonist-treated rats with cannulae that did not impinge on the LC exhibited freezing at levels not different from vehicle-treated animals. These results strongly implicate CRF receptors located in the LC region in influencing the display of stress-induced behavior.
Over the past several years, major advances have been made in understanding the pharmacology of anxiety, involving three broad classes of experimental approach. One approach studies the mechanism of action of drugs that are known to treat anxiety clinically, such as the benzodiazepines. A second approach uses various animal models of fear or anxiety that are sensitive to known anxiolytic drugs, to see if they will detect new compounds. A third approach involves describing the neural pathways and neurotransmitters that are active in a state of fear or anxiety; importantly, this approach is not derived from the mechanisms of known anxiolytics. In this review, Michael Davis describes such a 'neural systems' approach to the study of fear or anxiety that uses the paradigm of fear-potentiated startle.
There is considerable evidence from biochemical studies that the transmitter-depleting action of drugs and neurotoxins which act upon central noradrenergic (NA) axon terminals is not uniform in different brain regions. Among NA axons, those originating in the locus coeruleus (LC) have been proposed to be most susceptible to the action of NA neurotoxins such as N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). The studies described here were conducted to determine whether this differential susceptibility to DSP-4 reflects a pharmacological heterogeneity between different populations of NA axons. To determine whether DSP-4 acts selectively upon LC axons, we have characterized the effects of this drug on NA axons in different brain regions, by using noradrenaline and dopamine-beta-hydroxylase (D beta H) immunohistochemistry. Following systemic administration of DSP-4, there was an almost complete loss of noradrenaline and D beta H staining in brain regions innervated by LC axons. No effects of the drug treatment were detected in brain regions innervated primarily by non-coerulean NA axons. These results demonstrate that both the transmitter-depleting and the neurodegenerative action of DSP-4 are restricted to NA axons originating in the LC. To explore the basis for this selectivity, noradrenaline uptake studies were conducted using synaptosomes from brain regions in which NA axons differ in their response to DSP-4. The results reveal a significant difference in the affinity of DSP-4 for the noradrenaline uptake carrier in cortical and hypothalamic synaptosomes. This finding is compatible with the hypothesis that the noradrenaline uptake carrier is pharmacologically distinct in LC and non-coerulean NA axons. This heterogeneity in noradrenaline uptake raises the question whether other drugs may also have differential actions on LC and non-coerulean NA neurons.
Recent electrophysiological studies, measurements of 5-HT synthesis and in vivo voltammetry recordings of 5-HT metabolism have suggested that serotoninergic neurones in the median raphe (MR) are less sensitive to 5-HT1A autoreceptor stimulation relative to those in the dorsal raphe (DR). To further study the putative differences in regulation between ascending 5-HT projections from the raphe nuclei we have used microdialysis to measure the release of 5-HT in ventral hippocampus, globus pallidus, dorsal hippocampus, frontal cortex, nucleus accumbens and medial septum, following systemic administration of the specific 5-HT1A agonist 8-OH-DPAT. The results show that the baseline output of 5-HT was similar in each of the areas studied. While 8-OH-DPAT decreased dialysate levels of 5-HT in all areas, the inhibition of 5-HT release seen in globus pallidus was significantly less marked compared to that observed in the other five regions. The results indicate that 5-HT1A autoreceptor-mediated control of 5-HT release is functional in all of the brain areas studied, including those receiving a preferential 5-HT innervation from the DR and MR. We find little evidence in support of the idea that brain 5-HT neuronal projections are heterogenous with respect to 5-HT1A autoreceptor regulation of 5-HT release; the globus pallidus, however representing a possible exception to this.
The present study was designed to determine whether activation of locus coeruleus (LC) neurons by hemodynamic stress is mediated by local release of corticotropin-releasing factor (CRF) within the LC. The ability of local LC injection of the CRF antagonist, alpha helical CRF9-41, to prevent LC activation elicited by i.v. nitroprusside infusion was investigated in halothane-anesthetized rats. Nitroprusside infusion (10 micrograms/30 microliters/min for 15 min) consistently increased LC spontaneous discharge rate with the mean maximum increase of 32 +/- 5% (n = 8) occurring between 3 and 9 min after the initiation of the infusion. Prior local LC injection of alpha helical CRF9-41 (150 ng), but not of saline (150 nl), prevented LC activation by nitroprusside. Alpha helical CRF9-41 did not alter LC spontaneous discharge rate or LC discharge evoked by repeated sciatic nerve stimulation suggesting that the CRF antagonist selectively attenuates stress-elicited LC activation. In contrast to alpha helical CRF9-41, the excitatory amino acid antagonist, kynurenic acid, did not attenuated LC activation by nitroprusside at a dose (0.5 mumol in 5 microliters, i.c.v.) that prevented LC activation by sciatic nerve stimulation. Taken together, these findings suggest that hemodynamic stress elicited by nitroprusside infusion activates LC neurons by releasing CRF within the LC region. The onset of LC activation by nitroprusside was temporally correlated with electroencephalographic (EEG) activation recorded from the frontal cortex and hippocampus. EEG activation was characterized by a change from low frequency, high amplitude activity to high frequency low amplitude activity recorded from the cortex and theta rhythm recorded from the hippocampus. LC activation usually outlasted the EEG activation. Nitroprusside infusion following local LC injection of alpha helical CRF9-41 was also associated with EEG activation in most rats. However, the duration of hippocampal theta rhythm was shorter in rats administered alpha helical CRF9-41. Thus, LC activation during cardiovascular challenge may play some role in EEG activation but is not necessary for this effect.
Rats were trained to lever press for intravenous cocaine (1.0 mg/kg/injection) and then switched to bromocriptine (0.3, 1.0, or 3.0 mg/kg/injection) on a FR-1 reinforcement schedule. Bromocriptine sustained responding at all three doses; hourly drug intake increased linearly with log-dose. In a second experiment, animals were trained to respond for cocaine (1.0 mg/kg/injection) or heroin (0.1 mg/kg/injection) reinforcement; drug was available for the first 2 h of each daily session; saline was substituted for cocaine or heroin for 5 subsequent hours. One hour into each saline substitution session, an intravenous injection of saline or bromocriptine (0.0, 0.5, 1.0, or 2.0 mg/kg) was given. Bromocriptine reinstated both cocaine-trained and heroin-trained lever pressing; under these conditions, the drug was most effective in the heroin-trained animals. Reinforcing doses of clonidine (0.0625 and 0.125 mg/kg), methohexital, and nicotine (0.05 and 0.1 mg/kg), and a sub-intoxicating dose of ethanol (2 g/kg) failed to reinstate cocaine-trained responding. These data indicate that bromocriptine has cocaine-like and heroin-like stimulus and reinforcing effects.
In nine experienced users of cocaine, we examined the urge to use cocaine or other drugs following a 40 mg dose of intravenous (IV) cocaine with and without oral pretreatment with 2.5 mg bromocriptine. The urge to use cocaine was assessed with a questionnaire constructed to assess both "wanting" and "craving" for cocaine or other drugs. Fifteen minutes after the administration of cocaine (but not after placebo), subjects' ratings for both drug "wanting" and drug "craving" were significantly increased. Our results provide a laboratory demonstration of cocaine-induced increases in the urge to use drugs in humans. The findings, stressing the role of internal stimuli associated with drug administration, suggest the possibility of distinguishing among related, but perhaps distinct, components of the fluctuating levels of motivation to reuse drugs.
Dose-response curves for clonidine-produced analgesia in rats were constructed using the tail-flick and formalin tests. Subsequently, the relative role of alpha 1 and alpha 2 receptors in clonidine analgesia in each of these tests was determined using systemic administration of vehicle controls, tolazoline, yohimbine and prazosin prior to injection of an ED50 dose of clonidine. Clonidine was found to be significantly more potent in the formalin test than in the tail-flick test. Furthermore, clonidine analgesia in the tail-flick test was completely antagonized by tolazoline and yohimbine, but not by prazosin, whereas clonidine was antagonized by tolazoline and prazosin, but not by yohimbine in the formalin test. The implications of these findings with regard to the contributions of different alpha-receptor subtypes to clonidine-produced analgesia in different pain tests are discussed.
The effect of the alpha-2-adrenoceptor agonist clonidine on anxiety-related behavior was investigated using two different rat anxiety models: a modified Vogel's drinking conflict model and Montgomery's elevated plus-maze. In both models biphasic dose-response curves were obtained; in a narrow low-dose range (6.25-10.0 micrograms/kg) the drug produced anxiolytic-like effects, while anxiogenic-like properties were found after higher doses (12.5-80.0 micrograms/kg). Attempts to block the effects obtained were made in Montgomery's elevated plus-maze. The specific alpha-2-adrenoceptor antagonist idazoxan blocked the anxiolytic-like effect but did not influence the anxiogenic-like activity. Conversely, the specific alpha-1-adrenoceptor antagonist prazosin blocked the anxiogenic-like effect but did not alter the anxiolytic-like activity. These findings may suggest that alpha-1- and alpha-2-adrenergic receptor mechanisms are reciprocally involved in anxiety-related behavior.
In a first experiment, rats were trained initially to discriminate i.p. injections of 2.5 mg/kg of xylazine from saline in a two-lever, food-reinforced, fixed-ratio 10 drug discrimination procedure. The animals were then retrained on progressively lower doses of the training drug. The stimulus generalization gradient of xylazine was established each time the animals had reached criterion on successive training doses; the criterion required that lever selection be appropriate to the saline or xylazine injection on 10 consecutive sessions. The findings indicate the lowest xylazine training dose at which individual rats can reach criterion to range from 2.5 to less than or equal to 0.31 mg/kg; the median lowest discriminable dose was 0.89 mg/kg. The distribution of lowest discriminable dose accommodated a Gaussian shape. The slope of the xylazine gradient did not in a systematic manner vary as a function of training dose, and the ED50 value of xylazine was an almost constant fraction of training dose (1:2.0) at training doses ranging from 2.5 to 0.63 mg/kg. A second experiment examined the xylazine-like agonist and the xylazine-antagonist effects of clonidine, yohimbine, piperoxan and idazoxan in rats discriminating xylazine from saline at a training dose of 2.5 mg/kg. Clonidine produced generalization in all animals and antagonized the xylazine stimulus in one. Idazoxan produced near complete antagonism, and was generalized in one animal. Yohimbine and piperoxan produced magnitudes of agonist and antagonist effects that were intermediate between those of clonidine and idazoxan. Lisuride and d-lysergic acid diethylamide produced up to 71 and 29% generalization, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Clonidine, an alpha-2-adrenergic agonist, suppresses signs of opiate withdrawal in animals and in man. Electrical or chemical stimulation of the nucleus locus coeruleus (LC) increases noradrenergic activity and brain concentration of the noradrenergic metabolite MHPG, and produces many signs of opiate withdrawal. Thus, clonidine's ability to attenuate withdrawal might be due to the reduction of noradrenergic neuronal activity originating in the LC, but additional alpha-2-adrenergic receptors throughout the body and other mechanisms may also play a role. The present study explored the neuroanatomical and pharmacological selectivity of alpha-2-adrenergic receptors of the LC in the anti-withdrawal action of clonidine. Experiment 1 tested the hypothesis that behavioral and biochemical measures of naloxone-precipitated withdrawal from morphine would be blocked by infusions of clonidine (0.6 or 2.4 micrograms/microliters) into the LC. Significant reductions were observed in the occurrence of diarrhea, ptosis, weight loss and wet-dog shakes. Clonidine also reversed the naloxone-precipitated increase in hippocampus MHPG concentration. In experiment 2 subjects received an LC infusion or IP injection of a non-lipophilic alpha-2-agonist (ST-91), which does not penetrate the blood-brain barrier, or of clonidine into the dorsal parabrachial nucleus (DPB) to test the selectivity of the effects of clonidine infusions into the LC. ST-91 infusions into the LC reduced several of the observed withdrawal signs and increased others (e.g., jumping). Although peripheral injections of ST-91 attenuated some of the checked signs associated with naloxone-precipitated withdrawal, the frequency of wet-dog shakes was not reduced. ST-91 infusions into the LC, but not systemic ST-91 administration, prevented the withdrawal-induced increase in hippocampus MHPG concentration. Clonidine infused lateral to the LC into the DPB did not significantly attenuate withdrawal or reduce hippocampus MHPG levels. These results provide behavioral and biochemical evidence to support the suggestion that clonidine significantly attenuates naloxone-precipitated withdrawal through an interaction with noradrenergic neurons located in the vicinity of the LC.
In order to determine whether pharmacologically-induced alterations in the spontaneous activity of neurons in the locus coeruleus are associated with changes in blood pressure, the activity of the locus coeruleus and blood pressure were recorded simultaneously in anesthetized rats after the administration of agents known to affect both of these parameters. Spontaneous activity of the locus coeruleus was decreased by intracerebroventricular (i.c.v.) administration of both clonidine and St 91, [2,(2,6-diethyl-phenylimino)imidazolidine chloride], a charged analogue of clonidine. However, only clonidine decreased the mean blood pressure after intracerebroventricular administration suggesting that either the receptors mediating decreases in the activity of the locus coeruleus are different to those mediating hypotension, or that St 91 does not distribute to sites involved in the control of blood pressure even after intracerebroventricular administration. Intravenous administration of clonidine, but not of St 91, decreased the activity of the locus coeruleus and produced a prolonged hypotension, thus suggesting a central mechanism for these effects. Both clonidine and St 91 administered intravenously, produced a brief initial period of hypertension which was not associated with consistent changes in the spontaneous activity of the locus coeruleus. Thus, noradrenergic agonists can decrease the activity of the locus coeruleus without affecting blood pressure, and increase blood pressure without affecting the activity of the locus coeruleus. The spontaneous activity of cells in the locus coeruleus was increased by 100% after the intracerebroventricular administration of corticotropin-releasing factor (CRF; 3.0 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)
In six experiments we studied the effects of lesions to either the dorsal or ventral noradrenergic bundle on the acquisition and extinction of the conditioned emotional response (CER) as measured in a conditioned suppression paradigm. Infusions of the neurotoxin 6-hydroxydopamine (6-OHDA) into the trajectory of the dorsal noradrenergic ascending bundle (DNAB) impaired the acquisition of on-the-baseline and off-the-baseline conditioned suppression. The acquisition impairment for on-the-baseline conditioning was also shown to still be present when training did not commence until 8 weeks following central noradrenergic depletion. However, in rats previously trained on the CER, DNAB lesions did not affect performance. There was also a small resistance to extinction following on-, but not off-the-baseline conditioning. The acquisition impairment was shown not to be because of an altered sensitivity to the footshock. In contrast, infusions of 6-OHDA into the ventral noradrenergic ascending bundle (VNAB) had no effect upon the acquisition of the CER in an on-the-baseline procedure, but retarded its extinction to a much greater extent. The results here are discussed in terms of other acquisition deficits shown by rats with DNAB lesions, and with reference to Gray's "anxiety" and Mason's "selective attention" theories of locus coeruleus function.
The focus of this review of intracranial chemical injection (ICI) is on the methods used and how variations in the use of these methods affect the results obtained. A brief historical review indicates that investigators at the turn of the century were concerned with the local nature of ICI. Since this problem remains at this time, the logic of the protocols then used is considered applicable to present problems.
After a review of the available methods, a checklist containing a standard set of recommended procedures is provided. These recommendations do not depart from current practices, but serve to identify sources of variability among experiments that could readily be reduced.
A consideration of the sphere of influence of ICI focuses on the evaluation of the author's ventricular hypothesis. This hypothesis, as originally formulated, called attention to the potential of spread from sites of ICI to the ventricular system. This would blur the anatomical localization which is one of the major virtues of the ICI method. It is considered necessary to expand the view of spread from the application site to include an important contribution of the vasculature. The failure to find species generality is taken as one indicant that the critical sites of action of cholinergic agents which provoke drinking have not been discovered.
Recent evidence indicates that the subfornical organ may be one important site of carbachol-induced drinking. Such evidence does not deny the possibility of a “thirst circuit” but it is clear that such a circuit has not been adequately defined. Discrepancies concerning the alpha- and beta-adrenergic systems involved in feeding and the influence of dopamine applied to the striatum on motor behavior is briefly reviewed in terms of the different methods used.
Intracellular recordings in vivo from noradrenergic neurons in the rat locus coeruleus showed that membrane potential was
hyperpolarized by the administration of clonidine (an alpha 2-adrenoceptor agonist) or after a burst of spikes evoked by intracellular
pulses; both types of hyperpolarization were associated with a decrease in membrane input resistance, and both could be blocked
by the alpha 2-adrenoceptor antagonist piperoxane. These results suggest that a hyperpolarization of membrane potential mediated
by an alpha 2-adrenoceptor underlies both clonidine- and activation-induced inhibition of locus coeruleus cell firing.
In a leverpressing operant procedure, male rats were trained to respond for food reinforcement on one lever after an injection of clonidine (0.04 mg/kg) and to respond on an alternate lever for food reinforcement after an injection of saline. All 36 rats learned to discriminate the drug reliably from saline, thereby indicating that clonidine produces discriminative interoceptive stimuli. The discriminative stimulus was both dose- and time-dependent, with an ED50 of 0.018 mg/kg and an optimum time of action occurring from 15 to 60 min after injection. Although clonidine produced a reduction in response rate, this was not the basis of the discriminative stimulus as other drugs with similar depressant action did not generalize. The clonidine stimulus was dose-dependently antagonized by the alpha-2 adrenergic antagonist, yohimbine, whereas receptor antagonists of alpha-1 adrenergic, beta adrenergic, dopaminergic, serotonergic, cholinergic or opioid systems were ineffective in blocking the interoceptive stimulus produced by clonidine Lofexidine, guanabenz and methyldopa, all centrally acting hypotensive drugs that act through alpha-2 adrenoceptor mechanisms dose-dependently generalized to the clonidine cue, whereas hydralazine, minoxidil, propranolol and prazosin, hypotensive drugs acting through other mechanisms, did not generalize. These results suggest that clonidine produces interoceptive stimuli that are discriminable by rats and mediated through central alpha-2 adrenoceptor stimulation.
The locus coeruleus of male rats was destroyed bilaterally by injection of 6-hydroxydopamine. Rats injected with the vehicle and normal rats served as controls. Starting 20 days after the lesion, the locomotor activity of all rats was measured for 5 min every day. For the first 6 days, the lesioned rats were significantly less active than control rats; from the 7th to the 15th day, on the other hand, the locomotor activity of the two groups of rats was the same. From the 16th day onwards, the sedative effect of small doses of clonidine (2.5-100 micrograms/kg) was measured in lesioned and control animals. In spite of an almost total loss of noradrenaline in the cerebral cortex and hippocampus and a 33% loss of noradrenaline in the brain-stem of the lesioned rats, the sedative effect of clonidine was the same as in the control rats. This result suggests that the sedation produced by clonidine is not dependent on presynaptically located alpha 2-adrenoceptors.
In rats trained to self-administer heroin or cocaine intravenously, non-contingent priming injections of heroin or cocaine, respectively, reinstated responding after a period of extinction. In rats similarly trained to self-administer heroin or cocaine intravenously, morphine sulphate was applied centrally to sites in the ventral tegmental area (VTA), the periventricular grey (PVG) and the caudate nucleus following a period of extinction. Self-administration behavior was reinstated by morphine application to sites in the region of the VTA, but not to other sites, in both heroin and cocaine-trained animals. This priming effect of morphine was blocked or attenuated by prior administration of naltrexone, given intraperitoneally. Morphine in the VTA is known to activate mesolimbic dopamine neurons, suggesting that dopamine activity in this system may underlie the priming effects of both opiates and stimulants. Furthermore, the fact that the mesolimbic system is implicated in the positive motivational actions of both drug groups, suggests that morphine reinstates drug-taking behavior in these animals by activating appetitive motivational systems of the brain.
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.
Three experiments contrasted the effects of 6-hydroxydopamine-induced lesions of the ventral noradrenergic and dorsal noradrenergic projections, predominantly to hypothalamus and cortex, respectively, upon body weight changes and food-related behaviour in the rat. In general, ventral noradrenergic bundle lesions enhanced weight gain and these effects were exaggerated by the provision of palatable cheese to the standard chow diet. In contrast, lesions of the dorsal noradrenergic bundle produced minor changes in body weight. Associated with the effects of ventral noradrenergic bundle lesions were hyperphagia, enhanced suppression of intake of food adulterated with quinine, (at high concentration), a small attenuation of food neophobia, and enhanced acquisition, but not performance, of the eating response to tail-pinch stimulation. These ventral noradrenergic bundle lesions failed to alter basal activity levels, amphetamine anorexia or the diurnal pattern of eating or activity. In contrast, lesions of the dorsal noradrenergic bundle did not produce either hyperphagia or enhanced rejection of food adulterated with quinine. However, there was a strong attenuation of food neophobia and a retarded acquisition (but unimpaired performance) of eating in response to tail-pinch stimulation. The results are discussed in connection with previous studies of ventral and dorsal noradrenergic bundle lesions, with the effects of ventromedial hypothalamic lesions and with the underlying behavioural and physiological processes that mediate these contrasting effects of different neuroanatomical patterns of central noradrenaline depletion.