Habenular α5* nicotinic receptor signaling controls nicotine intake

Laboratory for Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, The Scripps Research Institute-Scripps Florida, Jupiter, Florida 33458, USA.
Nature (Impact Factor: 41.46). 01/2011; 471(7340):597-601. DOI: 10.1038/nature09797
Source: PubMed


Genetic variation in CHRNA5, the gene encoding the α5 nicotinic acetylcholine receptor subunit, increases vulnerability to tobacco addiction and lung cancer, but the underlying mechanisms are unknown. Here we report markedly increased nicotine intake in mice with a null mutation in Chrna5. This effect was 'rescued' in knockout mice by re-expressing α5 subunits in the medial habenula (MHb), and recapitulated in rats through α5 subunit knockdown in MHb. Remarkably, α5 subunit knockdown in MHb did not alter the rewarding effects of nicotine but abolished the inhibitory effects of higher nicotine doses on brain reward systems. The MHb extends projections almost exclusively to the interpeduncular nucleus (IPN). We found diminished IPN activation in response to nicotine in α5 knockout mice. Further, disruption of IPN signalling increased nicotine intake in rats. Our findings indicate that nicotine activates the habenulo-interpeduncular pathway through α5-containing nAChRs, triggering an inhibitory motivational signal that acts to limit nicotine intake.

Download full-text


Available from: Christie D Fowler,
52 Reads
  • Source
    • "Nicotinic antagonists at both β2* and α7 nAChRs can have antidepressant-like effects in mice (Andreasen et al, 2012; Andreasen et al, 2013; Mineur et al, 2009; Peng et al, 2013; Rollema et al, 2009). In addition, nAChR subtypes containing the α5, α2, α3 and β4 subunits have all been implicated in the aversive properties of nicotine, symptoms related to nicotine withdrawal and behaviors related to anxiety and depression (Fowler et al, 2011; Frahm et al, 2011; Salas et al, 2004; Salas et al, 2003; Upton and Lotfipour, 2015) . The non-competitive non-selective antagonist mecamylamine and the partial agonist cytisine are both effective in mouse models of antidepressant-efficacy and converge to decrease neuronal activity in the basolateral amygdala (Mineur et al, 2007), a brain region that is often hyperactivated in depressed patients (Drevets et al, 2008). "
    [Show abstract] [Hide abstract]
    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.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2015; DOI:10.1038/npp.2015.316 · 7.05 Impact Factor
    • "). CHRNA5 encodes the ␣5 nicotinic receptor subunit and plays a role in the pharmacodynamic pathway of nicotine dependence (Fowler et al., 2011). Further studies have demonstrated change in the receptor function in response to nicotine agonists given this amino acid change in the ␣5 nicotinic receptor subunit (Bierut et al., 2008; Brown et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent evidence suggests that the efficacy of smoking cessation pharmacotherapy can vary across patients based on their genotypes. This study tests whether the coding variant rs16969968 in the CHRNA5 nicotinic receptor gene predicts the effects of combination nicotine replacement therapy (cNRT) and varenicline on treatment outcomes. In two randomized smoking cessation trials comparing cNRT vs. placebo, and varenicline vs. placebo, we used logistic regression to model associations between CHRNA5 rs16969968 and abstinence at end of treatment. For abstinence at end of treatment, there was an interaction between cNRT and rs16969968 (X(2)=8.15, df=2, omnibus-p=0.017 for the interaction); individuals with the high-risk AA genotype were more likely to benefit from cNRT. In contrast, varenicline increased abstinence, but its effect did not vary with CHRNA5. However, the genetic effects differed between the placebo control groups across two trials (wald=3.94, df=1, p=0.047), this non-replication can alter the interpretation of pharmacogenetic findings. Results from two complementary smoking cessation trials demonstrate inconsistent genetic results in the placebo arms. This evidence highlights the need to compare the most effective pharmacotherapies with the same placebo control to establish pharmacogenetic evidence to aid decisions on medication choice for patients trying to quit smoking. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Drug and alcohol dependence 06/2015; 154. DOI:10.1016/j.drugalcdep.2015.06.022 · 3.42 Impact Factor
  • Source
    • "This change is associated with reduced receptor function in vitro (Bierut et al., 2008). Preclinical evidence suggests that that the alpha-5 nicotinic receptor subunit, encoded by CHRNA5, influences self-titrated nicotine exposure via tolerance to the toxic effects of high doses of nicotine (Fowler et al., 2011). There is also evidence that this variant is associated with a reduced likelihood of smoking cessation (Munafo et al., 2011; Taylor et al., 2014), and reduced body mass index (BMI) in individuals who smoke (Freathy et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: While nicotine replacement therapy (NRT) is an effective pharmacological smoking cessation treatment, its efficacy is influenced by adherence to and consumption of the prescribed dose. The genetic variant rs1051730 in the nicotinic receptor gene cluster CHRNA5-A3-B4 influences smoking quantity. The aim of this study was to explore the impact of rs1051730 genotype on adherence to and consumption of NRT prescription following a smoking cessation attempt. Secondary analysis of data from a pharmacogenetic smoking cessation trial. Participants (n=448) were prescribed a daily dose of NRT for four weeks post quit attempt, and monitored during weekly clinic visits. Outcome measures were NRT prescription adherence rate (%) and average daily NRT consumption (mg) at 7- and 28-days after the quit attempt. An association between rs1051730 genotype and both outcome measures was observed at 7-days after the quit date. Each copy of the minor allele corresponded to a 2.9% decrease in adherence to prescribed NRT dose (P=0.044), and a 1.0mg decrease in daily NRT consumption (P=0.026). Adjusting for number of cigarettes smoked during this period only slightly attenuated these associations. There was no clear statistical evidence of an association between genotype and adherence or consumption at 28-days. This is the first study to evaluate the impact of rs1051730 genotype on consumption of and adherence to NRT prescription during a smoking cessation attempt. We observed an association between this variant and both outcome measures at 7-days; however, this was only moderate. These findings require replication in an independent sample. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
    Drug and alcohol dependence 04/2015; 165. DOI:10.1016/j.drugalcdep.2015.03.035 · 3.42 Impact Factor
Show more