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Nicotinic Receptors in the Brain: Links between Molecular Biology and Behavior
Abstract
Molecular cloning has elucidated the sequence of a family of acetylcholine receptor subunits that are activated by nicotine. Subsequent studies on the localization of individual subunits and the physiological properties of nicotinic subunit combinations in vitro, have led to identification of subunit compositions of nicotinic receptors that may function in vivo, as the native receptor. A particular challenge for the field has been to use these molecular data to determine which individual nicotinic receptor subtype is responsible for mediating each of the behavioral effects of nicotine. Human and animal studies have shown that nicotine is reinforcing and likely responsible for the addictive properties of tobacco. In addition, nicotine has been shown to have effects on locomotion, cognition, affect, and pain sensitivity. Recent studies combining the techniques of molecular biology, pharmacology, electrophysiology, and behavioral analysis to analyze knock out mice that lack individual subunits of the nicotinic acetylcholine receptor, have helped identify the role of specific nicotinic subunits in some of these complex behaviors. These studies could ultimately be useful in designing specific nicotinic receptor agonists and antagonists that may have uses in the clinic.
... cholecystokinin via postsynaptic receptors containing the nicotinic α4 and β2 subunits 5 . These subunits constitute the primary site of nicotine action 6,7 . The observation that MOR and its endogenous agonist enkephalin are expressed by VIP-containing GABAergic neocortical interneurons 8 suggested a potential interaction site between nicotinic and opioid systems. ...
... Consistent with the expression of the high affinity α4 and β2 subunits 5,6,7 , a low dose of nicotine (1 µM) also depolarized these neurons and triggered action potentials (n=3, not shown). The almost complete overlap between nicotine and µ-opioid responsive interneuron populations in cortical layers I to V indicates that interactions between these neurotransmitter systems occur at the cellular level. ...
... Nicotine consumption likely affects this circuitry in a complex time-and dosedependent manner, especially in smoking behavior where nicotine concentration follows an intermittent spike pattern 1,3 . The predicted scenario can be correlated to the well-established sequence of tobacco effects 1,3,6,7 . Indeed, after an initial enhancement of GABAergic transmission that may participate in its transient anxiolytic properties, nicotine rapidly induces cellular tolerance to further nicotine administration based on two mechanisms. ...
Ce travail avait pour objectif l’étude fonctionnelle d’une population d’interneurones GABAergiques du néocortex. La combinaison des techniques d’électrophysiologie, de biologie moléculaire et d’histochimie nous a permis de montrer que les interneurones sensibles aux agonistes nicotiniques, qui expriment le peptide vasoactif intestinal et la cholecystokinine, peuvent être activés de manière synaptique par les fibres sérotoninergiques afférentes originaires des noyaux du raphé, via le récepteur à la sérotonine de type 3. La mise en évidence de l’expression sélective du récepteur opioïde de type μ et de la préproenképhaline dans cette population neuronale nous a conduit à démontrer l’existence d’une boucle d’autorégulation enképhalinergique, spécifique de ces interneurones. L’identification de mécanismes contrôlant la mise en jeu d’une population neuronale restreinte dans l’activité du réseau néocortical nous a permis de mieux cerner la place qu’elle occupe dans la physiologie du néocortex.
... Nicotine activates neuronal nicotinic acetylcholine receptors (nAChRs) in the brain. The involvement of nicotinic receptors includes their interactions with the dopaminergic system in substance abuse and neurodegenerative disorders [5][6][7]. ...
... Early reviews did not mention the α6 subunit [6], stated that the α6 subunit did not form a complex with β subunits, or did so with great difficulty [8]. We now understand that the α6 subtype can complex with the β2 subunit to form the α6β2* nAChR complex and that nAChRs are widely distributed in the brain dependent on their α subunits [7,9]. Normal functioning of nAChRs in the brain involves modulation of transmitter release due to nAChR presynaptic localization [5,8]. ...
... More selective drugs would block nicotine-induced dopamine release without off-target effects. We are interested in α6β2* nAChR because it is restricted to the ventral tegmental area (VTA) and nucleus accumbens, regions known for their involvement in reinforcement, sensitization, and locomotion [7,13]. The use of in vivo voltammetry has permitted the application of agents that are selective antagonists for the β2 subunit in the VTA, followed by real-time measurement of in vivo dopamine release in different regions of the limbic system. ...
Smoking-cessation drugs bind many off-target nicotinic acetylcholine receptors (nAChRs) and cause severe side effects if they are based on nicotine. New drugs that bind only those receptors, such as α6β2* nAChR, implicated in nicotine addiction would avoid the off-target binding. Indolizidine (-)-237D (IND (-)-237D), a bicyclic alkaloid, has been shown to block α6β2* containing nAChRs and functionally inhibit the nicotine-evoked dopamine release. To improve the affinity of indolizidine (-)-237D for α6β2*, we built a library of 2226 analogs. We screened virtually the library against a homology model of α6β2 nAChR that we derived from the recent crystal structure of α4β2 nAChR. We also screened the crystal structure of α4β2 nAChR as a control on specificity. We ranked the compounds based on their predicted free energy of binding. We selected the top eight compounds bound in their best pose and subjected the complexes to 100 ns molecular dynamics simulations to assess the stability of the complexes. All eight analogs formed stable complexes for the duration of the simulations. The results from this work highlight nine distinct analogs of IND (-)-237D with high affinity towards α6β2* nAChR. These leads can be synthesized and tested in in vitro and in vivo studies as lead candidates for drugs to treat nicotine addiction.
... In particular, cholinesterase inhibitors used to treat cognitive symptoms in early to moderate AD patients (Anand and Singh, 2013) do not induce a long-term improvement of cognition and the treatment is not always effective (Connelly et al., 2005;Lemstra et al., 2007). Also, a variety of nAChR agonists, although promising in preclinical studies, had a limited efficacy when experimented in clinical trials, probably for the rapid nAChRs desensitization (Picciotto, 2000). The outcome of clinical trials with anti-Aβ drugs is even more puzzling since the success obtained in animal models of AD has not been replicated in humans. ...
... The role of α7nAChRs in cognitive functions (Picciotto, 2000) relies on their ability to modulate synaptic function through the regulation of glutamate release (Cheng and Yakel, 2015). Thus, we first evaluated whether their genetic deletion affected pairedpulse facilitation (PPF), a form of short-term plasticity that might reflect release probability. ...
... Considering that α7nAChRs mediate the raise of pre-synaptic intracellular Ca 2+ levels during neuronal activity, thus modulating glutamate release, synaptic transmission, and cognitive function (Picciotto, 2000), it was crucial to exclude that the observed α7 KO phenotype was exclusively due to the failure of cholinergic transmission. Our finding that the impairment of synaptic plasticity and memory is paralleled by the increase of APP expression and Aβ levels suggests that the loss of α7nAChRs might trigger a chain of events through a negative feedback mechanism aimed at restoring calcium entry inside neurons by stimulating Aβ production. ...
The accumulation of amyloid-beta peptide (Aβ) and the failure of cholinergic transmission are key players in Alzheimer’s disease (AD). However, in the healthy brain, Aβ contributes to synaptic plasticity and memory acting through α7 subtype nicotinic acetylcholine receptors (α7nAChRs). Here, we hypothesized that the α7nAChR deletion blocks Aβ physiological function and promotes a compensatory increase in Aβ levels that, in turn, triggers an AD-like pathology.
To validate this hypothesis, we studied the age-dependent phenotype of α7 knock out mice. We found that α7nAChR deletion caused an impairment of hippocampal synaptic plasticity and memory at 12 months of age, paralleled by an increase of Amyloid Precursor Protein expression and Aβ levels. This was accompanied by other classical AD features such as a hyperphosphorylation of tau at residues Ser 199, Ser 396, Thr 205, a decrease of GSK-3β at Ser 9, the presence of paired helical filaments and neurofibrillary tangles, neuronal loss and astrocytosis.
Our findings suggest that α7nAChR malfunction might precede Aβ and tau pathology, offering a different perspective to interpret the failure of anti-Aβ therapies against AD and to find novel therapeutical approaches aimed at restoring α7nAChRs-mediated Aβ function at the synapse.
... ALLO modulates processes relevant to TUD, including reward [13][14][15], mood [16], anxiety [16], and cognition [17,18]. Delta-subunit containing GABA-A receptors for ALLO are located in similar brain regions as nicotinic acetylcholine receptors [19,20], suggesting ALLO's capacity to influence nicotine's effects. A recent study in male rats found that a positive allosteric modulator of delta-subunit containing GABA-A receptors in the amygdala blocked stress-induced enhancement of nicotine self-administration [21]. ...
... However, the fact that PROG administration generally increases ALLO:PROG ratio in serum suggests that this likely occurs in the brain as well, given the presence of similar enzymes in the brain and periphery [66]. Nevertheless, smoking-related measures in the current study, including the fMRI measures, might be more tightly linked to brain levels of ALLO or ALLO:PROG ratios since GABA-A receptors are localized to brain regions associated with nicotine action [19,20]. ...
Background
Progesterone administration has therapeutic effects in tobacco use disorder (TUD), with females benefiting more than males. Conversion of progesterone to the neurosteroid allopregnanolone is hypothesized to partly underlie the therapeutic effects of progesterone; however, this has not been investigated clinically.
Methods
Smokers ( n = 18 males, n = 21 females) participated in a randomized, double-blind, placebo-controlled crossover study of 200 mg progesterone daily across 4 days of abstinence. The ratio of allopregnanolone:progesterone was analyzed in relationship to nicotine withdrawal, smoking urges, mood states, subjective nicotine effects, and neural response to smoking cues.
Results
Allopregnanolone:progesterone ratio interacted with sex to predict withdrawal symptoms ( p = 0.047), such that females with higher allopregnanolone:progesterone ratios reported lower withdrawal severity ( b = − 0.98 [− 1.95, − 0.01]; p = 0.048). In addition, allopregnanolone:progesterone ratio interacted with sex to predict confusion ( p = 0.014) and fatigue ( p = 0.034), such that females with higher allopregnanolone:progesterone ratios reported less confusion ( b = − 0.45 [− 0.78, − 0.12]; p = 0.008) and marginally lower fatigue ( b = − 0.50 [− 1.03, 0.02]; p = 0.062. Irrespective of sex, higher ratios of allopregnanolone:progesterone were associated with stronger “good effects” of nicotine ( b = 8.39 [2.58, 14.20]); p = 0.005) and weaker “bad effects” of nicotine ( b = − 7.13 [− 13.53, − 0.73]; p = 0.029).
Conclusions
Conversion of progesterone to allopregnanolone correlated with smoking-related outcomes in both sex-dependent and sex-independent ways. Sex-dependent effects suggest that conversion of progesterone to allopregnanolone may contribute to greater therapeutic benefits in females but not males with TUD.
Trial registration Clinicaltrials.gov registration, retrospectively registered: NCT01954966; https://clinicaltrials.gov/ct2/show/NCT01954966 \
... EGFR activates the Akt pathway and its downstream effectors, X-linked inhibitor of apoptosis protein-survivin and the nuclear factor kappa B (NFκB) (Zdanowski et al., 2015). In general, the nAChRs can activate neuroprotective signaling cascades in neurons, astroglia, and microglia to promote cell survival, synaptic plasticity and maintain brain homeostasis (Picciotto et al., 2000;Echeverria and Zeitlin, 2012;Kawamata et al., 2012). For example α7nAChRs upregulate the transcription factors hypoxiainducible factor-1 (HIF-1), GATA-3, NFκB, and signal transducer and activator of transcription (STAT) 1 (Picciotto et al., 2000;FIGURE 2 | Scheme depicting different pro-survival signaling pathways activated by the nAChRs. ...
... In general, the nAChRs can activate neuroprotective signaling cascades in neurons, astroglia, and microglia to promote cell survival, synaptic plasticity and maintain brain homeostasis (Picciotto et al., 2000;Echeverria and Zeitlin, 2012;Kawamata et al., 2012). For example α7nAChRs upregulate the transcription factors hypoxiainducible factor-1 (HIF-1), GATA-3, NFκB, and signal transducer and activator of transcription (STAT) 1 (Picciotto et al., 2000;FIGURE 2 | Scheme depicting different pro-survival signaling pathways activated by the nAChRs. Nicotine-induced neuroprotection is mediated by receptors, primarily through the α7 and α4β2 receptors. ...
Parkinson’s disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) in the midbrain resulting in progressive impairment in cognitive and motor abilities. The physiological and molecular mechanisms triggering dopaminergic neuronal loss are not entirely defined. PD occurrence is associated with various genetic and environmental factors causing inflammation and mitochondrial dysfunction in the brain, leading to oxidative stress, proteinopathy, and reduced viability of dopaminergic neurons. Oxidative stress affects the conformation and function of ions, proteins, and lipids, provoking mitochondrial DNA (mtDNA) mutation and dysfunction. The disruption of protein homeostasis induces the aggregation of alpha-synuclein (α-SYN) and parkin and a deficit in proteasome degradation. Also, oxidative stress affects dopamine release by activating ATP-sensitive potassium channels. The cholinergic system is essential in modulating the striatal cells regulating cognitive and motor functions. Several muscarinic acetylcholine receptors (mAChR) and nicotinic acetylcholine receptors (nAChRs) are expressed in the striatum. The nAChRs signaling reduces neuroinflammation and facilitates neuronal survival, neurotransmitter release, and synaptic plasticity. Since there is a deficit in the nAChRs in PD, inhibiting nAChRs loss in the striatum may help prevent dopaminergic neurons loss in the striatum and its pathological consequences. The nAChRs can also stimulate other brain cells supporting cognitive and motor functions. This review discusses the cholinergic system as a therapeutic target of cotinine to prevent cognitive symptoms and transition to dementia in PD.
... Asterisks indicate statistical difference against the control group ( * p < 0.05); n = 15 animals per group similar effects have been reported in imidacloprid-exposed larvae (Crosby et al. 2015), rats (Abd-Elhakim et al. 2018), nicotine-exposed fish (Levin et al. 2007), and mice (Lefever et al. 2017). The hypothesis about this hypomotility would agree with the multiplicity of effects of nicotine reported by Picciotto et al. (2002), and this locomotor alteration would be related to the brain region and receptors activated by this substance (Picciotto et al. 2000;Domino 2001). ...
The imidacloprid-based insecticides (IBIs) are among the most used insecticides worldwide, and chronic and acute toxic effects (days exposure protocols) have been reported in several species in studies of IBIs at lethal concentrations. However, there is little information on shorter time exposures and environmentally relevant concentrations. In this study, we investigated the effect of a 30-min exposure to environmentally relevant concentrations of IBI on the behavior, redox status, and cortisol levels of zebrafish. We showed that the IBI decreased fish locomotion and social and aggressive behaviors and induced an anxiolytic-like behavior. Furthermore, IBI increased cortisol levels and protein carbonylation and decreased nitric oxide levels. These changes were mostly observed at 0.013 and 0.0013 µg·L⁻¹ of IBI. In an environmental context, these behavioral and physiological disbalances, which were immediately triggered by IBI, can impair the ability of fish to evade predators and, consequently, affect their survival.
Graphical abstract
... The cholinergic system contains two families of acetylcholine receptors: muscarinic receptors and nicotinic receptors. Nicotinic receptors are ligand-gated ion channels composed of 5 subunits; when acetylcholine binds to the receptor, an influx of sodium ions causes a rapid response [51]. Interest in development of nicotinic agents was spurred by the high prevalence of smoking on the part of people with schizophrenia and suggestions of alterations of genomic alterations associated with nicotinic cholinergic receptors [52,53]. ...
Cognitive impairment is a predictor of disability across different neuropsychiatric conditions, and cognitive abilities are also strongly related to educational attainment and indices of life success in the general population. Previous attempts at drug development for cognitive enhancement have commonly attempted to remedy defects in transmitters systems putatively associated with the conditions of interest such as the glutamate system in schizophrenia. Recent studies of the genomics of cognitive performance have suggested influences that are common in the general population and in different neuropsychiatric conditions. Thus, it seems possible that transmitter systems that are implicated for cognition across neuropsychiatric conditions and the general population would be a viable treatment target. We review the scientific data on cognition and the muscarinic cholinergic receptor system (M1 and M4) across different diagnoses, in aging, and in the general population. We suggest that there is evidence suggesting potential beneficial impacts of stimulation of critical muscarinic receptors for the enhancement of cognition in a broad manner, as well as the treatment of psychotic symptoms. Recent developments make stimulation of the M1 receptor more tolerable, and we identify the potential benefits of M1 and M4 receptor stimulation as a trans-diagnostic treatment model.
... Significant association between tobacco use and depression have been reported by other studies also [9,10,11]. The underlying mechanisms that give rise to such an association are unclear; however, it has been proposed that this linkage may arise from the effects of nicotine on neurotransmitter activity in the brain, causing changes to neurotransmitter activity and leading to increased risk of depression [27,28]. The implication is that simultaneous counseling for tobacco deaddiction should be a part of the treatment for depression among smokers. ...
Background: Depression is the most common geriatric psychiatric disorder. Other than organic, socio-demographic factors, substance use and co-morbidities have been found to play an important role in mental health. Objectives 1.To estimate proportion of depression among elderly OPD attendees. 2.To find out association between certain socio-demographic factors, substance use and co-morbidities with depression. Materials and Methods: Patients aged 60 years and older attending the Urban health training center during the period February-April of 2013 were included in the study. Geriatric depression scale 15 (GDS 15) was used to assess depression through face to face interviews and GDS score >7 was used as cutoff value for depression. Results: Total 73 participants were included in the study. The proportion of depression was 16% (95% CI:7.7-25.1). Statistically significant association was found with education, tobacco use, alcohol consumption and hypertension. Tobacco use and alcohol consumption were found as predictors of depression. Conclusion: Screening for depression in elderly in primary care setting is feasible. Taking history regarding tobacco and alcohol use may give a clue regarding underlying depression in these patients in primary care settings.
... ECs and EC receptors anatomically and functionally interact with nAChRs in brain areas such as the midbrain, the hippocampus, and the amygdala [3][4][5]. ECs regulate cholinergic afferents on the ventral tegmental area (VTA) dopaminergic neuronal cells, and therefore play an important role in modulating reward stimuli and addiction. Indeed, through multiple interactions nAChR and EC receptors crosstalk in the CNS and induce neuroadaptations in response to diverse stimuli. ...
Compartmentalization, together with transbilayer and lateral asymmetries, provide the structural foundation for functional specializations at the cell surface, including the active role of the lipid microenvironment in the modulation of membrane-bound proteins. The chemical synapse, the site where neurotransmitter-coded signals are decoded by neurotransmitter receptors, adds another layer of complexity to the plasma membrane architectural intricacy, mainly due to the need to accommodate a sizeable number of molecules in a minute subcellular compartment with dimensions barely reaching the micrometer. In this review, we discuss how nature has developed suitable adjustments to accommodate different types of membrane-bound receptors and scaffolding proteins via membrane microdomains, and how this “effort-sharing” mechanism has evolved to optimize crosstalk, separation, or coupling, where/when appropriate. We focus on a fast ligand-gated neurotransmitter receptor, the nicotinic acetylcholine receptor, and a second-messenger G-protein coupled receptor, the cannabinoid receptor, as a paradigmatic example.
... Nicotinic acetylcholine receptors (nACh-Rs) in the brain, belonging to the superfamily of the neurotransmitter-gated ion channels, play a crucial neuromodulatory role in the central nervous system [185]. There are two families of central nACh-Rs: the heteromeric nACh-R and the homomeric nACh-Rs, assembled from a single subunit type, typically alpha7 (alpha7-nAChRs) [186]. ...
Cognitive impairments associated with schizophrenia (CIAS) represent a central element of the symptomatology of this severe mental disorder. CIAS substantially determine the disease prognosis and hardly, if at all, respond to treatment with currently available antipsychotics. Remarkably, all drugs presently approved for the treatment of schizophrenia are, to varying degrees, dopamine D2/D3 receptor blockers. In turn, rapidly growing evidence suggests the immense significance of systems other than the dopaminergic system in the genesis of CIAS. Accordingly, current efforts addressing the unmet needs of patients with schizophrenia are primarily based on interventions in other non-dopaminergic systems. In this review article, we provide a brief overview of the available evidence on the importance of specific systems in the development of CIAS. In addition, we describe the promising targets for the development of new drugs that have been used so far. In doing so, we present the most important candidates that have been investigated in the field of the specific systems in recent years and present a summary of the results available at the time of drafting this review (May 2022), as well as the currently ongoing studies.
... In this regard, the mechanisms that may lead to changes in complex human behavior are still unclear. However, it is known that nicotine develops modifications in the nervous system that may affect cognition and aspects of emotional behavior [51,52]. In this sense, it has been observed that people tend to increase their TC in periods of increased stress [53,54]. ...
Teachers have been reported as having high levels of emotional exhaustion (EE). It has also been observed that tobacco consumption (TC) is higher during stressful events. However, there is little evidence about the association between EE and TC among teachers. A total of n = 560 teachers took part in this study, where 71.79% (n = 402) were women. For data gathering, the EE dimension of the Maslach Inventory for teachers was used, along with a TC questionnaire and the sociodemographic data of the participants. A binary logistical regression model was used for statistical analysis. Regarding TC, over 30% of teachers declared that they smoked; 65% of the teachers presented medium-high EE and 31% of teachers presented high EE. Teachers who said they were smokers had a greater risk of presenting high EE (OR: 1.7, p < 0.05), along with younger teachers (≤44 years; OR: 2.1, p < 0.01). In addition, teachers with high EE also have a high risk of TC. The present study reports an association between TC and high EE category among teachers, regardless of gender. An important association is also observed between the under-45 age group and high EE. These results indicate that teachers should have psychological support and interventions aiding them with facing work stress and TC habits, especially for younger teachers.
... Results mRNA coding for beta2 nicotinic subunit is expressed by specific groups of striatal INs, with CINs showing the highest level of expression Although different subtypes of nAChRs are expressed by striatal neurons, the most common nicotinic subunit is likely the beta2 subunit coded by the Chrnb2 gene (Picciotto et al., 2000;Quik et al., 2009;Quik and Wonnacott, 2011;Eskow Jaunarajs et al., 2015). Therefore, to investigate the function of nAChRs in the mouse striatum, we decided to focus on this subunit. ...
Acetylcholine is an important modulator of striatal activity, and it is vital to controlling striatal-dependent behaviors, including motor and cognitive functions. Despite this significance, the mechanisms determining how acetylcholine impacts striatal signaling are still not fully understood. In particular, little is known about the role of nAChRs expressed by striatal interneurons. In the present study, we used FISH to determine which neuronal types express the most prevalent beta2 nicotinic subunit in the mouse striatum. Our data support a common view that nAChR expression is mostly restricted to striatal interneurons. Surprisingly though, cholinergic interneurons were identified as a population with the highest expression of beta2 nicotinic subunit. To investigate the functional significance of beta2-containing nAChRs in striatal interneurons, we deleted them by injecting the AAV-Cre vector into the striatum of beta2-flox/flox male mice. The deletion led to alterations in several behavioral domains, namely, to an increased anxiety-like behavior, decrease in sociability ratio, deficit in discrimination learning, and increased amphetamine-induced hyperlocomotion and c-Fos expression in mice with beta2 deletion. Further colocalization analysis showed that the increased c-Fos expression was present in both medium spiny neurons and presumed striatal interneurons. The present study concludes that, despite being relatively rare, beta2-containing nAChRs are primarily expressed in striatal neurons by cholinergic interneurons and play a significant role in behavior.
... In fact, changes in nAChR expression in transgenic animals have been found to impair memory function 36,37 . Nicotine mainly binds to Type 2 nAChRs, which are composed of β2/α4 subunits in most brain regions 38 . Additionally, α5 nAChRs were also found to be involved in nicotine-mediated behaviors specific to the development of nicotine dependence 39 . ...
Human and animal studies have conclusively shown that prenatal nicotine exposure alters fetal brain development and causes persistent impairment in the cognitive function of offspring. However, the mechanisms underlying the effect of prenatal nicotine exposure on cognitive function in offspring are still unclear. The objective of this review is to discuss the published studies on the mechanisms underlying the effects of prenatal nicotine exposure on cognitive impairment and discuss the potential mechanisms of action. The findings of the reviewed studies show that the main mechanisms involved are alteration in the composition of nicotinic acetylcholine receptor subunits, increase in surface expression of the glutamate receptor subunit GluR2, a reduction in neurogenesis, alteration of Akt and ERK1/2 activity, and mitochondrial dysfunction in the hippocampus and cortex. These pathways could shed light on future molecular markers and therapeutic targets for the prevention and treatment of cognitive dysfunction induced by prenatal nicotine exposure.
... 1 Those tobacco compounds interact with presynaptic nAchRs in the central nervous system leading to an increased release of several neurotransmitters such as dopamine and glutamate, which in turn can affect the retina and the optic nerve. [2][3][4] There are known associations between smoking and ophthalmological conditions such as cataracts, macular degeneration, ischemic or oxidative mechanisms, reduction in the thickness of the medial and lateral frontal cortex and decreased activity of the occipital cortex. 5,6 There is also evidence that long-term heavy smokers have lower contrast sensitivity and lower performance in color discrimination than healthy controls, suggesting that smoking and chronic exposure to its compounds affect visual processing. ...
Objectives:
The effects of smoking on color vision have been scarcely studied. To bridge such gap, this study examined if there were differences in chromatic discrimination between heavy and light smokers. Methods: The psychophysical Trivector test was used to evaluate chromatic discrimination in healthy controls (n = 36), heavy smokers (n = 29), and light smokers (n = 32). The subject's task was to identify the orientation of the Landolt C ring gap - presented and randomized in one of the four positions (e.g., up, down, right, and left). Results: The thresholds for Protan (red), Deutan (green) and Tritan (blue) were lower in heavy smokers compared to nonsmokers but not to light smokers. Conclusions: The results confirm that heavy smoking and chronic exposure to its harmful compounds affect color discrimination when compared to light smoking; and this is more pronounced in heavy smokers than light smokers. This is particularly important to understand the differences among smokers on visual and multisensory processing.
... The larger group, with pentameric nAChRs made up of α and β subunits, contains nonselective cation channels. The effects of binding ACh to cholinergic receptors can result in stimulation or inhibition of neuronal signaling, depending on the receptor subtype and its location on a pre-or postsynaptic membrane [84][85][86]. ...
Statins are among the most widely used drug classes in the world. Apart from their basic mechanism of action, which is lowering cholesterol levels, many pleiotropic effects have been described so far, such as anti-inflammatory and antiatherosclerotic effects. A growing number of scientific reports have proven that these drugs have a beneficial effect on the functioning of the nervous system. The first reports proving that lipid-lowering therapy can influence the development of neurological and psychiatric diseases appeared in the 1990s. Despite numerous studies about the mechanisms by which statins may affect the functioning of the central nervous system (CNS), there are still no clear data explaining this effect. Most studies have focused on the metabolic effects of this group of drugs, however authors have also described the pleiotropic effects of statins, pointing to their probable impact on the neurotransmitter system and neuroprotective effects. The aim of this paper was to review the literature describing the impacts of statins on dopamine, serotonin, acetylcholine, and glutamate neurotransmission, as well as their neuroprotective role. This paper focuses on the mechanisms by which statins affect neurotransmission, as well as on their impacts on neurological and psychiatric diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), vascular dementia (VD), stroke, and depression. The pleiotropic effects of statin usage could potentially open floodgates for research in these treatment domains, catching the attention of researchers and clinicians across the globe.
... Three main types of nAChRs are described on hippocampal neurons, namely α7, α4β2, and α3β4 [27,28]. In our experiments, antagonists of α7 and α4β2 nAChRs-MLA and DhβE ...
Cholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine receptors affects neuronal excitability, synaptic transmission and rhythmic oscillations in the hippocampus. In this work, we studied the ability of the cholinergic system to sustain hippocampal epileptiform activity independently from glutamate and GABA transmission. Simultaneous CA3 and CA1 field potential recordings were obtained during the perfusion of hippocampal slices with the aCSF containing AMPA, NMDA and GABA receptor antagonists. Under these conditions, spontaneous epileptiform discharges synchronous between CA3 and CA1 were recorded. Epileptiform discharges were blocked by addition of the calcium-channel blocker Cd ²⁺ and disappeared in CA1 after a surgical cut between CA3 and CA1. Cholinergic antagonist mecamylamine abolished CA3-CA1 synchronous epileptiform discharges, while antagonists of α7 and α4β2 nAChRs, MLA and DhβE, had no effect. Our results suggest that activation of nicotinic acetylcholine receptors can sustain CA3-CA1 synchronous epileptiform activity independently from AMPA, NMDA and GABA transmission. In addition, mecamylamine, but not α7 and α4β2 nAChRs antagonists, reduced bicuculline-induced seizure-like activity. The ability of mecamylamine to decrease hippocampal network synchronization might be associated with its therapeutic effects in a wide variety of CNS disorders including addiction, depression and anxiety.
... Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated cation channels, which are mainly expressed in the central and peripheral nervous systems diseases (Picciotto et al., 2000;Aharonson et al., 2020). Recently, it become evident that nAChRs are also extensively expressed on nonneuronal cells, such as lung epithelial, endothelial, and immune cells (Wessler et al., 1999;Conti-Fine et al., 2000;Brüggmann et al., 2002;Heeschen et al., 2002;Moccia et al., 2004). ...
Background: It has been confirmed that the α7-nicotinic acetylcholine receptor (α7nAChR) is an important target for identifying vulnerable atherosclerotic plaques. Previously, we successfully designed and synthesized a series of ¹⁸F-labeled PET molecular probes targeting α7nAChR, which are mainly used in the diagnosis of Alzheimer's disease. Based on the characteristics of α7nAChR in blood vessels, we have firstly screened for a suitable novel ¹⁸F-labeled PET molecular probe ([¹⁸F]YLF-DW), with high selectivity for α7nAChR over α4β2nAChR and a good effect for the imaging of atherosclerotic animal models, to effectively identify vulnerable atherosclerotic plaques at an early stage. Meanwhile, we compared it with the “gold standard” pathological examination of atherosclerosis, to verify the reliability of [¹⁸F]YLF-DW in early diagnosis of atherosclerosis.
Methods: The vulnerable atherosclerotic plaques model of ApoE-/-mice were successfully established. Then based on the methods of 3D-QSAR and molecular docking, we designed oxazolo[4,5-b] pyridines and fluorenone compounds, which are targeted at α7nAChR. Through further screening, a novel alpha7 nicotinic acetylcholine receptor radioligand ([¹⁸F]YLF-DW) was synthesized and automatically ¹⁸F-labeled using a Stynthra RNplus module. Subsequently, we employed [¹⁸F]YLF-DW for the targeting of α7nAChR in atherosclerotic plaques and control group, using a micro-PET/CT respectively. After imaging, the mice were sacrificed by air embolism and the carotid arteries taken out for making circular sections. The paraffin embedded specimens were sectioned with 5 μm thickness and stained with oil red. After staining, immunohistochemistry experiment was carried out to verify the effect of micro-PET/CT imaging.
Results: The micro-PET/CT imaging successfully identified the vulnerable atherosclerotic plaques in the carotid arteries of ApoE-/-mice; whereas, no signal was observed in normal control mice. In addition, compared with the traditional imaging agent [¹⁸F]FDG, [¹⁸F]YLF-DW had a significant effect on the early plaques imaging of carotid atherosclerosis. The results of oil red staining and immunohistochemistry also showed early formations of carotid plaques in ApoE-/-mice and provided pathological bases for the evaluation of imaging effect.
Conclusion: We innovated to apply the novel molecular probe ([¹⁸F]YLF-DW) to the identification of vulnerable atherosclerotic plaques in carotid arteries, to detect atherosclerosis early inflammatory response and provide powerful input for the early diagnosis of atherosclerotic lesions, which may play an early warning role in cardiovascular acute events.
... Außerdem wird die leistungssteigernde Wirkung von Nikotin über diese Rezeptoren vermittelt[106]. So haben der endogene Ligand ACh und der exogene Ligand Nikotin modulatorischen Einfluss auf zahlreiche Transmittersysteme[111]. Zu diesen gehört die Veränderung der Dopamin-Ausschüttung im meso-kortiko-limbischen System, welche durch glutamaterge und GABAerge (γ-aminobutyric acid, γ-Aminobuttersäure) Interneurone vermittelt wird[4,165]. ...
Das Ziel dieser Versuchsreihe war es den Wirkstoff ST178 im Tiermodell auf antipsychotische Eigenschaften zu untersuchen. Zum Nachweis der antipsychotischen Wirksamkeit von ST178 in-vivo wurde ein Tiermodell der Schizophrenie verwendet, welches auf der Amphetamin-Sensibilisierung von Ratten basiert. Im Anschluss verwendeten wir die Paradigmen „Amphetamin-induzierte Hyperlokomotion“, „Präpuls-Inhibition“ und „Licht-induzierte Aktivität“ um die antipsychotische Wirksamkeit von ST178 zu bewerten. Unsere Ergebnisse bezüglich der Reduktion der Amphetamin-induzierten Hyperlokomotion und der Remission der Präpuls-Inhibition durch ST178 wiesen eindeutig auf die antipsychotische Wirksamkeit von ST178 mit eindeutiger Dosis-Wirkungs-Beziehung hin und bestätigten damit die Erwartungen aus in-vitro-Testungen. The aim of these experiments was to test ST178 for antipsychotic effects in an animal model for schizophrenia. To test ST178 for antipsychotic efficacy in-vivo, an animal model of schizophrenia which was based on the sensitization of rats to amphetamine was used. The reduction of amphetamine-induced hyperlocomotion and the remission of prepulse inhibition by ST178 clearly indicated antipsychotic efficacy with an apparent dose-response relation, confirming expectations from in-vitro testing.
... The half-life of nicotine is approximately 20 min to 2 h, but the half-life of cotinine is 20 h. Moreover, cotinine lodges in the body longer than nicotine [10] before being excreted through the kidneys; notably, 10% of nicotine is excreted in urea without being metabolized [11]. ...
We reported the first comprehensive autopsy case of death due to intravenous injection of nicotine. We examined the distribution of nicotine in the body tissues and fluid and exposed the pathophysiology of nicotine poisoning. A 19-year-old woman was rushed to the hospital in cardiorespiratory arrest and was confirmed dead upon arrival. Liquid nicotine, hydrogen peroxide water, and a syringe were found in the hotel room where she stayed. On autopsy, nicotine concentration was the highest (15,023 μg/mg) in the tissue around the injection mark on the right upper arm. Among the body fluids, the intraperitoneal fluid had the highest, whereas the pericardial fluid had the lowest (0.736 μg/mL) nicotine concentration. Among the organs, the brain had the highest (11.637 μg/mg), whereas the fat tissue had the lowest (1.307 μg/mg) nicotine concentration. The concentration of cotinine, which is the metabolite of nicotine, was the highest in the tissue around the injection mark on the right arm (5.495 μg/mg) and was almost the same among the other body fluids and organs. The respective concentrations of nicotine and cotinine were 1.529 μg/mL and 0.019 μg/mL in the left heart blood and 3.157 μg/mL and 0.002 μg/mL in right heart blood. In this case, the nicotine concentrations in blood reached the lethal level. The distributions of nicotine and cotinine, as indicated by the intravenous injection, were related to the distribution of organs that metabolize nicotine and the distribution of nicotinic acetylcholine receptors.
... A higher rate of depression was found in the smokers (23.7%) in a study conducted in Austria 21 . The underlying mechanisms proposed that this linkage may arise from the effects of nicotine on the neurotransmitter activity in the brain, causing changes in the neurotransmitter activity, which leads to an increased risk of depression 22 . The high BMI, no formal education and a family history of psychiatric illness were found to be significantly associated with anxiety among the obese patients with chronic medical illnesses. ...
Introduction: Concomitant obesity and chronic medical illness is a significant health problem in Malaysia and worldwide. The comorbid psychological impact in obese patients is associated with a social stigma and low self-esteem. The aim of this study was to determine the prevalence and the factors associated with depression, anxiety and stress in obese patients with chronic medical illnesses attending an outpatient clinic. Methods: This was a cross-sectional study among obese patients with chronic medical illnesses presenting at the Universiti Sains Malaysia Hospital outpatient clinic. A total of 274 patients were involved. The 21-item Depression, Anxiety and Stress Scale questionnaire was used, and the results were evaluated using single and multiple logistic regression analyses. Results: The prevalences of depression, anxiety and stress among the obese patients with chronic medical illnesses were 13.9%, 23.4% and 10.9%, respectively. Younger age [p=0.003, adjusted odds ratio (AOR),1.0; 95%confidence interval (CI),0.91–0.98], unemployed employment(p=0.013, AOR,3.7;95% CI,1.32–10.09) and smoking (p=0.022, AOR,3.2; 95% CI,1.18–8.55) were associated with depression. No formal education (p=0.011, AOR,5.7; 95%CI,1.49–21.89), high body mass index (p=0.029, AOR,1.1;95% CI,1.01–1.13) and family history of psychiatric illness (p=0.018, AOR,5.1; 95% CI,1.33–19.56) were associated with anxiety. Stress was strongly associated with females (p=0.004, AOR,5.0; 95% CI,1.70–15.13) and smoking(p=0.002, AOR,6.5; 95% CI,2.03–20.7). Conclusion: Interestingly, younger age group was associated with depression. Current smokers, no education, family history of psychiatric illness and female sex were significantly associated with anxiety and stress. This notifies new emerging knowledge on factors associated with obese patients that would empower the development of effective preventive strategies for it.
... Biochemical alterations in the hippocampus could result in cognitive deficit-like behavior in the animals. Moreover, α7 nAChRs are highly expressed in the hippocampus and prefrontal cortex [39,87]. These receptors play a critical role in reducing inflammation [42]. ...
Neuroinflammation is often associated with the development of major depressive disorder (MDD)-related symptoms. Previous studies have indicated that activation of glial cells, upregulation of proinflammatory cytokines and dysregulation of adrenergic system in the central nervous system (CNS) could be the key mediators to modulate depression-related behaviors after peripheral immune activation. Central α7 nicotinic acetylcholine receptor (α7 nAChR) has a role in the regulation of the cholinergic anti-inflammatory pathway. The present study determined the effects of PNU120596, α7 nAChR positive allosteric modulator (PAM), on lipopolysaccharide (LPS)-induced anxiety, cognitive deficit, and depression-like behaviors in mice. These behaviors were evaluated 24 h after LPS (1 mg/kg) administration using elevated plus-maze, Y-maze, and forced swim test, respectively. The effects of PNU120596 on mRNA of neuroinflammatory markers and norepinephrine (NE) level in behaviorally-relevant brain regions such as the hippocampus and prefrontal cortex were examined. PNU120596 administration (1 or 4 mg/kg) showed anxiolytic, pro-cognitive, and antidepressant-like effects by preventing LPS-induced behavioral abnormalities. Following LPS treatment, PNU120596 hindered activation markers of the microglia and astrocytes (cluster of differentiation molecule 11b and glial fibrillary acidic protein) and upregulation of proinflammatory cytokines such as interleukin 1 beta and tumor necrosis factor-alpha in the hippocampus and prefrontal cortex. NE level that was reduced by peripheral LPS challenge was normalized by PNU120596 effects in both brain regions. Overall, the results in this study indicate that activation of α7 nAChR by PAM effectively prevents LPS-induced anxiety, cognitive deficit, and depression-like behaviors and regulates relevant neuroinflammatory markers in the hippocampus and prefrontal cortex.
Neuroinflammation contributes to the pathophysiology of major depressive disorder (MDD) by inducing neuronal excitability via dysregulation of microglial brain-derived neurotrophic factor (BDNF), Na-K-Cl cotransporter-1 (NKCC1), and K-Cl cotransporter-2 (KCC2) due to activation of BDNF-tropomyosin receptor kinase B (TrkB) signaling. Allosteric modulation of α7 nAChRs has not been investigated on BDNF, KCC2, and NKCC1 during LPS-induced depressive-like behavior. Therefore, we examined the effects of PNU120596, an α7 nAChR positive allosteric modulator, on the expression of BDNF, KCC2, and NKCC1 in the hippocampus and prefrontal cortex using Western blot analysis, immunofluorescence assay, and real-time polymerase chain reaction. The effects of ANA12, a TrkB receptor antagonist, on LPS-induced cognitive deficit and depressive-like behaviors were determined using the Y-maze, tail suspension test (TST), and forced swim test (FST). Pharmacological interactions between PNU120596 and ANA12 were also examined. Experiments were conducted in male C57BL/6J mice. LPS administration (1 mg/kg) resulted in increased expression of BDNF and the NKCC1/KCC2 ratio and decreased expression of KCC2 in the hippocampus and prefrontal cortex. PNU120596 pretreatment (4 mg/kg) attenuated the LPS-induced increase in the expression of BDNF and NKCC1/KCC2 ratio and the reduction in KCC2 expression in these brain regions. In addition, ANA12 (0.25 or 0.50 mg/kg) reduced the LPS-induced cognitive deficit and depressive-like behaviors measured by a reduced spontaneous alternation in the Y-maze and increased immobility duration in TST and FST. Coadministration of PNU120596 (1 mg/kg) and ANA12 (0.25 mg/kg) prevented the LPS-induced cognitive deficit and depressive-like behaviors. Overall, PNU120596 prevented the LPS-induced depressive-like behavior by likely decreasing neuronal excitability via targeting microglial α7 nAChR in the hippocampus and prefrontal cortex.
Clinical and preclinical studies have identified immunosuppressive effects of nicotine, with potential implications for treating nicotine addiction. Here we review how nicotine can regulate microglia, the resident macrophages in the brain, and corresponding effects of nicotine on neuroimmune signaling. There is significant evidence that activation of α7 nicotinic acetylcholine receptors (nAChRs) on microglia can trigger an anti-inflammatory cascade that alters microglial polarization and activity, cytokine release, and intracellular calcium concentrations, leading to neuroprotection. These anti-inflammatory effects of nicotine-dependent α7 nAChR signaling are lost during withdrawal, suggesting that neuroimmune signaling is potentiated during abstinence, and thus, heightened microglial activity may drive circuit disruption that contributes to withdrawal symptoms and hyperkatifeia. In sum, the clinical literature has highlighted immunomodulatory effects of nicotine and the potential for anti-inflammatory compounds to treat addiction. The preclinical literature investigating the underlying mechanisms points to a role of microglial engagement in the circuit dysregulation and behavioral changes that occur during nicotine addiction and withdrawal, driven, at least in part, by activation of α7 nAChRs on microglia. Specifically targeting microglial signaling may help alleviate withdrawal symptoms in people with nicotine dependence and help to promote abstinence.
People with severe mental disorders have a higher mortality rate due to preventable conditions like cardiovascular diseases and respiratory diseases. Nicotine addiction is a preventable risk factor, with tobacco use being twice as high in people with mental disorders. An integrative model that divides mental disorders into externalising, internalising, and thought disorders could be useful for identifying common causalities and risk factors. This review aims to examine the interface between smoking and internalising disorders, specifically schizophrenia, depressive disorders, and anxiety disorders. The review finds that there is a clear association between smoking behaviour and these disorders. Schizophrenia is associated with polymorphisms that result in an imbalance between glutamate and GABA release and abnormalities of dopaminergic pathways. Nicotine improves dopaminergic signalling and balances glutamatergic and GABAergic pathways, improving symptoms and increasing the risk of nicotine dependence. In depressive disorders, smoking is associated with functional changes in brain regions affected by smoking and self-medication. In anxiety disorders, there is a bidirectional relationship with smoking, involving the amygdala and changes in dopaminergic pathways and cortisol production. Smoking poses a threat to people living with psychiatric disorders and calls for further research to assess the interactions between nicotine dependence and internalising and thought disorders.
The second volume of Behavioral Genetics of the Mouse provides a comprehensive overview of the major genetically modified mouse lines used to model human neurobehavioral disorders; from disorders of perception, of autonomous and motor functions to social and cognitive syndromes, drug abuse and dependence as well as neurodegenerative pathologies. Mouse models obtained with different types of genetic manipulations (i.e. transgenic, knockout/in mice) are described in their pathological phenotypes, with a special emphasis on behavioral abnormalities. The major results obtained with many of the existing models are discussed in depth highlighting their strengths and limitations. A lasting reference, the thorough reviews offer an easy entrance into the extensive literature in this field, and will prove invaluable to students and specialists alike.
Background:
Dysfunction of cholinergic neurotransmission is a hallmark of Alzheimer's disease (AD); forming the basis for using acetylcholine (ACh) esterase (AChE) inhibitors to mitigate symptoms of ACh deficiency in AD. The Cholinergic Receptor Muscarinic 1 (CHRM1) is highly expressed in brain regions impaired by AD. Previous analyses of postmortem AD brains revealed unaltered CHRM1 mRNA expression compared to normal brains. However, the CHRM1 protein level in AD and other forms of dementia has not been extensively studied. Reduced expression of CHRM1 in AD patients may explain the limited clinical efficacy of AChE inhibitors.
Objective:
To quantify CHRM1 protein in the postmortem hippocampus and temporal cortex of AD, Parkinson's disease (PD), and frontotemporal dementia (FTD) patients.
Methods:
Western blotting was performed on postmortem hippocampus (N = 19/73/7/9: unaffected/AD/FTD/PD) and temporal cortex (N = 9/74/27: unaffected/AD/PD) using a validated anti-CHRM1 antibody.
Results:
Quantification based on immunoblotting using a validated anti-CHRM1 antibody revealed a significant loss of CHRM1 protein level (<50%) in the hippocampi (78% AD, 66% PD, and 85% FTD) and temporal cortices (56% AD and 42% PD) of dementia patients. Loss of CHRM1 in the temporal cortex was significantly associated with early death (<65-75 years) for both AD and PD patients.
Conclusion:
Severe reduction of CHRM1 in a subset of AD and PD patients can explain the reported low efficacy of AChE inhibitors as a mitigating treatment for dementia patients. Based on this study, it can be suggested that future research should prioritize therapeutic restoration of CHRM1 protein levels in cholinergic neurons.
Obesity is a prevalent disease, but effective treatments remain limited. Agonists of the alpha-7 nicotinic acetylcholine receptor (α7nAChR) promote negative energy balance in mice, but these effects are not well-studied in rats. We tested the hypothesis that the α7nAChR agonist GTS-21 would decrease food intake and body weight in adult male Sprague Dawley rats. Contrary to our hypothesis, acute systemic administration of GTS-21 produced no significant effects on chow or high-fat diet (HFD) intake. Acute intracerebroventricular (ICV) GTS-21 also had no impact on chow intake, and actually increased body weight at the highest dose tested. Previous studies suggest that GTS-21 engages the food intake-suppressive glucagon-like peptide-1 (GLP-1) system in mice. As there are known species differences in GLP-1 physiology between mice and rats, we tested the ability of GTS-21 to elicit GLP-1 secretion in rats. Our results showed that plasma levels of total GLP-1 in rats were not significantly altered by peripheral GTS-21 injection. These results represent an advance in understanding how α7nAChR activation impacts energy balance control in rodents and suggest that there may be important differences between rats and mice in the ability of GTS-21/α7nAChR activation to increase secretion of GLP-1.
Psychotic episodes are debilitating disease states that can cause extreme distress and impair functioning. There are sex differences that drive the onset of these episodes. One difference is that, in addition to a risk period in adolescence and early adulthood, women approaching the menopause transition experience a second period of risk for new-onset psychosis. One leading hypothesis explaining this menopause-associated psychosis (MAP) is that estrogen decline in menopause removes a protective factor against processes that contribute to psychotic symptoms. However, the neural mechanisms connecting estrogen decline to these symptoms are still not well understood. Using the tools of computational psychiatry, links have been proposed between symptom presentation and potential algorithmic and biological correlates. These models connect changes in signaling with symptom formation by evaluating changes in information processing that are not easily observable (latent states). In this manuscript, we contextualize the observed effects of estrogen (decline) on neural pathways implicated in psychosis. We then propose how estrogen could drive changes in latent states giving rise to cognitive and psychotic symptoms associated with psychosis. Using computational frameworks to inform research in MAP may provide a systematic method for identifying patient-specific pathways driving symptoms and simultaneously refine models describing the pathogenesis of psychosis across all age groups.
Background
A recent study has identified the role of CHRNA5-A3-B4 gene cluster variants rs16969968 and rs578776 of nicotinic acetylcholine receptors (nAChRs) on smoking status in Bengali ethnicity. The aim of the current study was to investigate whether these rs16969968-rs578776-rs11072768 single nucleotide polymorphisms (SNPs) of CHRNA5-A3-B4 gene cluster were associated with nicotine dependence (ND) and related phenotypes.
Methods
The Fagerstrom Test for Nicotine Dependence (FTND) and Cigarette Dependence Scale (CDS-12) were used to assess the degree of ND, and genotyping was done using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method on a cohort of 129 male smokers participating in a structured questionnaire-based survey.
Results
Smokers with AA genotype of CHRNA5 rs16969968 SNP were at significantly increased risk of developing ND compared to its wild type variant with odds ratio (ORs) of 1.20 (FTND: 95% CI 0.25-5.37, p= 0.253) and 2.48 (CDS-12: 95% CI 0.46-13.26, p= 0.081), respectively. Conversely, smokers with AA genotype of CHRNA3 rs578776 variant had a strong protective effect against ND development (ORs= 0.27, 95% CI 0.09-0.80, p=0.076). There was no such link reported in CHRNB4 rs11072768 variant carriers. Similarly, G-A/G-A diplotype of rs16969968_rs578776 variants was discovered to be a protective factor against ND. Moreover, demographic features such as age, occupation and dwelling status were found to be significantly associated with ND.
Conclusion
Taken together, CHRNA5-A3-B4 gene cluster variants rs16969968 and rs578776 as well as specific demographic characteristics regulate ND and related smoking phenotypes in Bangladeshi male smokers. Further studies with large sample sizes are required to substantially validate the significance.
Nicotine is the chief ingredient of tobacco, which leads to dependence. Delirium shares some features with symptoms of nicotine withdrawal, including confusion, agitation, impairments in attention, and working memory. Various case reports have described complete resolution of delirium after nicotine replacement therapy, leading to interest in nicotine withdrawal delirium as an independent entity. Clinical trials have found smoking to be independently linked to delirium in ICU settings, where smoking cessation precipitates nicotine withdrawal. Although systematic reviews and trials of nicotine replacement therapy in delirium have been inconclusive, biological plausibility of nicotine withdrawal delirium exists. Nicotine withdrawal can lead to delirium by affecting various neurotransmitters, especially acetylcholine. Neurodegeneration caused by inflammatory cytokines and activation of corticotropin-releasing factor in nicotine withdrawal can also lead to delirium. Methodological issues in studying nicotine withdrawal delirium need to be addressed, and evidence-based protocols for nicotine replacement therapy in delirium management need to be established.
Electronic cigarettes or e-cigarettes are the most frequently used tobacco product among adolescents. Despite the widespread use of e-cigarettes and the known detrimental cardiac consequences of nicotine, the effects of e-cigarettes on the cardiovascular system are not well-known. Several in vitro and in vivo studies delineating the mechanisms of the impact of e-cigarettes on the cardiovascular system have been published. These include mechanisms associated with nicotine or other components of the aerosol or thermal degradation products of e-cigarettes. The increased hyperlipidemia, sympathetic dominance, endothelial dysfunction, DNA damage, and macrophage activation are prominent effects of e-cigarettes. Additionally, oxidative stress and inflammation are unifying mechanisms at many levels of the cardiovascular impairment induced by e-cigarette exposure. This review outlines the contribution of e-cigarettes in the development of cardiovascular diseases and their molecular underpinnings.
Cocaine use disorder (CUD) is a significant public health issue that generates substantial personal, familial, and economic burdens. Still, there are no FDA-approved pharmacotherapies for CUD. Cocaine-dependent individuals report anxiety during withdrawal, and alleviation of anxiety and other negative affective states may be critical for maintaining drug abstinence. However, the neurobiological mechanisms underlying abstinence-related anxiety in humans or anxiety-like behavior in rodents are not fully understood. This review summarizes investigations regarding anxiety-like behavior in mice and rats undergoing cocaine abstinence, as assessed using four of the most common anxiety-related assays: the elevated plus (or its derivative, the elevated zero) maze, open field test, light-dark transition test, and defensive burying task. We first summarize available evidence that cocaine abstinence generates anxiety-like behavior that persists throughout protracted abstinence. Then, we examine investigations concerning neuropeptide, neurotransmitter, and neuromodulator systems in cocaine abstinence-induced anxiety-like behavior. Throughout, we discuss how differences in sex, rodent strain, cocaine dose and dosing strategy, and abstinence duration interact to generate anxiety-like behavior.
Nicotinic acetylcholine receptors are receptors for the neurotransmitter acetylcholine in which binding of acetylcholine triggers the opening of a transmembrane channel through the centre of the receptor protein. Nicotinic receptors are part of a gene superfamily of transmitter gated ion channels that includes receptors for glycine and gamma amino butyric acid. Nicotinic receptors are distinct from muscarinic acetylcholine receptors, which are part of a gene superfamily of metabotropic G‐protein linked receptors.
The accumulation of amyloid-beta peptide (Aβ) and the failure of cholinergic transmission are key players in Alzheimer’s disease (AD). However, in the healthy brain, Aβ contributes to synaptic plasticity and memory acting through α7 subtype nicotinic acetylcholine receptors (α7nAChRs). Here, we hypothesized that the α7nAChR deletion blocks Aβ physiological function and promotes a compensatory increase in Aβ levels that, in turn, triggers an AD-like pathology.
To validate this hypothesis, we studied the age-dependent phenotype of α7 knock out mice. We found that α7nAChR deletion caused an impairment of hippocampal synaptic plasticity and memory at 12 months of age, paralleled by an increase of Amyloid Precursor Protein expression and Aβ levels. This was accompanied by other classical AD features such as a hyperphosphorylation of tau at residues Ser 199, Ser 396, Thr 205, a decrease of GSK-3β at Ser 9, the presence of paired helical filaments and neurofibrillary tangles, neuronal loss and an increase of GFAP-positive astrocytes.
Our findings suggest that α7nAChR malfunction might precede Aβ and tau pathology, offering a different perspective to interpret the failure of anti-Aβ therapies against AD and to find novel therapeutical approaches aimed at restoring α7nAChRs-mediated Aβ function at the synapse.
Background
Though anatoxin-a (antx-a) is a globally important cyanobacterial neurotoxin in inland waters, information on sublethal toxicological responses of aquatic organisms is limited. We examined influences of (±) antx-a (11–3490 µg/L) on photolocomotor behavioral responses and gene transcription associated with neurotoxicity, oxidative stress and hepatotoxicity, in two of the most common alternative vertebrate and fish models, Danio rerio (zebrafish) and Pimephales promelas (fathead minnow). We selected environmentally relevant treatment levels from probabilistic exposure distributions, employed standardized experimental designs, and analytically verified treatment levels using isotope-dilution liquid chromatography tandem mass spectrometry. Caffeine was examined as a positive control.
Results
Caffeine influences on fish behavior responses were similar to previous studies. Following exposure to (±) antx-a, no significant photolocomotor effects were observed during light and dark transitions for either species. Though zebrafish behavioral responses profiles were not significantly affected by (±) antx-a at the environmentally relevant treatment levels examined, fathead minnow stimulatory behavior was significantly reduced in the 145–1960 µg/L treatment levels. In addition, no significant changes in transcription of target genes were observed in zebrafish; however, elavl3 and sod1 were upregulated and gst and cyp3a126 were significantly downregulated in fathead minnows.
Conclusion
We observed differential influences of (±) antx-a on swimming behavior and gene transcription in two of the most common larval fish models employed for prospective and retrospective assessment of environmental contaminants and water quality conditions. Sublethal responses of fathead minnows were consistently more sensitive than zebrafish to this neurotoxin at the environmentally relevant concentrations examined. Future studies are needed to understand such interspecies differences, the enantioselective toxicity of this compound, molecular initiation events within adverse outcome pathways, and subsequent individual and population risks for this emerging water quality threat.
Mecamylamine is a nonselective antagonist of nicotinic acetylcholine receptors that was developed as an antihypertensive medication and is now being studied for its beneficial effects in several pathological conditions, such as substance abuse, depression, anxiety and epilepsy. In this work, we investigate the effect of mecamylamine on the manifestations of seizure-like activity evoked by perfusion of hippocampal slices with low-Mg2+ solution of artificial cerebrospinal fluid. Reducing Mg2+ concentration in extracellular solution induced two distinct types of epileptiform activity: recurring seizure-like activity and continuous discharges. Application of mecamylamine significantly increased internal frequency of recurring seizurelike activity and significantly decreased inter-event intervals between continuous discharges. We also show that mecamylamine significantly decreased internal frequency of continuous epileptiform discharges. The results of our work show that mecamylamine exerts modulatory effect on the low-Mg2+ epileptiform activity induced in hippocampal acute rat brain slices. Additionally, obtained results indicate the role of nicotinic acetylcholine receptors in the modulation of hippocampal network activity, which might explain some of the therapeutic effects of mecamylamine in CNS.
Accounts in Drug Discovery describes recent case studies in medicinal chemistry with a particular emphasis on how the inevitable problems that arise during any project can be surmounted or overcome. The Editors cover a wide range of therapeutic areas and medicinal chemistry strategies, including lead optimization starting from high throughput screening "hits" as well as rational, structure-based design. The chapters include "follow-ons" and "next generation" compounds that aim to improve upon first generation agents. This volume surveys the range of challenges commonly faced by medicinal chemistry researchers, including the optimization of metabolism and pharmacokinetics, toxicology, pharmaceutics and pharmacology, including proof of concept in the clinic for novel biological targets. The case studies include medicinal chemistry stories on recently approved and marketed drugs, but also chronicle "near-misses", i.e., exemplary compounds that may have proceeded well into the clinic but for various reasons did not result in a successful registration. As the vast majority of projects fail prior to registration, much can be learned from such narratives. By sharing a wide range of drug discovery experiences and information across the community of medicinal chemists in both industry and academia, we believe that these accounts will provide insights into the art of medicinal chemistry as it is currently practiced and will help to serve the needs of active medicinal chemists.
The discovery and development of effective medicines for the treatment of psychiatric disorders such as schizophrenia and depression has been heralded as one of the great medical achievements of the past century. Indeed, the profound impact of these medicines on our understanding of the pathophysiology underlying these diseases, the treatment of psychiatric patients and even our social perception of mental illnesses cannot be underestimated. However, there is still an urgent medical need for even more effective, safe and well-tolerated treatments. For example, currently available treatments for schizophrenia address mainly the positive symptoms and largely neglect the negative symptoms and cognitive disfunction which greatly impact overall morbidity. Similarly, whilst the current first line antidepressants show significantly improved side effect profiles compared to the first generation therapies, there still up to 40% of patients who are treatment resistant, and even in the patient population which responds well, the onset of action is slow at typically 2-3 weeks. The aim of this book is to provide the first point of call for those involved or just interested in this rapidly expanding and increasingly fragmented field of research and drug discovery. The editors will combine their wide ranging experience and extensive network of contacts with leading scientists and opinion leaders in this field to provide an authoritative reference text covering the evolution, major advances, challenges and future directions in drug discovery and medicinal chemistry for major psychiatric disorders.
Cholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine receptors affects neuronal excitability, synaptic transmission and rhythmic oscillations in the hippocampus. In this work, we study the ability of the cholinergic system to sustain hippocampal epileptiform activity independently from glutamate and GABA transmission. Simultaneous CA3 and CA1 field potential recordings were obtained during the perfusion of hippocampal slices with the aCSF containing AMPA, NMDA and GABA receptor antagonists. Under these conditions, recurrent field discharges synchronous between CA3 and CA1 were recorded. Field discharges were blocked by addition of calcium-channel blocker Cd ²⁺ and disappeared in CA1 after a surgical cut between CA3 and CA1. Cholinergic antagonist mecamylamine abolished CA3-CA1 synchronous field discharges, while antagonists of α7 and α4β2 nAChRs – MLA and DhβE had no effect. Our results suggest that activation of nicotinic acetylcholine receptors is able to sustain CA3-CA1 synchronous epileptiform activity independently from AMPA NMDA and GABA transmission. In addition, mecamylamine but not α7 and α4β2 nAChRs antagonists reduce bicuculline-induced seizure-like activity. The ability of mecamylamine to decrease hippocampal network synchronization might be associated with its therapeutic effects in a wide variety of CNS disorders including addiction, depression and anxiety.
Background:
Preliminary studies have tested nicotine as a novel treatment for OCD patients who respond partially/incompletely or not at all to first and second-line treatment strategies, with the former represented by SSRIs or clomipramine, and the latter by switching to another SSRI, or augmentation with atypical antipsychotics, and/or combination with/switching to cognitive-behavioural therapy. Some studies found nicotine-induced reduction of obsessive thoughts and/or compulsive behaviour in OCD patients. We aimed to evaluate the efficacy of nicotine administration in OCD patients.
Methods:
We searched the PubMed, ScienceDirect Scopus, CINHAL, Cochrane, PsycINFO/PsycARTICLES, and EMBASE databases from inception to the present for relevant papers. The 'Preferred Reporting Items for Systematic Review and Meta-Analyses' (PRISMA) standards were used. We included all studies focusing on the effects of nicotine administration on OCD patients' obsessions or compulsions. Studies could be open-label, cross-sectional, randomized controlled trials, case series or case reports.
Results:
A total of five studies could be included. Nicotine administration may ameliorate behavioural features and recurrent thoughts of severe, treatment-resistant OCD patients; however, in one study it was not associated with OC symptom improvement or cognitive enhancement across various executive function subdomains.
Conclusions:
Although encouraging, the initial positive response from the use of nicotine in OCD needs testing in large controlled studies. This, however, raises ethical issues related to nicotine administration, due to its addiction potential, which were not addressed in the limited literature we examined. As an alternative, novel treatments with drugs able to mimic only the positive effects of nicotine could be implemented.
Nicotine, the primary psychoactive component in tobacco, plays a major role in the initiation and maintenance of tobacco dependence and addiction, a leading cause of preventable death worldwide. An essential need thus exists for more effective pharmacotherapies for nicotine-use cessation. Previous reports suggest that pharmacological and genetic blockade of CB1 receptors attenuate nicotine reinforcement and reward; while exogenous agonists enhanced these abuse-related behaviors. In this study, we utilized complementary genetic and pharmacologic approaches to test the hypothesis that increasing the levels of the endocannabinoid 2-arachindonoylglycerol (2-AG), will enhance nicotine reward by stimulating neuronal CB1 receptors. Contrary to our hypothesis, we found that inhibition of monoacylglycerol lipase (MAGL), the primary catabolic enzyme of 2-AG, attenuates nicotine conditioned place preference (CPP) in mice, through a non-CB1 receptor-mediated mechanism. MAGL inhibition did not alter palatable food reward or Lithium Chloride (LiCl) aversion. In support of our findings, repeated MAGL inhibition did not induce a reduction in CB1 brain receptor levels or hinder function. To explore the potential mechanism of action, we investigated if MAGL inhibition affected other fatty acid levels in our CPP paradigm. Indeed, MAGL inhibition caused a concomitant decrease in arachidonic acid (AA) levels in various brain regions of interest, suggesting an AA cascade-dependent mechanism. This idea is supported by dose-dependent attenuation of nicotine preference by the selective COX-2 inhibitors valdecoxib and LM-4131. Collectively, these findings, along with our reported studies on nicotine withdrawal, suggest that inhibition of MAGL represents a promising new target for the development of pharmacotherapies to treat nicotine dependence.
New findings on neural regulation of immunity are allowing the design of novel pharmacological strategies to control inflammation and nociception. Herein, we report that choline, a 7-nicotinic acetylcholine receptor (α7nAChRs) agonist, prevents carrageenan-induced hyperalgesia without affecting inflammatory parameters (neutrophil migration or cytokine/chemokines production) or inducing sedation or even motor impairment. Choline also attenuate prostaglandin-E2 (PGE2)-induced hyperalgesia via α7nAChR activation and this antinociceptive effect was abrogated by administration of LNMMA (a nitric oxide synthase inhibitor), ODQ (an inhibitor of soluble guanylate cyclase; cGMP), and glibenclamide (an inhibitor of ATP-sensitive potassium channels). Furthermore, choline attenuates long-lasting Complete Freund’s Adjuvant and incision-induced hyperalgesia suggesting its therapeutic potential to attenuate pain in rheumatoid arthritis or post-operative recovery, respectively. Our results suggest that choline modulates inflammatory hyperalgesia by activating the nitric oxide/cGMP/ATP sensitive K(+) channels without interfering in inflammatory events, and could be used in persistent pain conditions.
Failure of anti-amyloid-beta peptide (Aβ) therapies against Alzheimer's disease (AD), a neurodegenerative disorder characterized by high amounts of the peptide in the brain, raised the question of the physiological role of Aβ released at low concentrations in the healthy brain.To address this question, here we studied the pre- and post-synaptic mechanisms underlying the neuromodulatory action of picomolar amounts of oligomeric Aβ42 (oAβ42) on synaptic glutamatergic function in male and female mice.We found that pM oAβ42 induces an increase of frequency of miniature excitatory postsynaptic currents and a decrease of paired pulse facilitation, associated with an increase in docked vesicle number, indicating that it augments neurotransmitter release at presynaptic level. oAβ42 also produced postsynaptic changes as shown by an increased length of postsynaptic density, accompanied by an increased expression of plasticity-related proteins such as cAMP-responsive element binding protein phosphorylated at Ser133, calcium-calmodulin-dependent kinase II phosphorylated at Thr286, and brain-derived neurotrophic factor, suggesting a role for Aβ in synaptic tagging. These changes resulted in the conversion of early into late long-term potentiation through the nitric oxide/cGMP/protein kinase G intracellular cascade consistent with a cGMP-dependent switch from short to long-term memory observed in vivo after intrahippocampal administration of picomolar amounts of oAβ42 These effects were present upon extracellular but not intracellular application of the peptide, and involved α7 nicotinic acetylcholine receptors.These observations clarified the physiological role of oAβ42 in synaptic function and memory formation providing solid fundamentals for investigating the pathological effects of high Aβ levels in the AD brains.
The data suggest genetic factors play an important role in regulating vulnerability to becoming a smoker, but only limited progress has been made in humans in terms of identifying genes critical in regulating nicotine dependence. However, some progress has been made in understanding the regulation of responses to nicotine in the mouse. This chapter will outline strategies that have been, or could be, used to identify genes that regulate behaviors. Specific examples of how these strategies have been used to gain an understanding of genetic influences on nicotine-related behaviors will be provided.
Purpose of review: To provide an overview of the underlying neurobiology of tobacco smoking in schizophrenia, and implications for treatment of this comorbidity.
Recent findings: Explanations for heavy tobacco smoking in schizophrenia include pro-cognitive effects of nicotine, and remediation of the underlying pathophysiology of schizophrenia. Nicotine may ameliorate neurochemical deficits through nicotine acetylcholine receptors (nAChRs) located on the dopamine, glutamate, and GABA neurons. Neurophysiological indices including electroencephalography, electromyography, and smooth pursuit eye movement (SPEM) paradigms may be biomarkers for underlying neuronal imbalances that contribute to the specific risk of tobacco smoking initiation, maintenance, and difficulty quitting within schizophrenia. Moreover, several social factors including socioeconomic factors and permissive smoking culture in mental health facilities, may contribute to the smoking behaviors (initiation, maintenance, and inability to quit smoking) within this disorder.
Summary: Tobacco smoking may alleviate specific symptoms associated with schizophrenia. Understanding the neurobiological underpinnings and psychosocial determinants of this comorbidity may better explain these potential beneficial effects, while also providing important insights into effective treatments for smoking cessation.
Presynaptic nicotinic ACh receptors (nAChRs) are abundant in the nervous system, where they are thought to regulate the release of various neurotransmitters. Whole-cell recordings performed on rat interpeduncular nucleus neurons using the thin-slice technique showed that nicotine dramatically increased the frequency of postsynaptic GABAergic currents. This effect was observed at low micromolar concentration of agonist; it was mimicked by cytisine, dimethylphenylpiperazinium, and ACh in the presence of eserine. It was blocked by hexamethonium, dihydro-beta-erythroidine, and mecamylamine. The presynaptic action was suppressed in the presence of TTX. A comparable effect of nicotine was found using a preparation of acutely isolated neurons that had retained synaptic terminals attached to their cell body as evidenced by immunoreactivity to synaptophysin and presence of spontaneous GABAergic and glutamatergic synaptic activity. Nicotinic agonists increased the frequency of GABAergic postsynaptic currents, an effect blocked by curare and mecamylamine. This action was also suppressed in the presence of TTX. These data suggest the presence of nAChRs at a preterminal level on axons of intrinsic GABAergic neurons. We propose that, in contrast to presynaptic nAChRs, activation of these “preterminal” nAChRs can trigger a spike discharge and thus have a generalized action on the GABAergic afferent.
Latent inhibition (LI) refers to decrement in conditioning to a stimulus as a result of its prior nonreinforced preexposure. This robust phenomenon has been shown in classical and instrumental conditioning procedures and in many mammalian species, including humans. Development of LI reflects decreased associability of, or attention to, stimuli that predict no significant outcome. The fact that LI reflects attentional processes has become important to neuroscientists who see LI as a convenient tool for measuring the effects of drug treatments and lesions on attention. Data on brain systems studied for their involvement in LI are surveyed. These are presented in sections on noradrenergic, cholinergic, dopaminergic, serotonergic, and septo-hippocampal manipulations. It is concluded that the neural substrates of LI include the mesolimbic dopaminergic system (MDS), the mesolimbic serotonergic system (MSS), and the hippocampus. The preexposed stimulus loses its capacity to affect behavior in conditioning, even though it predicts reinforcement, because the hippocampus inhibits the switching mechanism of the nucleus accumbens via the subiculum-accumbens pathway. This hippocampal action is modulated by the MSS via its interactions with the hippocampal system or MDS, or both. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Nicotinic agonist-stimulated efflux of 86Rb1 from mouse brain synaptosomes was monitored continuously by on-line radioac- tivity detection. The concentration-effect curve following a 5-s stimulation with acetylcholine was biphasic (EC50 5 7.2 and 550 mM). a-Bungarotoxin (100 nM) did not inhibit the response, but dihydro-b-erythroidine (DHbE) blocked both phases with differing potency (average IC50 5 .22 and 8.9 mM for responses activated by low and high acetylcholine concentrations, re- spectively). Differential sensitivity DHbE inhibition was used to measure stimulation of 86Rb1 efflux by 17 nicotinic agonists, which differed markedly in potency and efficacy. All agonists were more potent at the DHbE-sensitive site. Both components were inhibited by the six antagonists tested. Methyllycaconitine and DHbE were more potent for the DHbE-sensitive compo- nent, whereas hexamethonium was more potent at the DHbE- resistant component. Both DHbE-sensitive and DHbE-resistant responses were reduced more than 95% in b2-null mutant mice, establishing the requirement for the b2 subunit for both components. Both components were widely, but not identi- cally, distributed throughout the brain. The DHbE-sensitive component appears to be identical with agonist-stimulated 86 Rb1 efflux described previously and is likely to be mediated by a4b2 receptors. The DHbE-resistant component is a novel, active, and widely distributed response mediated by nicotinic receptor(s) that also require the b2 subunit.
The neurons of the locus ceruleus are responsible for most of the noradrenergic innervation in the brain and nicotine potentiates noradrenaline release from
their terminals. Here we investigated the diversity and subcellular distribution of nicotinic acetylcholine receptors (nAChRs)
in the locus ceruleus both somatically, by combining single-cell reverse transcription–PCR with electrophysiological characterization, and at the
level of nerve terminals, by conducting noradrenaline efflux experiments. The proportion of neurons in the locus ceruleus expressing the nicotinic subunit mRNAs varied from 100% (β2) to 3% (α2). Yet, two populations of neurons could be distinguished
on the basis of the pattern of expression of nAChR mRNAs and electrophysiological properties. One population (type A) of small
cells systematically expressed α3 and β4 mRNAs (and often α6, β3, α5, α4), and nicotinic agonists elicited large currents
with a potency order of cytisine > nicotine. Another population (type B) of cells with large soma did not contain α3 and β4
mRNAs but, systematically, α6 and β3 (and often α4) and responded to nicotinic agonists in the order of nicotine > cytisine.
The nicotinic modulation of noradrenaline release in the hippocampus displayed an order of potency nicotine > cytisine, suggesting
that noradrenergic terminals in the hippocampus originate largely from type B cells of the locus ceruleus. Accordingly, immunocytochemical labeling showed that β3 is present in hippocampal terminals. The α6β3β2(α4) heterooligomer
thus behaves as the main nicotinic regulator of the ceruleo–hippocampal pathway.
An extensive phylogenetic analysis of the nicotinic-acetylcholine-receptor subunit gene family has been performed by cladistic and phenetic methods. The conserved parts of amino acid sequences have been analyzed by CLUSTAL V and PHYLIP software. The structure of the genes was also taken in consideration. The results show that a first gene duplication may have occurred before the appearance of Bilateria. Three subfamilies then appeared: I-the neuronal -bungarotoxin binding-site subunits (7, 8); III-the neuronal nicotinic subunits (2–6, 2–4), which also contain the muscle acetylcholine-binding subunit (1); and IV—the muscle non- subunits (1, , ). The Insecta subunits (subfamily II) could be orthologous to family III and IV. Several tissular switches of expression from neuron to muscle and the converse can be inferred from the extant expression of subunits and the reconstructed trees. The diversification of the neuronal nicotinic subfamily begins in the stem lineage of chordates, the last duplications occurring shortly before the onset of the mammalian lineage. Such evolution parallels the increase in complexity of the cholinergic systems.
One function of the hippocampus is to ascertain the novelty of incoming sensations and encode significant new information into memory. The regulation of response to repeated stimuli may prevent overloading of this function by redundant sensory input. Recent pharmacological studies implicate the role of α-bungarotoxin-sensitive nicotinic cholinergic receptors in the inhibition of hippocampal response to repeated auditory stimuli. The number of hippocampal α-bungarotoxin-sensitive receptors has a major genetic determinant, as demonstrated by a significant variance between different inbred mouse strains. The purpose of the present study was to determine whether there was a related genetic correlation for the gating of auditory response. Nine inbred mouse strains, representing a continuum of hippocampal α-bungarotoxin binding, were tested for the electrophysiological response to repeated auditory stimulation, followed by whole hippocampus membrane α-bungarotoxin binding studies. Several parameters of the auditory evoked response showed significant genetic variance over the nine strains, and a significant correlation was found between hippocampal α-bungarotoxin binding and both the amplitude of the initial evoked response and its inhibition to repeated auditory stimuli. There was no correlation of the auditory evoked response with high-affinity nicotine binding. These data further support the hypothesis that α-bungarotoxin-sensitive nicotinic receptors are involved in the regulation of hippocampal response to repeated auditory stimuli and suggest that this function is genetically controlled.
A family of genes has been identified that encodes subunits of nicotinic acetylcholine receptors (nAChRs) and is expressed in the nervous system. Functional neuronal nAChRs can be expressed in Xenopus oocytes by injection of RNA encoding 1 of 2 different beta-subunits (beta 2, beta 4) in pairwise combination with RNA encoding 1 of 3 different alpha-subunits (alpha 2, alpha 3, alpha 4). We examined the sensitivity of these 6 different alpha- beta-subunit combinations to the nicotinic agonists ACh, nicotine, cytisine, and 1,1-dimethyl-4-phenylpiperazinium (DMPP). Each subunit combination displayed a distinct pattern of sensitivity to these 4 agonists. The alpha 2 beta 2 combination was 5-fold more sensitive to nicotine than to acetylcholine, while the alpha 3 beta 2 combination was 17-fold less sensitive to nicotine than to ACh, and the alpha 3 beta 4 combination was equally sensitive to both nicotine and ACh. nAChRs composed of alpha 2, alpha 3, or alpha 4 in combination with beta 2 were 14-100-fold less sensitive to cytisine than to ACh. In contrast, nAChRs composed of alpha 2, alpha 3, or alpha 4 in combination with beta 4 were 3-17-fold more sensitive to cytisine than to ACh. The alpha 2 beta 2, alpha 3 beta 2, and alpha 3 beta 4 combinations were each equally sensitive to DMPP and ACh, while the alpha 2 beta 4, alpha 4 beta 2, and alpha 4 beta 4 combinations were 4-24-fold less sensitive to DMPP than to ACh. We also demonstrated that these differences are neither a consequence of variation in the relative amounts of RNA injected nor an artifact of oocyte expression. The oocyte system can accurately express ligand-gated ion channels because mouse muscle nAChRs expressed in oocytes display pharmacological properties similar to those reported for these receptors expressed on BC3H-1 cells. We conclude that both the alpha- and the beta-subunits contribute to the pharmacological characteristics of neuronal nAChRs.
Although multiple related genes encoding nicotinic acetylcholine receptor (AChR) subunits have been identified, how each of
these subunits contributes to AChRs in neurons is not known. Sympathetic neurons express four classes of AChR channels and
six AChR subunit genes (alpha 3, alpha 4, alpha 5, alpha 7, beta 2, and beta 4). The contribution of individual subunits to
AChR channel subtypes in these neurons was examined by selective deletion with antisense oligonucleotides. An alpha 3 antisense
oligonucleotide decreased the number and altered the properties of the normally expressed ACh-activated channels. The remaining
AChR channels have distinct biophysical and pharmacological properties that indicate an important functional contribution
of the alpha 7 subunit.
Fear reactions of rats given bilateral lesions to the septum, hippocampus, or amygdala were compared with those of rats given sham lesions, in 2 animal models of anxiety: the shock-probe burying test and the elevated plus-maze test. Septal lesions produced anxiolytic effects in both tests (i.e., an increase in open-arm activity and a decrease in burying), whereas hippocampal and amygdaloid lesions produced neither of these effects. On the other hand, hippocampal and amygdaloid lesions impaired rats' passive avoidance of the electrified shock-probe, whereas septal lesions did not. These dissociations suggest that limbic structures such as the septum, amygdala, and hippocampus exert parallel but distinct control over different fear reactions.
Abstract Although the neuronal nicotinic receptor a6 subunit was cloned several years ago, its functional significance remains to be investigated. Here we describe an in situ hybridization study of the mRNA for this subunit in the adult rat central nervous system using oligonucleotide probes. Specific a6 mRNA labelling was restricted to a few nuclei throughout the brain; it was particularly high in several catecholaminergic nuclei [the locus coeruleus (A6), the ventral tegmental area (A10) and the substantia nigra (A9)] at levels significantly higher than those found for any other known nicotinic receptor subunit mRNA. Labelling for a6 mRNA was also detected at lower levels in the reticular thalamic nucleus, the supramammillary nucleus and the mesencephalic V nucleus. Some cells of the medial habenula (medioventral part) and of the interpeduncular nucleus (central and lateral parts) were also labelled. The distribution of a6 mRNA was compared with the distribution of the other known nicotinic acetylcholine receptor subunit mRNAs. In several nuclei, the expression of a6 was complementary to those of other a subunits. Moreover, some of the cell groups (such as the substantia nigra, the ventral tegmental area and the locus coeruleus) previously thought to contain mainly a3 mRNA in fact were found to contain high levels of α6 mRNA. Finally, we found extensive colocalization of α6 and p3, indicating the possible existence of nicotinic receptor hetero-oligomers containing both subunits. The present results show that a6 is the major nicotinic acetylcholine receptor a subunit expressed in dopaminergic cell groups of the mesencephalon and noradrenergic cells of the locus coeruleus. This suggests the involvement of the a6 subunit in some of the major functions of central nicotinic circuits, including the modulation of locomotor behaviour and reward.
DELLA CASA, V., I. HÖFER AND J. FELDON. Latent inhibition in smokers and nonsmokers: Interaction with number or intensity of preexposures? PHARMACOL BIOCHEM BEHAV 62(2) 353–359, 1999.—Latent inhibition (LI) refers to the slowing of learning about a stimulus after preexposure, i.e., previous presentation of the stimulus without any consequence. This report summarizes results of four studies investigating the effect of being a smoker or nonsmoker on auditory LI as a function of procedural parameters, namely number (10 vs. 30) and intensity (low vs. high) of preexposed stimuli. In general, the number of preexposures did not affect LI, whereas low-intensity stimuli led to greater LI than high-intensity stimuli. These findings underline the importance of automatic vs. controlled processing of the preexposed stimuli for the development of human LI. Smokers showed increased LI compared to nonsmokers in low-intensity task versions as well as compared to both smokers and nonsmokers in high-intensity versions. These findings may indicate that nicotinic effects on LI depend on the robustness of LI in the control group.
We have isolated a 16-amino acid peptide from the venom of the marine snail Conus magus which potently blocks nicotinic acetylcholine receptors (nAChRs) composed of alpha 3 beta 2 subunits. This peptide, named alpha-conotoxin MII, was identified by electrophysiologically screening venom fractions against cloned nicotinic receptors expressed in Xenopus oocytes. The peptide's structure, which has been confirmed by mass spectrometry and total chemical synthesis, differs significantly from those of all previously isolated alpha-conotoxins. Disulfide bridging, however, is conserved. The toxin blocks the response to acetylcholine in oocytes expressing alpha 3 beta 2 nAChRs with an IC50 of 0.5 nM and is 2-4 orders of magnitude less potent on other nAChR subunit combinations. We have recently reported the isolation and characterization of alpha-conotoxin ImI, which selectively targets homomeric alpha 7 neuronal nAChRs. Yet other alpha-conotoxins selectively block the muscle subtype of nAChR. Thus, it is increasingly apparent that alpha-conotoxins represent a significant resource for ligands with which to probe structure-function relationships of various nAChR subtypes.
The Flinders Sensitive Line (FSL) rat, selectively bred for increased responses to the anticholinesterase DFP, was originally proposed as an animal model of depression because, like depressed humans, it is supersensitive to the behavioral and hormonal effects of cholinergic (muscarinic) agonists. The present review critically examines earlier and recent data collected on FSL rats to assess whether the model has good face, construct and/or predictive validity. With respect to face validity, FSL rats resemble depressed humans, at least superficially, in that they demonstrate: (a) reduced locomotor activity, (b) reduced body weight, (c) increased REM sleep, and (d) cognitive (learning) difficulties. So far, studies designed to assess the presence of anhedonia, a cardinal symptom of melancholic depression, have been inconclusive, but there are trends for the FSL rats to be more anhedonic than their control counterparts, the Flinders Resistant Line (FRL) rats, when exposed to chronic mild stress. Thus, FSL rats fulfill the criterion of face validity. Because FSL rats also are more sensitive to cholinergic agonists and have phase advanced circadian rhythms, they meet the criteria for the cholinergic and circadian rhythm models of depression and, therefore, have good construct validity. A key behavioral symptom exhibited by the FSL rat is demonstration of an exaggerated immobility when exposed to stressors such as foot shock and forced swimming. This behavioral abnormality has been normalized by a number of well-recognized antidepressant drugs such as imipramine and desipramine, as well as newer generation antidepressants with promising clinical effects such as sertraline and rolipram. However, several treatments that have not been routinely used to treat depression (lithium, exposure to bright light, the anticholinesterase DFP) have been ineffective in reversing the exaggerated immobility. Thus, the evidence in the present review indicates that the FSL rat model of depression fulfills the criteria of face, construct, and predictive validities.
This study establishes that presynaptic nicotinic receptors modulate dopamine release in the mouse striatum. Nicotinic agonists elicit a dose-dependent increase in the release of [3H]dopamine from synaptosomes prepared from mouse striatum. At low concentrations, this release is Ca2+ dependent, whereas at higher concentrations Ca2+-independent, mecamylamine-insensitive release was also observed. The Ca2+-dependent nicotine-evoked release was not blocked by α-bungarotoxin but was effectively blocked by neuronal bungarotoxin as well as several other nicotinic receptor antagonists. The relationship between potency for stimulation of release for agonists and potency for inhibition of release for antagonists was compared to the affinity of these compounds for the [3H]nicotine binding site. The overall correlation between release and binding potency was not high, but the drugs may be classified into separate groups, each of which has a high correlation with binding. This finding suggests either that more than one nicotinic receptor regulates dopamine release or that not all agonists interact with the same receptor in an identical fashion.
Many of the symptoms of nicotine withdrawal are similar to those of other drug withdrawal syndromes: anxiety, awakening during sleep, depression, difficulty concentrating, impatience, irritability/anger and restlessness. Slowing of the heart rate and weight gain are distinguishing features of tobacco withdrawal. Although nicotine withdrawal may not produce medical consequences, it lasts for several weeks and can be severe in some smokers. Like most other drug withdrawals, nicotine withdrawal is time-limited, occurs in non-humans, is influenced by instructions/expectancy and abates with replacement therapy and gradual reduction. Unlike some other drug withdrawal syndromes, protracted, neonatal or precipitated withdrawal does not occur. Whether nicotine withdrawal is associated with tolerance, acute physical dependence, greater duration and intensity of use, rapid reinstatement, symptom stages, cross-dependence with other nicotine ligands, reduction by non-pharmacological interventions and genetic influences is unclear. Whether nicotine withdrawal plays a major role in relapse to smoking has not been established but this is also true for other drug withdrawal syndromes.
The acquisition of low-dose (0.25 mg/kg/infusion) intravenous cocaine self-administration was measured in rats that had received nine daily injections of amphetamine (1.0 mg/kg, IP), nicotine (0.6 mg/kg base weight, SC) or vehicle. For control rats, the acquisition of self-administration was gradual with the number of responses per 2 h daily test session increasing between days 3 and 9. By comparison, rats preexposed with amphetamine and nicotine demonstrated elevated response means during the early days of testing, suggesting more rapid acquisition. All groups eventually reached similar asymptotic levels of responding. The enhanced responding observed during the early days of testing in the rats preexposed with amphetamine and nicotine was due to an increased number of subjects that reliably self-administered cocaine. Thus, the rats preexposed with amphetamine and nicotine seemed predisposed to the reinforcing effects of cocaine. In contrast to the self-administration data, preexposure to nicotine failed to sensitize rats to the locomotor activating effects of cocaine. In fact, the same preexposure regimen appeared to produce tolerance to this effect of cocaine. These data give evidence that different mechanisms may mediate sensitization to the reinforcing and locomotor activating effects of cocaine.
The primary pathology in Alzheimer's disease (DAT) occurs in the basal forebrain cholinergic system (BFCS), which provides the major cholinergic innervation to the neocortex, hippocampus and amygdala. Consistent with the 'cholinergic hypothesis' of dementia in DAT, the most effective treatments so far developed for DAT are drugs which act to boost the functions of the BFCS. These include the centrally acting cholinesterase inhibitor tacrine, and the cholinergic agonist nicotine, acute administration of which leads to an improvement in attentional functions, in line with recent animal studies of the role of the BFCS in cognition. We conclude that future research should include the development of more potent, longer-lasting, less toxic cholinergic agents, which appear to be the best candidates for alleviating the cognitive symptomatology of DAT. Such drugs may also be useful in the treatment of a number of other cognitive disorders, including Lewy body dementia, attention deficit/hyperactivity disorder, and schizophrenia.
Abnormal sensory inhibition is a measurable indicator of a sensory processing deficit which is observed in schizophrenia,
and other disorders, and which may be heritable. This deficit has also been observed in certain inbred mouse strains where
the intensity of the deficit has been correlated with reduction in the number of hippocampal α-bungarotoxin-sensitive nicotinic
receptors. Nicotine and certain nicotinic agonists produce brief periods of normal sensory inhibition in these mice. Similarly,
nicotine also transiently normalizes sensory inhibition in schizophrenics. The present study assessed the effects of a novel
nicotinic partial agonist (GTS-21), selective for the α-bungarotoxin site, on sensory inhibition in DBA mice, a strain with
no sensory inhibition under routine experimental conditions. GTS-21 produced a dose-dependent normalization of sensory inhibition
which was blocked by α-bungarotoxin but not mecamylamine. In contrast to other nicotinic agonists, normalization of sensory
inhibition by GTS-21 and two related anabaseine compounds, DMAB-anabaseine and DMAC-anabaseine, was observed when administered
a second time to the animal, after a 40-min delay. Our results indicated that the anabaseine compounds increase sensory inhibition
through α7 nicotinic receptors, and that their ability to act repeatedly on these receptors may be less affected by desensitization.
As neurodegenerative disorders are better characterized, the importance of genetic and environmental interactions is becoming more evident. Among the neurodegenerative disorders, Alzheimer's disease and Parkinson's disease are both characterized by large losses of nicotinic binding sites in brain. In addition, losses in nicotinic receptors occur during normal aging. Chronic administration of nicotine in man or experimental animals increases the number of nicotinic receptors in brain. Nicotine has been shown to possess some neuroprotective properties for both cholinergic and dopaminergic neurons. These neuroprotective properties, when better understood, may provide important information on normal aging and neurodegenerative disorder related neuronal cell death. Understanding the functional aspects of neuronal nicotinic receptor subtypes may lead to successful therapeutic treatments or disease preventative strategies for neurodegenerative disorders.
Epidemiological studies indicate a high incidence of cigarette smoking among depressed individuals. Moreover, individuals
with a history of depression have a much harder time giving up smoking. It has been postulated that smoking may reflect an
attempt at self-medication with nicotine by these individuals. Although some animal and human studies suggest that nicotine
may act as an antidepressant, further verification of this hypothesis and involvement of nicotinic cholinergic system in depressive
symptoms is required. Flinders Sensitive Line (FSL) rats have been proposed as an animal model of depression. These rats,
selectively bred for their hyperresponsiveness to cholinergic stimulation, show an exaggerated immobility in the forced swim
test compared to their control Flinders Resistant Line (FRL) rats. Acute or chronic (14 days) administration of nicotine (0.4 mg/kg
SC) significantly improved the performance of the FSL but not the FRL rats in the swim test. The effects of nicotine on swim
test were dissociable from its effects on locomotor activity. Moreover, the FSL rats had significantly higher [3H]cytisine binding (selective for the α4β2 nicotinic receptor subtype) but not [125I]alpha-bungarotoxin binding (selective for the α7 subtype) in the frontal cortex, striatum, midbrain and colliculi compared to FRL rats. These data strongly implicate the
involvement of central nicotinic receptors in the depressive characteristics of the FSL rats, and suggest that nicotinic agonists
may have therapeutic benefits in depressive disorders.
DELLA CASA, V., I. HÖFER AND J. FELDON. Latent inhibition in smokers and nonsmokers: Interaction with number or intensity of preexposures? PHARMACOL BIOCHEM BEHAV 62(2) 353–359, 1999.—Latent inhibition (LI) refers to the slowing of learning about a stimulus after preexposure, i.e., previous presentation of the stimulus without any consequence. This report summarizes results of four studies investigating the effect of being a smoker or nonsmoker on auditory LI as a function of procedural parameters, namely number (10 vs. 30) and intensity (low vs. high) of preexposed stimuli. In general, the number of preexposures did not affect LI, whereas low-intensity stimuli led to greater LI than high-intensity stimuli. These findings underline the importance of automatic vs. controlled processing of the preexposed stimuli for the development of human LI. Smokers showed increased LI compared to nonsmokers in low-intensity task versions as well as compared to both smokers and nonsmokers in high-intensity versions. These findings may indicate that nicotinic effects on LI depend on the robustness of LI in the control group.
Although the molecular biology of neuronal nicotinic acetylcholine receptors (nAChRs) provides evidence for multiple receptor subtypes, few selective pharmacological tools exist to identify these subtypes in vivo. However, the diversity of behavioral effects of available nAChR agonists and antagonists reviewed in this paper suggests that neuronal nAChR subtypes may play distinct roles in a variety of behavioral outcomes. Further characterization of the behavioral effects of the activation of discrete nAChR subtypes may eventually provide information useful in designing selective nAChR ligands targeting a variety of CNS disorders.
The effects of nicotinic receptor agonists on the elevated plus-maze test of anxiety were investigated in CD1 mice after intraperitoneal injections. Nicotine and lobeline, but not cytisine, exhibited a significant increase in the time spent by the mice in the open arms, a measure of anxiolytic activity. Nicotine also increased the total number of arm entries, a measure of general activity, but this effect was secondary to its anxiolytic-like properties. Nicotinic receptor antagonists on their own did not modify the behavior of mice in the maze. The effect of nicotine was mediated by central nicotinic receptors as it was blocked by the centrally-acting nicotinic antagonists mecamylamine and chlorisondamine, but not by hexamethonium (a peripherally acting blocker). Cotinine, the major metabolite of nicotine, was evaluated at different times after systemic injections and had no effect in the plus-maze. The anxiolytic-like profile induced by nicotinic receptor stimulation was not associated with potentiation of alcohol effects, a liability associated with the benzodiazepine therapy. This study demonstrates the anxiolytic-like properties of nicotine and lobeline in mice, and suggests that central nicotinic receptors are involved in the expression of emotional behavior.
An implicit assumption guiding many studies of neurochemical systems involved in learning and memory in animal subjects is that animal and human memory systems use the same or similar mechanisms. Because acquisition and retention performance can be influenced by many processes other than information storage, special effort is required to distinguish influences on memory processes from other factors influencing performance. This article reviews the findings of recent studies investigating the effects, on memory, of drugs affecting adrenergic, opioid peptidergic, GABAergic and cholinergic systems. The review focuses primarily on studies using posttraining treatments and tests for retention given no sooner than a day after the training. Extensive evidence suggests that such drugs interact within the amygdaloid complex and that projections from the amygdala influence memory storage in other brain regions. The assumption that comparable processes occur in animal and human subjects is supported by evidence that, in human subjects, emotionally influenced memory is blocked by a β-adrenergic blocker and by lesions of the amygdaloid complex.
The paper presents an animal model of schizophrenic-like attentional deficit, consisting of an inability to ignore irrelevant stimuli. It is based on the paradigm of latent inhibition (LI), in which animals learn to ignore repeatedly presented stimuli not followed by meaningful consequences. In a series of experiments it was demonstrated that the capacity to ignore irrelevant stimuli is lost in rats treated with systemic or intra-accumbens injections of amphetamine, in normal volunteers given amphetamine, in high “psychosis-prone” persons, in acute schizophrenic patients and in untreated male adult rats that were raised until weaning under conditions of extremely restricted stimulation. In addition, LI is lost following the disruption of the hippocampal input to the nucleus accumbens. In all of the above conditions tested for antagonism by anti-psychotic drugs a loss of LI is reversed. On the basis of these results we propose an animal model which accomodates a neurodevelopmental dysfunction, hippocampal pathology, mesolimbic DA overactivity, vulnerability to stress, and gender differences, all of which have been postulated as factors in the pathophysiology of schizophrenia.
The startle reflex is a contraction of the skeletal and facial musculature in response to an intense sensory stimulus. While the 'primary' neural control of startle involves brain structures at, or below, the level of the mesencephalon, the startle reflex (SR) exhibits several forms of plasticity that are modulated by the forebrain. Sensorimotor gating of the SR occurs when the reflex is inhibited by a weak 'pre-pulse' that occurs 30-500 ms prior to the startling stimulus. Since 'pre-pulse inhibition' (PPI) of startle may be impaired in certain psychiatric and neurologic disorders (e.g. schizophrenia, schizotypal personality disorder and Huntington's disease), there has been considerable interest in determining the neural substrates of this form of startle plasticity. In rats, PPI is modulated by neural elements linking the limbic cortex with the striatum and pallidum. These substrates may include hippocampal glutamate efferents to the ventral striatum and striatal GABAergic efferents to the ventral pallidum. The striatal dopaminergic modulation of PPI appears to involve primarily D2, but not D1, receptors. Pallidal efferents may impinge directly on the 'primary' startle circuitry via projections to the mesencephalon or, indirectly, via projections to the thalamus. Evidence is reviewed for other neurochemical substrates of PPI-including acetylcholine and opiates. Sensorimotor gating of the startle reflex appears to have a discrete and identifiable set of neural substrates that may be important for our understanding of neuropsychiatric disorders characterized by deficient suppression or 'gating' of sensory, cognitive or motor processes.
The association between smoking and depression has been widely investigated. Smoking cessation is known to induce depression to a variable extent, and patients with a history of depression are more likely to experience depressive symptoms. To investigate the hypothesis that nicotine may have an antidepressantlike effect, we used learned helpless rats as an animal model of depression.
Learned helplessness was produced according to our previous method. Learned helpless rats were implanted with nicotine and escape test was performed at 7 and 14 days after the implantation.
The number of escape failure in the rats receiving 1.5 mg/kg/day of nicotine was significantly reduced (p < .05) compared to control at day 14. Furthermore, this effect was blocked when the nicotinic receptor antagonist mecamylamine was coadministered.
These results suggest that chronic nicotine may act as an antidepressant, probably via nicotinic receptors.
Tobacco smoking is a worldwide public health problem. In the United States alone, over 400,000 deaths and $50 billion in medical costs annually are directly attributed to smoking. Accumulated evidence indicates that nicotine is the component of tobacco smoke that leads to addiction, but the means by which nicotine produces addiction remain unclear. Nicotine is less effective as a positive reinforcer than other drugs of abuse in non-dependent animals. Nevertheless, nicotine-withdrawal symptoms, including depressed mood, anxiety, irritability and craving in dependent subjects may contribute to the addictive liability of nicotine. We show here that spontaneous nicotine withdrawal in rats resulted in a significant decrease in brain reward function, as measured by elevations in brain reward thresholds, which persisted for four days. Further, systemic injections of a competitive nicotinic-receptor antagonist led to a dose-dependent increase in brain reward thresholds in chronic nicotine-treated rats. The decreased function in brain reward systems during nicotine withdrawal is comparable in magnitude and duration to that of other major drugs of abuse, and may constitute an important motivational factor that contributes to craving, relapse and continued tobacco consumption in humans.
Inheritance of a defect in a neuronal mechanism that regulates response to auditory stimuli was studied in nine families with multiple cases of schizophrenia. The defect, a decrease in the normal inhibition of the P50 auditory-evoked response to the second of paired stimuli, is associated with attentional disturbances in schizophrenia. Decreased P50 inhibition occurs not only in most schizophrenics, but also in many of their nonschizophrenic relatives, in a distribution consistent with inherited vulnerability for the illness. Neurobiological investigations in both humans and animal models indicated that decreased function of the α7-nicotinic cholinergic receptor could underlie the physiological defect. In the present study, a genome-wide linkage analysis, assuming autosomal dominant transmission, showed that the defect is linked [maximum logarithm of the odds (lod) score = 5.3 with zero recombination] to a dinucleotide polymorphism at chromosome 15q13-14, the site of the α7-nicotinic receptor. Despite many schizophrenics’ extremely heavy nicotine use, nicotinic receptors were not previously thought to be involved in schizophrenia. The linkage data thus provide unique new evidence that the α7-nicotinic receptor gene may be responsible for the inheritance of a pathophysiological aspect of the illness.
Previous in situ hybridization experiments reported that beta4 (beta 4) neuronal nicotinic acetylcholine receptor (nAChR) transcripts were found only in the medial habenula (MHB). Co-expression in Xenopus oocytes of the beta 4 subunit and any one of three ligand-binding or alpha subunits results in the formation of functional nAChRs. Comparisons between the pharmacology of nAChRs expressed in oocytes and the pharmacology of nAChRs found in the rat CNS prompted a further investigation of the localization of transcripts encoding the beta 4 nAChR subunit. Using two beta 4-specific cRNA probes, in situ hybridization was performed in rat brain. beta 4 mRNA was detected at high levels in the presubiculum, parasubiculum, subiculum and dentate gyrus of the hippocampal formation, in layer IV of the isocortex, in the medial habenula, in the interpeduncular nucleus, and in the trigeminal motor nerve nucleus. Moderate hybridization signals were seen in the isocortex (layers I-III), in olfactory regions, in fields CA1 through CA4 of Ammon's horn and the entorhinal cortex of the hippocampal formation, in the supramammillary nucleus, in the pontine nucleus, in the cerebellum, and in the locus coeruleus. No hybridization above background was detected in the septum, basal ganglia, sensory portions of the brainstem, or spinal cord.
Nicotinic acetylcholine receptors have been found to be important for maintaining optimal performance on a variety of cognitive tasks. In humans, nicotine-induced improvement of rapid information processing is particularly well documented. In experimental animals nicotine has been found to improve learning and memory on a variety of tasks, while the nicotinic antagonist mecamylamine has been found to impair memory performance. Nicotine has been found to be effective in attenuating memory deficits resulting from lesions of the septohippocampal pathway or aging in experimental animals. Nicotinic receptors are decreased in the cortex of patients with Alzheimer's disease. Preliminary studies have found that some aspects of the cognitive deficit in Alzheimer's disease can be attenuated by nicotine. Nicotine may prove to be useful therapeutic treatment for this and other types of dementia.
Few animals models are currently in use for the recognized clinical problem of nicotine dependence and abstinence. This study introduces a rapid and convenient model using the rat. Sixteen male rats were rendered nicotine dependent by 7 days of continuous subcutaneous infusion of either 3 mg/kg/day (n = 8) or 9 mg/kg/day (n = 8) nicotine tartrate salt; 8 control rats were infused with saline alone. Rats were observed for 15 min before, during, and after the drug infusion period using a tally sheet modified from a standard checklist of opiate abstinence signs. There were few signs observed in any group at baseline and at the end of the infusion period. However, nicotine-infused rats showed a significant, dose-related increase over the control group at 16 h after the end of infusion, largely subsiding by 40 h. The most frequently observed signs during withdrawals included: teeth-chattering/chews, writhes/gasps, ptosis, tremors/shakes, and yawns. A significant drop in locomotor activity and increase in weight gain following termination of nicotine infusion provided additional evidence of an abstinence syndrome. This syndrome was alleviated by SC administration of 0.4 mg/kg nicotine tartrate.
The effects of acute and subchronic nicotine and (+)‐amphetamine on the extracellular levels of dopamine and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in nucleus accumbens (NAc) have been studied in conscious, freely‐moving rats by use of in vivo microdialysis.
In rats which had been habituated to the test apparatus for approximately 80 min, the acute subcutaneous (s.c.) administration of nicotine (0.1 or 0.4 mg kg ⁻¹ ) caused a dose‐dependent increase ( P < 0.01) in spontaneous activity and evoked significant increases ( P < 0.05) in the extracellular levels of DOPAC and HVA.
Measurements made 24 h after the last injection of nicotine showed that pretreatment with the higher doses tested (0.4 mg kg ⁻¹ ) resulted in increased basal levels of dopamine ( P < 0.01) and decreased basal levels of DOPAC ( P < 0.05) in the NAc dialysates.
Pretreatment with nicotine (0.1 or 0.4 mg kg ⁻¹ daily for 5 days) enhanced the effects of the drug on spontaneous locomotor activity and enhanced the effects of the drug on extracellular levels of dopamine to the extent that the response became significant ( P < 0.05).
If a dopamine uptake inhibitor, nomifensine, was added to the Ringer solution used to dialyse the probe, the s.c. administration of both acute and subchronic nicotine (0.4 mg kg ⁻¹ ) resulted in significant increases ( P < 0.05) in the dopamine concentration in the dialysate. Under these conditions, pretreatment with nicotine prior to the test day prolonged ( P < 0.05) the dopamine response to a challenge dose of nicotine.
Subcutaneous injections of (+)‐amphetamine (0.2 or 0.5 mg kg ⁻¹ ) evoked dose‐dependent increases in both spontaneous activity and the concentration of dopamine in NAc dialysates. These responses were unaffected by 5 days pretreatment with the drug.
The results of this study support the conclusion that the enhanced locomotor response to nicotine observed in animals pretreated with the drug prior to the test day is associated with potentiation of its effects on dopamine secretion in the NAc.
Rapid decrement of response to repeated stimuli is a characteristic of hippocampal neurons. To assess the possible role in this process of cholinergic afferents from the medial septal nucleus, a series of cholinergic antagonists were administered intraventricularly to chloral hydrate-anesthetized rats. Auditory stimuli were delivered in pairs to the rats, and the evoked response was recorded from an electrode in the CA3 layer of the hippocampus. The most prominent component of the auditory evoked potential recorded in this region (N40) showed over 60% decrement in the amplitude of the response to the second stimulus when the two stimuli were delivered 0.5 s apart. Only neuromuscular-type nicotinic antagonists, alpha-bungarotoxin and (+)-tubocurarine, disrupted this decrement of response to repeated auditory stimuli. The muscarinic antagonist, scopolamine, and the ganglionic-type nicotinic antagonists, kappa-bungarotoxin and mecamylamine, were without effect. The results suggest that a subset of nicotinic receptors mediate the gating of response to auditory stimuli in the hippocampus.
Drugs of abuse are very powerful reinforcers, and even in conditions of limited access (where the organism is not dependent) these drugs will motivate high rates of operant responding. This presumed hedonic property and the drugs' neuropharmacological specificity provide a means of studying the neuropharmacology and neuroanatomy of brain reward. Three major brain systems appear to be involved in drug reward--dopamine, opioid and GABA. Evidence suggests a midbrain-forebrain-extrapyramidal circuit with its focus in the nucleus accumbens. Data implicating dopamine and opioid systems in indirect sympathomimetic and opiate reward include critical elements in both the nucleus accumbens and ventral tegmental areas. Ethanol reward appears to depend on an interaction with the GABAA receptor complex but may also involve common elements such as dopamine and opioid peptides in this midbrain-forebrain-extrapyramidal circuit. These results suggest that brain reward systems have a multidetermined neuropharmacological basis that may involve some common neuroanatomical elements.
Rats were trained to self-administer nicotine on a fixed-ratio schedule of reinforcement. Infusion of the nicotinic antagonist chlorisondamine into the cerebral ventricles produced a sustained reduction in nicotine self-administration compared to vehicle-treated controls. Lesions of the mesolimbic dopamine system were produced by microinfusion of 6-hydroxydopamine into the nucleus accumbens. Following production of the lesions, nicotine self-administration was markedly reduced for the 3-week test period; motor impairment did not appear to be responsible. Post mortem analysis of brain tissue showed that the lesion produced a pronounced decrease in dopamine content of the nucleus accumbens and the olfactory tubercle, and a small depletion in the striatum. These data demonstrate that the reinforcing effects of nicotine occur within the central nervous system, and that the mesolimbic dopamine projection plays an important role in these effects.
Neuronal nicotinic acetylcholine receptors are oligomeric protein complexes whose component subunits are each encoded by a family of homologous genes. The current challenge is to determine the functional contributions of the related subunits to the receptor-linked ion channels they compose and to uncover the physiological impact of the distinct channel classes expressed in vivo. In the past year, new approaches to the analysis of these receptors have yielded important insights into their stoichiometry, pharmacology and functional properties.