Functional Upregulation of alpha4* Nicotinic Acetylcholine Receptors in VTA GABAergic Neurons Increases Sensitivity to Nicotine Reward

The authors grant the Society for Neuroscience an exclusive license to publish their work for the first 6 months. After 6 months the work becomes available to the public to copy, distribute, or display under a Creative Commons Attribution 4.0 International (CC BY 4.0) license. Chronic nicotine exposure increases sensitivity to nicotine reward during a withdrawal period, which may facilitate relapse in abstinent smokers, yet the molecular neuroadaptation(s) that contribute to this phenomenon are unknown. Interestingly, chronic nicotine use induces functional upregulation of nicotinic acetylcholine receptors (nAChRs) in the mesocorticolimbic reward pathway potentially linking upregulation to increased drug sensitivity. In the ventral tegmental area (VTA), functional upregulation of nAChRs containing the ␣4 subunit (␣4* nAChRs) is restricted to GABAergic neurons. To test the hypothesis that increased functional expression of ␣4* nAChRs in these neurons modulates nicotine reward behaviors, we engineered a Cre recombinase-dependent gene expression system to selectively express ␣4 nAChR subunits harboring a " gain-of-function " mutation [a leucine mutated to a serine residue at the 9Ј position (Leu9ЈSer)] in VTA GABAergic neurons of adult mice. In mice expressing Leu9ЈSer ␣4 nAChR subunits in VTA GABAergic neurons (Gad2 VTA :Leu9ЈSer mice), subreward threshold doses of nicotine were sufficient to selectively activate VTA GABAergic neurons and elicit acute hypolocomotion, with subsequent nicotine exposures eliciting tolerance to this effect, compared to control animals. In the conditioned place preference procedure, nicotine was sufficient to condition a significant place preference in Gad2 VTA :Leu9ЈSer mice at low nicotine doses that failed to condition control animals. Together, these data indicate that functional upregulation of ␣4* nAChRs in VTA GABAergic neurons confers increased sensitivity to nicotine reward and points to nAChR subtypes specifically expressed in GABAergic VTA neurons as molecular targets for smoking cessation therapeutics.