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.

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Available from: Christie D Fowler
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    • "Finally, the strong impact of Chrna5 expression in mouse MHb and VTA on nicotine consumption despite low levels of mRNA expression in mice and humans signifies the importance of the specific cell types on which these receptors are expressed. The MHb afferents that express the α5 subunit project to the interpeduncular nucleus[19], which also contains GABAergic neurons expressing the α5 subunit[18], modulating aversiveness associated with nicotine intake[16]and withdrawal[43]. Dopaminergic neurons in the VTA express the α5 receptor subunit[44]and project to multiple addictionrelated brain regions, including the cortex and insula via the mesocortical pathway and limbic areas, the nucleus accumbens, lateral habenula, and amygdala through the mesolimbic pathway[45]. "

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    • "For example, it has been demonstrated in several systems that neurotransmitters can be coreleased (El Mestikawy et al., 2011; Gras et al., 2008; Guzman et al., 2011; Hnasko et al., 2010; Hnasko and Edwards, 2012; Ren et al., 2011; Shabel et al., 2014), and that cooperation between vesicular neurotransmitter transporters located in the same synaptic vesicle (SV) can reciprocally increase the packaging of their respective neurotransmitters into SVs, a process termed vesicular synergy (El Mestikawy et al., 2011; Gras et al., 2008; Hnasko et al., 2010). Furthermore, infusion of glutamate receptor antagonists into the IPN results in decreased nicotine intake (Fowler et al., 2011) and withdrawal (Zhao-Shea et al., 2013) suggesting that glutamate-mediated fast synaptic transmission is also important in nicotine addiction. Given evidence that both glutamate and ACh play important roles at habenular-IPN synapses, and that vesicular synergy contributes to the physiology and function of other critical CNS circuits, we were interested in examining the interactions between these transmitter systems in habenular neurons and in determining their contributions to nicotine dependence. "
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    ABSTRACT: A great deal of interest has been focused recently on the habenula and its critical role in aversion, negative-reward and drug dependence. Using a conditional mouse model of the ACh-synthesizing enzyme choline acetyltransferase ( Chat ), we report that local elimination of acetylcholine (ACh) in medial habenula (MHb) neurons alters glutamate corelease and presynaptic facilitation. Electron microscopy and immuno-isolation analyses revealed colocalization of ACh and glutamate vesicular transporters in synaptic vesicles (SVs) in the central IPN. Glutamate reuptake in SVs prepared from the IPN was increased by ACh, indicating vesicular synergy. Mice lacking CHAT in habenular neurons were insensitive to nicotine-conditioned reward and withdrawal. These data demonstrate that ACh controls the quantal size and release frequency of glutamate at habenular synapses, and suggest that the synergistic functions of ACh and glutamate may be generally important for modulation of cholinergic circuit function and behavior.
    Full-text · Article · Dec 2015 · eLife Sciences
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    • "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). "
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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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