title: Functional Upregulation of α4* Nicotinic Acetylcholine Receptors in VTA GABAergic Neurons Increases Sensitivity to Nicotine Reward.
abstract: 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 α4 subunit (α4* nAChRs) is restricted to GABAergic neurons. To test the hypothesis that increased functional expression of α4* nAChRs in these neurons modulates nicotine reward behaviors, we engineered a Cre recombinase-dependent gene expression system to selectively express α4 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 α4 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 α4* 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.
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ngolab
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry and.
authors.forename: Liwang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry and.
authors.forename: Rubing
authors.initials: R
authors.lastname: Zhao-Shea
authors.affiliation: Gene Therapy Center, Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01604.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry and.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Gardner
authors.affiliation: Brudnick Neuropsychiatric Research Institute, Department of Psychiatry and andrew.tapper@umassmed.edu.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Tapper
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D064032:Calbindin 2 / Q000378:metabolism; D064026:Calbindins / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D012201:Reward; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D017557:Ventral Tegmental Area / Q000166:cytology* / Q000187:drug effects
chemical_list: D001426:Bacterial Proteins; D064032:Calbindin 2; D064026:Calbindins; D004079:Dihydro-beta-Erythroidine; D005968:Glutamate Decarboxylase; D008164:Luminescent Proteins; D009538:Nicotine; D018722:Nicotinic Agonists; D016760:Proto-Oncogene Proteins c-fos; D011978:Receptors, Nicotinic; D014446:Tyrosine 3-Monooxygenase; C054562:yellow fluorescent protein, Bacteria; C401141:glutamate decarboxylase 2
keywords: GABA; nicotine; nicotinic receptor; reward