Picciotto MR, Addy NA, Mineur YS, Brunzell DH. It is not "either/or": Activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood. Prog Neurobiol 84: 329-342

Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA.
Progress in Neurobiology (Impact Factor: 9.99). 05/2008; 84(4):329-42. DOI: 10.1016/j.pneurobio.2007.12.005
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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.

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Available from: Darlene H Brunzell, Oct 05, 2015
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    • "Like b2 subunit-containing nAChRs, a7 nAChRs are widely expressed in mouse brain, including in regions that regulate aggression and related behaviors, such as cortex, hypothalamus, hippocampus, and amygdala [42] [43]. a7 nAChRs are ionotropic receptors that generate an excitatory current but are also prone to desensitization by nicotine [44] [45]. If nicotine's serenic action were due to desensitization of a7 nAChRs, we might expect MLA on its own to be serenic, which is not supported by the current data. "
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    ABSTRACT: 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 (0.25mg/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 (5mg/kg), but not the heteromeric (β2 or β4 subunit-containing) nAChR antagonist dihydro-β-erythroidine (DHβE, 3mg/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. Copyright © 2015. Published by Elsevier Inc.
    Biochemical pharmacology 07/2015; DOI:10.1016/j.bcp.2015.07.019 · 5.01 Impact Factor
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    • "Smoking-related reinforcement is also likely to depend on several other factors relating to the regulation of signaling via nicotinic acetylcholine receptors (nAChRs). Experimental results from several model systems ranging from transfected xenopus oocytes to postmortem autoradiography in human brain suggest that nicotine causes not only nAChR activation, but also upregulation of nAChRs and both short-term and long-term desensitization of nAChRs (reviewed by Govind et al., 2009; Picciotto et al., 2008). The timing of cigarette administrations in these experiments was chosen in order to measure changes in subjective effects of smoking in a receptorsensitized (after overnight abstinence) and receptor-desensitized state (30 minutes after the first cigarette) in smokers. "
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    • "It has been postulated that these approaches could have positive effects on mood in smokers trying to quit. Nicotine delivered through skin patches can also improve mood in non-smokers (Salin-Pascual et al., 1995, 1996), potentially through sustained desensitization of nAChRs (Mineur and Picciotto, 2010; Picciotto et al., 2008). Recently, a clinical trial of a nicotinic-based antidepressant that blocks nAChRs (dexmecamylamine) failed to show efficacy in patients who were resistant to SSRIs (Vieta et al., 2014), however, similar compounds have shown promising effects in smaller clinical trials, and enhanced the effects of SSRIs in human depressed subjects (George et al., 2008; Philip et al., 2009), suggesting that a subset of patients may be more responsive to these medications or have an underlying alteration of cholinergic signaling. "
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    ABSTRACT: 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 a Special Issue entitled 'Nicotinic Acetylcholine Receptor'. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 01/2015; 96(Pt B). DOI:10.1016/j.neuropharm.2014.12.028 · 5.11 Impact Factor
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