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Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area.
Neuropsychopharmacology. 2011 Apr; 36(5):1021-32.N

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+Show Affiliations

Department of Psychiatry, University of Massachusetts Medical School, Worcester, MA, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21289604

Citation

Zhao-Shea, Rubing, et al. "Nicotine-mediated Activation of Dopaminergic Neurons in Distinct Regions of the Ventral Tegmental Area." Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 36, no. 5, 2011, pp. 1021-32.
Zhao-Shea R, Liu L, Soll LG, et al. Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area. Neuropsychopharmacology. 2011;36(5):1021-32.
Zhao-Shea, R., Liu, L., Soll, L. G., Improgo, M. R., Meyers, E. E., McIntosh, J. M., Grady, S. R., Marks, M. J., Gardner, P. D., & Tapper, A. R. (2011). Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 36(5), 1021-32. https://doi.org/10.1038/npp.2010.240
Zhao-Shea R, et al. Nicotine-mediated Activation of Dopaminergic Neurons in Distinct Regions of the Ventral Tegmental Area. Neuropsychopharmacology. 2011;36(5):1021-32. PubMed PMID: 21289604.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area. AU - Zhao-Shea,Rubing, AU - Liu,Liwang, AU - Soll,Lindsey G, AU - Improgo,Ma Reina, AU - Meyers,Erin E, AU - McIntosh,J Michael, AU - Grady,Sharon R, AU - Marks,Michael J, AU - Gardner,Paul D, AU - Tapper,Andrew R, Y1 - 2011/02/02/ PY - 2011/2/4/entrez PY - 2011/2/4/pubmed PY - 2011/7/14/medline SP - 1021 EP - 32 JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JO - Neuropsychopharmacology VL - 36 IS - 5 N2 - 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. SN - 1740-634X UR - https://www.unboundmedicine.com/medline/citation/21289604/Nicotine_mediated_activation_of_dopaminergic_neurons_in_distinct_regions_of_the_ventral_tegmental_area_ L2 - http://dx.doi.org/10.1038/npp.2010.240 DB - PRIME DP - Unbound Medicine ER -