title: Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area.
abstract: Nicotine activation of nicotinic acetylcholine receptors (nAChRs) within the dopaminergic (DAergic) neuron-rich ventral tegmental area (VTA) is necessary and sufficient for nicotine reinforcement. In this study, we show that rewarding doses of nicotine activated VTA DAergic neurons in a region-selective manner, preferentially activating neurons in the posterior VTA (pVTA) but not in the anterior VTA (aVTA) or in the tail VTA (tVTA). Nicotine (1 μM) directly activated pVTA DAergic neurons in adult mouse midbrain slices, but had little effect on DAergic neurons within the aVTA. Quantification of nAChR subunit gene expression revealed that pVTA DAergic neurons expressed higher levels of α4, α6, and β3 transcripts than did aVTA DAergic neurons. Activation of nAChRs containing the α4 subunit (α4(*) nAChRs) was necessary and sufficient for activation of pVTA DAergic neurons: nicotine failed to activate pVTA DAergic neurons in α4 knockout animals; in contrast, pVTA α4(*) nAChRs were selectively activated by nicotine in mutant mice expressing agonist-hypersensitive α4(*) nAChRs (Leu9'Ala mice). In addition, whole-cell currents induced by nicotine in DAergic neurons were mediated by α4(*) nAChRs and were significantly larger in pVTA neurons than in aVTA neurons. Infusion of an α6(*) nAChR antagonist into the VTA blocked activation of pVTA DAergic neurons in WT mice and in Leu9'Ala mice at nicotine doses, which only activate the mutant receptor indicating that α4 and α6 subunits coassemble to form functional receptors in these neurons. Thus, nicotine selectively activates DAergic neurons within the pVTA through α4α6(*) nAChRs. These receptors represent novel targets for smoking-cessation therapies.
authors.affiliation: Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Rubing
authors.initials: R
authors.lastname: Zhao-Shea
authors.forename: Liwang
authors.initials: L
authors.lastname: Liu
authors.forename: Lindsey G
authors.initials: LG
authors.lastname: Soll
authors.forename: Ma Reina
authors.initials: MR
authors.lastname: Improgo
authors.forename: Erin E
authors.initials: EE
authors.lastname: Meyers
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Grady
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marks
authors.forename: Paul D
authors.initials: PD
authors.lastname: Gardner
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Tapper
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D048429:Cell Size / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism*; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D042282:Microdissection / Q000379:methods; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013696:Temperature; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology*
chemical_list: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D001285:Atropine; D001640:Bicuculline; D004298:Dopamine; D018691:Excitatory Amino Acid Antagonists; D058787:GABA-A Receptor Antagonists; D008464:Mecamylamine; D018727:Muscarinic Antagonists; D009538:Nicotine; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D014446:Tyrosine 3-Monooxygenase