PMID- 21289604 OWN - NLM STAT- MEDLINE DCOM- 20110713 LR - 20211020 IS - 1740-634X (Electronic) IS - 0893-133X (Print) IS - 0893-133X (Linking) VI - 36 IP - 5 DP - 2011 Apr TI - Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area. PG - 1021-32 LID - 10.1038/npp.2010.240 [doi] AB - 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 muM) 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 alpha4, alpha6, and beta3 transcripts than did aVTA DAergic neurons. Activation of nAChRs containing the alpha4 subunit (alpha4(*) nAChRs) was necessary and sufficient for activation of pVTA DAergic neurons: nicotine failed to activate pVTA DAergic neurons in alpha4 knockout animals; in contrast, pVTA alpha4(*) nAChRs were selectively activated by nicotine in mutant mice expressing agonist-hypersensitive alpha4(*) nAChRs (Leu9'Ala mice). In addition, whole-cell currents induced by nicotine in DAergic neurons were mediated by alpha4(*) nAChRs and were significantly larger in pVTA neurons than in aVTA neurons. Infusion of an alpha6(*) 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 alpha4 and alpha6 subunits coassemble to form functional receptors in these neurons. Thus, nicotine selectively activates DAergic neurons within the pVTA through alpha4alpha6(*) nAChRs. These receptors represent novel targets for smoking-cessation therapies. FAU - Zhao-Shea, Rubing AU - Zhao-Shea R AD - Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA. FAU - Liu, Liwang AU - Liu L FAU - Soll, Lindsey G AU - Soll LG FAU - Improgo, Ma Reina AU - Improgo MR FAU - Meyers, Erin E AU - Meyers EE FAU - McIntosh, J Michael AU - McIntosh JM FAU - Grady, Sharon R AU - Grady SR FAU - Marks, Michael J AU - Marks MJ FAU - Gardner, Paul D AU - Gardner PD FAU - Tapper, Andrew R AU - Tapper AR LA - eng GR - DA012242/DA/NIDA NIH HHS/United States GR - DA003194/DA/NIDA NIH HHS/United States GR - R01 DA012242/DA/NIDA NIH HHS/United States GR - R21 AA018042/AA/NIAAA NIH HHS/United States GR - R01 MH053631/MH/NIMH NIH HHS/United States GR - R01 DA003194-28/DA/NIDA NIH HHS/United States GR - R01NS030243/NS/NINDS NIH HHS/United States GR - R01AA017656/AA/NIAAA NIH HHS/United States GR - R21AA018042/AA/NIAAA NIH HHS/United States GR - R01 NS030243/NS/NINDS NIH HHS/United States GR - R01 DA012242-07/DA/NIDA NIH HHS/United States GR - R01 DA003194/DA/NIDA NIH HHS/United States GR - R01 DA012242-08/DA/NIDA NIH HHS/United States GR - R01 AA017656/AA/NIAAA NIH HHS/United States GR - R01MH53631/MH/NIMH NIH HHS/United States GR - R01 DA003194-29/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20110202 PL - England TA - Neuropsychopharmacology JT - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JID - 8904907 RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (GABA-A Receptor Antagonists) RN - 0 (Muscarinic Antagonists) RN - 0 (Nicotinic Agonists) RN - 0 (Nicotinic Antagonists) RN - 0 (Proto-Oncogene Proteins c-fos) RN - 0 (RNA, Messenger) RN - 0 (Receptors, Nicotinic) RN - 0 (nicotinic acetylcholine receptor alpha4 subunit) RN - 6EE945D3OK (Mecamylamine) RN - 6M3C89ZY6R (Nicotine) RN - 6OTE87SCCW (6-Cyano-7-nitroquinoxaline-2,3-dione) RN - 7C0697DR9I (Atropine) RN - EC 1.14.16.2 (Tyrosine 3-Monooxygenase) RN - VTD58H1Z2X (Dopamine) RN - Y37615DVKC (Bicuculline) SB - IM MH - 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology MH - Action Potentials/drug effects MH - Analysis of Variance MH - Animals MH - Atropine/pharmacology MH - Bicuculline/pharmacology MH - Cell Count/methods MH - Cell Size/drug effects MH - Dopamine/*metabolism MH - Drug Interactions MH - Electric Stimulation/methods MH - Excitatory Amino Acid Antagonists/pharmacology MH - GABA-A Receptor Antagonists/pharmacology MH - Gene Expression Regulation/drug effects/genetics MH - In Vitro Techniques MH - Male MH - Mecamylamine/pharmacology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Microdissection/methods MH - Muscarinic Antagonists/pharmacology MH - Neurons/*drug effects/metabolism MH - Nicotine/*pharmacology MH - Nicotinic Agonists/*pharmacology MH - Nicotinic Antagonists/pharmacology MH - Patch-Clamp Techniques/methods MH - Proto-Oncogene Proteins c-fos/metabolism MH - RNA, Messenger/metabolism MH - Receptors, Nicotinic/deficiency/genetics/metabolism MH - Temperature MH - Tyrosine 3-Monooxygenase/metabolism MH - Ventral Tegmental Area/*cytology PMC - PMC3077271 MID - NIHMS258009 EDAT- 2011/02/04 06:00 MHDA- 2011/07/14 06:00 PMCR- 2012/04/01 CRDT- 2011/02/04 06:00 PHST- 2011/02/04 06:00 [entrez] PHST- 2011/02/04 06:00 [pubmed] PHST- 2011/07/14 06:00 [medline] PHST- 2012/04/01 00:00 [pmc-release] AID - npp2010240 [pii] AID - 10.1038/npp.2010.240 [doi] PST - ppublish SO - Neuropsychopharmacology. 2011 Apr;36(5):1021-32. doi: 10.1038/npp.2010.240. Epub 2011 Feb 2.