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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
Source: PubMed

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.

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Available from: Darlene H Brunzell
    • "Although these receptors are upregulated, chronic exposure to nicotine desensitizes α4β2 nAChRs, which leads to a decreased response to nicotine (Wonnacott, 1990). The consensus is that while more receptors are expressed following repeated nicotine exposure, these receptors are inactive, therefore an increased amount of nicotine is needed to produce the same response (Balfour, 1994; Picciotto et al., 2008). In a clinical study, Brody et al. (2006) reported that average smokers maintain nicotine levels sufficient to occupy 88–95% of α4β2 nAChRs in brain. "
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    ABSTRACT: Polysubstance abuse of alcohol and nicotine has been overlooked in our understanding of the neurobiology of addiction and especially in the development of novel therapeutics for its treatment. Estimates show that as many as 92% of people with alcohol use disorders also smoke tobacco. The health risks associated with both excessive alcohol consumption and tobacco smoking create an urgent biomedical need for the discovery of effective cessation treatments, as opposed to current approaches that attempt to independently treat each abused agent. The lack of treatment approaches for alcohol and nicotine abuse/dependence mirrors a similar lack of research in the neurobiology of polysubstance abuse. This review discusses three critical needs in medications development for alcohol and nicotine co-abuse: (1) the need for a better understanding of the clinical condition (i.e. alcohol and nicotine polysubstance abuse) (2) the need to better understand how these drugs interact in order to identify new targets for therapeutic development and (3) the need for animal models that better mimic this human condition. Current and emerging treatments available for the cessation of each drug and their mechanisms of action are discussed within this context followed by what is known about the pharmacological interactions of alcohol and nicotine. Much has been and will continue to be gained from studying comorbid alcohol and nicotine exposure.
    No preview · Article · Nov 2015 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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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: Electrophysiological and neurochemical studies implicate cholinergic signaling in the basolateral amygdala in behaviors related to stress. Both animal studies and human clinical trials suggest that drugs that alter nicotinic acetylcholine receptor (nAChR) activity can affect behaviors related to mood and anxiety. Clinical studies also suggest that abnormalities in cholinergic signaling are associated with major depressive disorder, whereas pre-clinical studies have implicated both β2 subunit-containing (β2*) and α7 nAChRs in the effects of nicotine in models of anxiety- and depression-like behaviors. We therefore investigated whether nAChR signaling in the amygdala contributes to stress-mediated behaviors in mice. Local infusion of the non-competitive non-selective nAChR antagonist mecamylamine or viral-mediated down-regulation of the β2 or α7 nAChR subunit into the amygdala all induced robust anxiolytic- and antidepressant-like effects in several mouse behavioral models. Further, whereas α7 nAChR subunit knockdown was somewhat more effective at decreasing anxiety-like behavior, only β2 subunit knockdown decreased resilience to social defeat stress and c-fos immunoreactivity in the basolateral amygdala. In contrast, α7, but not β2, subunit knockdown effectively reversed the effect of increased ACh signaling in a mouse model of depression. These results suggest that signaling through β2* nAChRs is essential for baseline excitability of the basolateral amygdala, and a decrease in signaling through β2 nAChRs alters anxiety- and depression-like behaviors even in unstressed animals. In contrast, stimulation of α7 nAChRs by acetylcholine may mediate the increased depression-like behaviors observed during the hypercholinergic state observed in depressed individuals.Neuropsychopharmacology accepted article preview online, 16 October 2015. doi:10.1038/npp.2015.316.
    Full-text · Article · Oct 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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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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    DESCRIPTION: Background: Aggressive behavior often complicates the treatment of many neuropsychiatric disorders, especially neurodevelopmental and neurodegenerative disorders. Levels and signaling of nicotinic acetylcholine receptors (nAChRs) are altered in many of these conditions. Previous studies have demonstrated that acute administration of nicotine can reduce aggression in animal models. We therefore hypothesized that pharmacological agents active at specific nAChR subunits might be therapeutic for aggression occurring in these conditions. To that end, we sought to identify the molecular basis for nicotine’s anti-aggressive (“serenic”) effect, and to characterize the effects of GTS-21, an α7 nAChR partial agonist, on aggression in mouse models. Methods: Aggressive behavior was quantified using socially-isolated adult male C57BL/6 and BALB/c mice in a resident-intruder paradigm. Nicotine or GTS-21 was administered i.p. 10 minutes prior to initiation of resident-intruder tests. Antagonists (DHβE, 3 mg/kg, or MLA, 5 mg/kg) were administered i.p. 15 minutes prior to nicotine or GTS-21. Social interaction and locomotor testing was performed using a Noldus EthovisionXT system. c-Fos expression was quantified as a marker of neuronal activity. Results: As previously reported, aggressive behavior was dose-dependently reduced by nicotine administration, with the serenic effect of a moderate dose (0.25 mg/kg) eliminated by the α7 nAChR antagonist MLA but not by the heteromeric nAChR antagonist DHβE. We further found dose-dependent serenic effects of the α7 nAChR partial agonist GTS-21 in BALB/c mice, a low sociability and moderately aggressive mouse strain. GTS-21 was further evaluated to identify its effects on locomotor activity, sociability with conspecifics, and regulation of neuronal activity in brain regions important for regulation of aggression. Conclusion: Selective activation of the α7 nAChR may be a promising therapeutic avenue for reducing aggressive behavior. Furthermore, as multiple α7 nAChRs agonists are well tolerated in human subjects, efficacy in humans with pathological aggression can be tested in controlled clinical trials.
    Full-text · Poster · Oct 2015
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