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Aggression is frequently comorbid with neuropsychiatric conditions and is a predictor of worse outcomes, yet current pharmacotherapies are insufficient and have debilitating side effects, precluding broad use. Multiple models of aggression across species suggest that the nicotinic acetylcholine receptor (nAChR) agonist nicotine has anti-aggressive (serenic) properties. Here we demonstrate dose-dependent serenic effects of acute nicotine administration in three distinct mouse strains: C57BL/6, BALB/c, and CD1. While acute nicotine administration (0.25 mg/kg) modestly reduced solitary homecage locomotion, this could not account for nicotine’s serenic effects since social encounters eliminated the hypolocomotor effect, and nicotine did not alter social interaction times. Pretreatment with the homomeric (α7 subunit) nAChR antagonist methyllycaconitine (5 mg/kg), but not the heteromeric (β2 or β4 subunit-containing) nAChR antagonist dihydro-β-erythroidine (DHβE, 3 mg/kg), blocked the serenic effects of nicotine. By contrast, pretreatment with DHβE blocked the effect of acute nicotine administration on locomotion, uncoupling nicotine’s serenic and hypolocomotor effects. Finally, the α7 nAChR partial agonist GTS-21 reduced aggression in C57BL/6 mice. These results support the idea that acute nicotine administration has serenic effects and provide evidence for specificity of this effect distinct from effects on locomotion. Furthermore, pharmacological studies suggest that activation of α7 nAChRs underlies the serenic effects of nicotine. Further studies of nAChRs could enhance understanding of the neurobiology of aggression and may lead to the development of novel, more specific treatments for pathological aggression. [ABSTRACT FROM AUTHOR]

Background: The calcium-dependent phosphatase calcineurin is highly expressed in the amygdala, a brain area important for behaviors related to mood disorders and anxiety. Organ transplant patients are administered the calcineurin inhibitor cyclosporine A (CsA) chronically and demonstrate an increased incidence of anxiety and mood disorders. It is therefore important to determine whether chronic blockade of calcineurin may contribute to symptoms of anxiety and depression in these patients. Methods: Pharmacological (CSA) and viral-mediated gene transfer (adeno-associated viral expression of short hairpin RNA [shRNA]) approaches were used to inhibit calcineurin activity systemically or selectively in the amygdala of the mouse brain to determine the role of calcineurin in behaviors related to anxiety and depression. Results: Systemic inhibition of calcineurin activity with CsA or local downregulation of calcineurin levels in the amygdala using adeno-associated viral-delivered shRNAs targeting calcineurin B increased measures of anxiety-like behavior in the elevated plus maze, the light/dark box, and the open field test. A decrease in locomotor activity was also observed in mice treated systemically with CsA. In the forced swim model of depression-like behavior, both systemic CsA treatment and shRNA-mediated calcineurin blockade in the amygdala significantly increased immobility. Conclusions: Taken together, these data demonstrate that decreasing calcineurin activity in the amygdala increases anxiety-like behaviors and to some extent depression-like behaviors. These studies suggest that chronic administration of CsA to organ transplant patients could have significant effects on anxiety and mood and this should be recognized as a potential clinical consequence of treatment to prevent transplant rejection. [ABSTRACT FROM AUTHOR]

Tobacco smoking in humans is one of the most persistent and widespread addictions and is driven by nicotine in tobacco smoke. Over the last several decades, understanding of the molecular and cellular basis for nicotine addiction has increased tremendously as a result of pharmacological, molecular genetic, electrophysiological and behavioral studies of nicotine reinforcement. Studies of the biological basis for nicotine reinforcement has helped in the design of new treatments for smoking cessation such as varenicline; however, smokers report that they smoke for many reasons, including the ability to control symptoms of anxiety and depression or the desire to control appetite. Further, developmental exposure to tobacco smoke increases the likelihood of adult smoking. Here we review what is known about the molecular and circuit basis for a number of behaviors related to tobacco smoking. Leveraging the knowledge from studies of different behaviors mediated by nicotine receptors in multiple brain circuits could provide points of convergence that will inform future therapeutic development for smoking cessation. This article is part of a Special Issue entitled ‘NIDA 40th Anniversary Issue’. [ABSTRACT FROM AUTHOR]

There is a well-established connection between smoking and depression. Depressed individuals are over-represented among smokers, and ex-smokers often experience increased depressive symptoms immediately after stopping smoking. Nicotine in tobacco binds, activates and desensitizes nicotinic acetylcholine receptors (nAChRs), but it is not known whether activation or desensitization is more important for the effects of nicotine on depressive symptoms. Here we review, based on clinical and preclinical studies of nicotinic drugs, the hypothesis that blockade (rather than activation) of neuronal nAChRs might be important for the effects of nicotinic agents on depressive symptoms. The endogenous neurotransmitter for nAChRs is acetylcholine, and the effects of nicotine on depression-like behaviors support the idea that dysregulation of the cholinergic system might contribute to the etiology of major depressive disorder. Thus, pharmacological agents that limit acetylcholine signaling through neuronal nAChRs might be promising for the development of novel antidepressant medications. [ABSTRACT FROM AUTHOR]

Background: Organ transplant patients receive chronic administration of the calcineurin inhibitor cyclosporin-A (CsA) and demonstrate increased incidence of mood disorders. Significant calcineurin expression can be observed with immunohistochemistry in the amygdala, a brain area important for behaviors related to mood disorders and anxiety. It is therefore important to determine whether chronic blockade of calcineurin might contribute to symptoms of anxiety and depression in these patients. Methods: Pharmacological CsA and viral-mediated gene transfer (adeno-associated viral expression of short hairpin RNA [AAV-shRNA]) approaches were used to inhibit calcineurin activity globally and selectively in the amygdala of the mouse brain to determine the role of calcineurin in behaviors related to depression and anxiety. Results: Systemic inhibition of calcineurin activity with CsA or local downregulation of calcineurin levels in the amygdala with AAV-delivered shRNAs targeting calcineurin A increased behavioral measures of anxiety in both the elevated plus maze and light/dark tests with no changes in locomotor activity. In the forced swim and tail suspension models of depression-like behavior, calcineurin blockade in the amygdala increased immobility similarly to manipulations that lead to a depression-like phenotype. Conclusions: Taken together, these data demonstrate that decreasing calcineurin activity in the amygdala increases anxiety- and depression-like behaviors. These studies suggest that chronic administration of CsA to organ transplant patients could have significant effects on anxiety and mood and that this should be recognized as a clinical consequence of treatment to prevent transplant rejection. [Copyright &y& Elsevier]

Abstract: Animal facilities aim to combine animal welfare with cost-efficiency and limited care staff requirements, and individually ventilated cage (IVC) systems were developed towards these goals. While IVC have great sanitary advantages both for the animals but also for the care staff, these systems involve potentially deleterious features such as high levels of air renewal, noise, and subtle vibrations of the racks because of the air filtering system used, but also reduce the frequency of stressful cage changes. It is unknown in how far these conditions may influence the animals'' behavior. This issue becomes critical as many facilities are switching to IVC systems, possibly complicating replication of data or biasing ongoing studies. We investigated the effects of IVC housing in mice on different behaviors including anxiety, exploration, and learning in males and females of three common and phenotypically distant strains. Results demonstrate robust effects of IVC in multiple behavioral tests with the direction of the effect strongly dependent on strain and sex. These data should serve to alert researchers that a switch to IVC housing during the course of an experiment has the potential to bias results in a serious manner. In addition, behavioral baseline data will have to be re-established once the switch has been completed. [Copyright &y& Elsevier]

Abstract: In this study, we compared the depression-like symptoms induced by olfactory bulbectomy (OBX) in the two inbred Wistar and Long Evans rat strains. We also analyzed the self-regulated oral intake of nicotine in these strains and the effect of nicotine on the depression-like symptoms of olfactory bulbectomy. Furthermore, we compared the antidepressant-like effects of nicotine on Wistar rats to those of transcranial magnetic stimulation (TMS), which has emerged as a therapeutic alternative for depression management. Our results show that Wistar rats develop depression-like symptoms, demonstrated by the forced swim test (FST), 4 weeks after OBX. However, in bulbectomized Long Evans rats these symptoms cannot be assessed due to a higher degree of variability of the swimming behavior of this strain. These results suggest that there are some innate differences in susceptibility to stress between these two rat strains. In Wistar rats, voluntary oral nicotine intake (1.2mg/(kgday) for 14 days) as well as nicotine administered as a single daily i.p. injection (1.5mg/(kgday) for 14 days) decrease the depression-like symptoms of OBX. Daily transcranial magnetic stimulation (60Hz and 0.7mT for 2h/day for 14 days) also decreases depression-like symptoms but is less effective than nicotine. In conclusion, our results support the idea that there are possible innate differences for depression susceptibility and that nicotine and TMS may be useful in the treatment of this syndrome. [Copyright &y& Elsevier]

Abstract: Human twin studies have suggested that there is a substantial genetic component underlying nicotine dependence, ongoing smoking and ability to quit. Similarly, animal studies have identified a number of genes and gene products that are critical for behaviors related to nicotine addiction. Classical genetic approaches, gene association studies and genetic engineering techniques have been used to identify the gene products involved in nicotine dependence. One class of genes involved in nicotine-related behavior is the family of nicotinic acetylcholine receptors (nAChRs). These receptors are the primary targets for nicotine in the brain. Genetic engineering studies in mice have identified a number of subunits that are critical for the ability of nicotine to activate the reward system in the brain, consisting of the dopaminergic cell bodies in the ventral tegmental area and their terminals in the nucleus accumbens and other portions of the mesolimbic system. In this review we will discuss the various lines of evidence suggesting that nAChRs may be involved in smoking behavior, and will review the human and animal studies that have been performed to date examining the genetic basis for nicotine dependence and smoking. [Copyright &y& Elsevier]

Abstract: The nicotine in tobacco is thought to modulate neuronal systems regulating mood. Moreover, it appears possible that blockade rather than activation of β2-containing (β2*) nicotinic acetylcholine receptors (nAChRs) may lead to antidepressant-like effects. We used cytisine, a partial agonist of α4/β2*nAChRs and a full agonist at α3/β4*nAChRs, in several tests of antidepressant efficacy. Further, we used c-fos expression to identify potential neurobiological correlates of the antidepressant-like effects of cytisine. Cytisine had antidepressant-like effects in several animal models of antidepressant efficacy. In addition, immunohistochemical analyses indicated that cytisine could reduce c-fos immunoreactivity in the basolateral amygdala by ∼50%. These data show that cytisine acts like classical antidepressants in rodent models of antidepressant efficacy. In addition, cytisine''s ability to block α4/β2*nAChRs may be responsible for its antidepressant-like properties, and these may be mediated through a reduction of neuronal activity in the basolateral amygdala. These studies also suggest that both antagonists and partial agonists of α4/β2*nAChRs would be interesting targets for the development of novel antidepressant drugs. [Copyright &y& Elsevier]

Abstract: The widely accepted stress-diathesis hypothesis of depression postulates that genetic factors contribute to biological vulnerability. Based on this concept, the unpredictable chronic mild stress (UCMS) animal model was developed. Most effects of UCMS can be reversed by antidepressant agents, illustrating a strong predictive validity. In rodents, UCMS also has good face validity as it can elicit depression-like symptoms. While abundant for rats, the UCMS literature on mice is relatively limited. Reports sometimes are contradictory, making it difficult to establish a clear profile of stress-induced depression-like behaviors in mice. As different groups often use different strains for their experiments, differential strain susceptibility to UCMS may provide at least a partial explanation of these discrepancies. Moreover, differences in testing methodology add another level of complexity. Very little is known about the role of genetic factors and their interactions with the environment in the development of stress-induced behavioral changes relevant to depression, though recent studies unequivocally demonstrated the effects of specific gene polymorphisms on stress-induced depressive symptoms, as well as the effects of stress on gene expression. In the present study, we investigated the effects of UCMS on a battery of different tests measuring anxiety and depression-like behaviors in three behaviorally and genetically distinct inbred strains. The goals of these experiments are to obtain a clearer behavioral profile of genetically/phenotypically distant mouse strains after UCMS treatment and to evaluate the limitations and strengths of the UCMS model in mice. [Copyright &y& Elsevier]

Abstract: Mice exhibiting deficits in social behavior may provide valuable models for autistic-like behavioral problems. We tested social interactions in male mice from three inbred strains: C57BL/6J (B6), BALB/cJ (C) and DBA/2J (D2). All three strains showed gradual habituation of the number of social interactions with an ovariectomized female over four subsequent 2min sessions, returning to initial levels when presented with another stimulus mouse. Next, we studied males with a knockout mutation in the Fmr1 gene on a B6 background. KO animals showed strongly reduced levels of social interaction, which were about similar as those of habituated controls. This social behavior deficit suggests that Fmr1 KO mice could possibly be used as models for autistic behaviors. [Copyright &y& Elsevier]

The inbred strain FVB/N is becoming increasingly popular to generate transgenic animals. We compared animals from this strain with well-characterized C57BL/6J animals on four different behavioral tests: the elevated plus maze test of anxiety, a standard opponent aggression test, the open-field test, and spatial learning in a radial maze. Our results indicate that FVB/N animals have slightly higher levels of anxiety and aggression, are hyperactive, and have a clear learning deficit. The latter finding seems to be related to an exceptionally small intrapyramidal and infrapyramidal mossy fiber projection. It is recommended that transgenic experiments employing this strain use F1 crosses between FVB/N and C57BL/6J as much as possible for behavioral experiments intended to evaluate spatial learning. [Copyright &y& Elsevier]

Background: Excessive glutamatergic neurotransmission is hypothesized to be associated with depressive-like behaviors and possibly major depressive disorder (MDD). Recent evidence that β-lactam antibiotic agents stimulate uptake of glutamate suggests that this class of compounds might possess antidepressant-like activity. Methods: Three-month old, male, C57BL/6J mice were administered ceftriaxone (200 mg/kg IP) for 14–18 days, then tested in the tail-suspension, forced swim, and novelty-suppressed feeding tests to determine whether ceftriaxone had similar effects to classical antidepressant compounds in these models. Results: Ceftriaxone treatment had an antidepressant-like effect across models. Reduced immobility and decreased freezing were observed in the forced swim and tail suspension tests. The same trend was seen in novelty-suppressed feeding, but the effect was not statistically significant. Conclusion: Ceftriaxone demonstrates antidepressant-like effects in several mouse models. This is consistent with the hypothesis that enhanced uptake of glutamate might have antidepressant-like effects. [Copyright &y& Elsevier]

Abstract: Nicotine can both activate and desensitize/inactivate nicotinic acetylcholine receptors (nAChRs). An ongoing controversy in the field is to what extent the behavioral effects of nicotine result from activation of nAChRs, and to what extent receptor desensitization is involved in these behavioral processes. Recent electrophysiological studies have shown that both nAChR activation and desensitization contribute to the effects of nicotine in the brain, and these experiments have provided cellular mechanisms that could underlie the contribution of both these processes to nicotine-mediated behaviors. For instance, desensitization of nAChRs may contribute to the salience of environmental cues associated with smoking behavior and activation and desensitization of nAChRs may contribute to both primary and conditioned drug reward. Similarly, studies of the antidepressant-like effects of nicotinic agents have revealed a balance between activation and desensitization of nAChRs. This review will examine the evidence for the contribution of these two very different consequences of nicotine administration to behaviors related to nicotine addiction, including processes related to drug reinforcement and affective modulation. We conclude that there are effects of nAChR activation and desensitization on drug reinforcement and affective behavior, and that both processes are important in the behavioral consequences of nicotine in tobacco smoking. [Copyright &y& Elsevier]

Abstract: Repeated exposure to nicotine induces adaptive changes in the central nervous system including the mesolimbic dopamine (DA) projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). These modifications can modulate nicotine reward and reinforcement, but also anxiety and depression-related behaviors. The development of addiction-related phenotypes is known to be modulated by regulation of glutamate receptors, as well as activation of transcription factors including cAMP response element-binding protein (CREB), in the NAc. We investigated the effects of nicotine pre-exposure on nicotine preference and levels of GluR1/2 and CREB in the mesolimbic system in male mice C57BL/6J and BALB/c inbred mice. We also evaluated locomotor activity, anxiety-like and depression-like behaviors known to be affected by nicotine. There were few behavioral changes in mice subjected to chronic nicotine exposure, but there was a marked regulation of GluR2 in the mesolimbic system. Both treated and non-treated animals showed a significant preference for nicotine when facing a choice with a control solution. These results suggest that voluntary nicotine drinking induces nicotine preference in mice, but does not alter a number of affective behaviors. In addition, alterations in CREB and GluR1 levels are not sufficient to explain preference for nicotine in a 2-bottle choice paradigm. [Copyright &y& Elsevier]

Stress and trauma exposure disturbs stress regulation systems and thus increases the vulnerability for stress-related disorders which are characterized by negative affect, including major depressive disorder, anxiety disorders and posttraumatic stress disorder. Similarly, stress and trauma exposure results in increased vulnerability to problematic alcohol use and alcohol use disorder, especially among women, who are more likely to drink to cope with negative affect than their male counterparts. Given these associations, the relationship between stress-related disorders and alcohol use is generally stronger among women leading to complex comorbidities across these disorders and alcohol misuse. This review highlights the therapeutic potential for progestogen- and androgen-derived neurosteroids, which affect both stress- and alcohol-related disorders, to target the overlapping symptoms related to negative affect. This article is part of the special issue on 'Vulnerabilities to Substance Abuse.' • The relationship between stress-related disorders and alcohol use is stronger among women. • Progestogen/androgen-derived neurosteroids underlie both alcohol/stress-related disorders. • Allopregnanolone may reduce alcohol consumption through the reduction of negative affect. [ABSTRACT FROM AUTHOR]

• Influenza infections unseasonably low during May to July 2020 in Cambodia. • Outbreak of influenza A (H3N2) virus infection occurred in a pagoda in August 2020. • Mask use and social distancing were infrequent and inconsistent in this population. • Measures to prevent COVID-19 spread may have delayed the influenza season. • Ongoing influenza surveillance and vaccination are priorities. Global influenza virus circulation decreased during the COVID-19 pandemic, possibly due to widespread community mitigation measures. Cambodia eased some COVID-19 mitigation measures in June and July 2020. On 20 August a cluster of respiratory illnesses occurred among residents of a pagoda, including people who tested positive for influenza A but none who were positive for SARS-CoV-2. A response team was deployed on 25 August 2020. People with influenza-like illness (ILI) were asked questions regarding demographics, illness, personal prevention measures, and residential arrangements. Respiratory swabs were tested for influenza and SARS-Cov-2 by real-time reverse transcription PCR, and viruses were sequenced. Sentinel surveillance data were analyzed to assess recent trends in influenza circulation in the community. Influenza A (H3N2) viruses were identified during sentinel surveillance in Cambodia in July 2020 prior to the reported pagoda outbreak. Among the 362 pagoda residents, 73 (20.2%) ILI cases were identified and 40 were tested, where 33/40 (82.5%) confirmed positive for influenza A (H3N2). All 40 were negative for SARS-CoV-2. Among the 73 residents with ILI, none were vaccinated against influenza, 47 (64%) clustered in 3/8 sleeping quarters, 20 (27%) reported often wearing a mask, 27 (36%) reported often washing hands, and 11 (15%) reported practicing social distancing. All viruses clustered within clade 3c2.A1 close to strains circulating in Australia in 2020. Circulation of influenza viruses began in the community following the relaxation of national COVID-19 mitigation measures, and prior to the outbreak in a pagoda with limited social distancing. Continued surveillance and influenza vaccination are required to limit the impact of influenza globally. [ABSTRACT FROM AUTHOR]

When exposed to chronic social stress, animals display behavioral changes that are relevant to depressive-like phenotypes. However, the cascading relationship between incremental stress exposure and neural dysfunctions over time remains incompletely understood. We characterized the longitudinal effect of social defeat on goal-directed actions and prefrontal cortical activity in mice using a novel head-fixed sucrose preference task and two-photon calcium imaging. Behaviorally, stress-induced loss of reward sensitivity intensifies over days. Motivational anhedonia, the failure to translate positive reinforcements into future actions, requires multiple sessions of stress exposure to become fully established. For neural activity, individual layer 2/3 pyramidal neurons in the cingulate and medial secondary motor subregions of the medial prefrontal cortex have heterogeneous responses to stress. Changes in ensemble activity differ significantly between susceptible and resilient mice after the first defeat session and continue to diverge following successive stress episodes before reaching persistent abnormal levels. Collectively, these results demonstrate that the cumulative impact of an ethologically relevant stress can be observed at the level of cellular activity of individual prefrontal neurons. The distinct neural responses associated with resilience versus susceptibility suggests the hypothesis that the negative impact of social stress is neutralized in resilient animals, in part through an adaptive reorganization of prefrontal cortical activity. [ABSTRACT FROM AUTHOR]

Menthol is a commonly used flavorant in tobacco and e-cigarettes, and could contribute to nicotine sensitivity. To understand how menthol could contribute to nicotine intake and addiction, it is important to determine whether specific mechanisms related to sex and age could underlie behavioral changes induced by menthol-laced nicotinic products. Using a validated paradigm of nicotine-dependent locomotor stimulation, adolescent and adult C57BL/6J mice of both sexes were exposed to nicotine, or nicotine laced with menthol, as their sole source of fluid, and psychostimulant effects were evaluated by recording home cage locomotor activity for ten days. Nicotine and cotinine blood levels were measured following exposure. Results show an interaction between treatment, age, and sex on liquid consumption, indicating that mice responded differently to menthol and nicotine based on their age and sex. Adult male mice greatly increased their nicotine intake when given menthol. In female mice of both age groups, menthol did not have this effect. Despite an increase in nicotine intake promoted by menthol, adult male mice showed a significant decrease in locomotion, suggesting that menthol blunted nicotine-induced psychostimulation. This behavioral response to menthol was not detected in adolescent mice of either sex. These data confirm that menthol is more than a flavorant, and can influence both nicotine intake and its psychostimulant effects. These results suggest that age- and sex-dependent mechanisms could underlie menthol’s influence on nicotine intake and that studies including adolescent and adult menthol smokers of both sexes are warranted. [ABSTRACT FROM AUTHOR]

The co-morbidity between smoking and mood disorders is striking. Preclinical and clinical studies of nicotinic effects on mood, anxiety, aggression, and related behaviors, such as irritability and agitation, suggest that smokers may use the nicotine in tobacco products as an attempt to self-medicate symptoms of affective disorders. The role of nicotinic acetylcholine receptors (nAChRs) in circuits regulating mood and anxiety is beginning to be elucidated in animal models, but the mechanisms underlying the effects of nicotine on aggression-related behavioral states (ARBS) are still not understood. Clinical trials of nicotine or nicotinic medications for neurological and psychiatric disorders have often found effects of nicotinic medications on ARBS, but few trials have studied these outcomes systematically. Similarly, the increase in ARBS resulting from smoking cessation can be resolved by nicotinic agents, but the effects of nicotinic medications on these types of mental states and behaviors in non-smokers are less well understood. Here we review the literature on the role of nAChRs in regulating mood and anxiety, and subsequently on the closely related construct of ARBS. We suggest avenues for future study to identify how nAChRs and nicotinic agents may play a role in these clinically important areas. This article is part of the Special Issue entitled ‘The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition’. [ABSTRACT FROM AUTHOR]

Abstract: Cholinergic signaling is thought to be involved in morphine dependence and withdrawal, but the specific mechanisms involved remain unclear. The current study aimed to identify alterations in the cholinergic system that may contribute to the development of morphine dependence and withdrawal. Acetylcholinesterase (AChE) activity and [3H]–epibatidine binding were evaluated in order to determine if morphine dependence and withdrawal induces alterations in cholinergic signaling or expression of high affinity nicotinic acetylcholine receptors (nAChRs) in the midbrain (MB), medial habenula (MHb) and interpeduncular nucleus (IPN). The effect of cholinergic signaling through nAChRs on morphine-withdrawal induced jumping behavior was then determined. Lastly, the contribution of β4-containing nAChRs receptors in the MHb to morphine-withdrawal induced jumping behavior and neuronal activity as indicated by c-fos expression was assessed. Chronic morphine administration decreased AChE activity in MB and MHb, an effect that was no longer present following precipitated withdrawal. Morphine dependent mice showed increased nicotinic acetylcholine receptor (nAChR) levels in MB. Further, nicotine (0.4mg/kg) and lobeline (3mg/kg) decreased jumping behavior while mecamylamine (1mg/kg) had no effect. Knock-down of β4 subunit-containing nAChRs in the MHb attenuated c-fos activation, but did not decrease morphine withdrawal-induced jumping. Thus, morphine withdrawal induces cholinergic signaling in the MHb, but this does not appear to be responsible for the effects of cholinergic drugs on somatic signs of opiate withdrawal, as measured by jumping behavior. [Copyright &y& Elsevier]