Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area
Department of Psychiatry; Department of Physiology; Tapper Lab
Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology | Psychiatry
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.
DOI of Published Version
Neuropsychopharmacology. 2011 Apr;36(5):1021-32. Epub 2011 Feb 2. Link to article on publisher's site
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Zhao-Shea R, Liu L, Soll LG, Improgo MD, Meyers EE, McIntosh JM, Grady SR, Marks MJ, Gardner PD, Tapper AR. (2011). Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area. GSBS Student Publications. https://doi.org/10.1038/npp.2010.240. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/1676