Brudnick Neuropsychiatric Research Institute; Department of Psychiatry; Gene Therapy Center; Department of Microbiology and Physiological Systems
Medical Subject Headings
Action Potentials; Animals; Bacterial Proteins; Calbindin 2; Calbindins; Conditioning, Operant; Dihydro-beta-Erythroidine; Dose-Response Relationship, Drug; GABAergic Neurons; Glutamate Decarboxylase; Luminescent Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Nicotine; Nicotinic Agonists; Proto-Oncogene Proteins c-fos; Receptors, Nicotinic; *Reward; Tyrosine 3-Monooxygenase; Up-Regulation; Ventral Tegmental Area
Behavioral Neurobiology | Molecular and Cellular Neuroscience | Substance Abuse and Addiction
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 alpha4 subunit (alpha4* nAChRs) is restricted to GABAergic neurons. To test the hypothesis that increased functional expression of alpha4* nAChRs in these neurons modulates nicotine reward behaviors, we engineered a Cre recombinase-dependent gene expression system to selectively express alpha4 nAChR subunits harboring a "gain-of-function" mutation [a leucine mutated to a serine residue at the 9' position (Leu9'Ser)] in VTA GABAergic neurons of adult mice. In mice expressing Leu9'Ser alpha4 nAChR subunits in VTA GABAergic neurons (Gad2(VTA):Leu9'Ser 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):Leu9'Ser mice at low nicotine doses that failed to condition control animals. Together, these data indicate that functional upregulation of alpha4* 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.
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Citation: J Neurosci. 2015 Jun 3;35(22):8570-8. doi: 10.1523/JNEUROSCI.4453-14.2015. Link to article on publisher's site
DOI of Published Version
GABA, nicotine, nicotinic receptor, reward
The Journal of neuroscience : the official journal of the Society for Neuroscience
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Ngolab, Jennifer; Liu, Liwang; Zhao-Shea, Rubing; Gao, Guangping; Gardner, Paul D.; and Tapper, Andrew R., "Functional Upregulation of alpha4* Nicotinic Acetylcholine Receptors in VTA GABAergic Neurons Increases Sensitivity to Nicotine Reward" (2015). GSBS Student Publications. 1982.