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.
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Acknowledgements
This study was supported by the National Institute On Alcohol Abuse and Alcoholism award numbers R01AA017656 and R21AA018042 (ART), the National Institute of Mental Health R01MH53631 (JMM), the National Institute on Drug Abuse award numbers DA003194 (MJM) and DA012242 (MJM and JMM), and the National Institute on Neurological Disorders and Stroke award number R01NS030243 (PDG). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, the National Institute on Neurological Disorders and Stroke, or the National Institutes of Health.
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Zhao-Shea, R., Liu, L., Soll, L. et al. Nicotine-Mediated Activation of Dopaminergic Neurons in Distinct Regions of the Ventral Tegmental Area. Neuropsychopharmacol 36, 1021–1032 (2011). https://doi.org/10.1038/npp.2010.240
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DOI: https://doi.org/10.1038/npp.2010.240
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