PT  - JOURNAL ARTICLE
AU  - Staci E Engle
AU  - Pei-Yu Shih
AU  - J Michael McIntosh
AU  - Ryan M Drenan
TI  - α4α6β2* nAChR Activation on VTA DA Neurons is Sufficient to Stimulate a Depolarizing Conductance and Enhance Surface AMPA Receptor Function
AID  - 10.1124/mol.113.087346
DP  - 2013 Jan 01
TA  - Molecular Pharmacology
PG  - mol.113.087346
4099  - http://molpharm.aspetjournals.org/content/early/2013/06/20/mol.113.087346.short
4100  - http://molpharm.aspetjournals.org/content/early/2013/06/20/mol.113.087346.full
AB  - Tobacco addiction is a serious threat to public health in the United States and abroad, and development of new therapeutic approaches is a major priority. Nicotine activates and/or desensitizes nicotinic acetylcholine receptors (nAChRs) throughout the brain. nAChRs in ventral tegmental area (VTA) dopamine (DA) neurons are crucial for the rewarding and reinforcing properties of nicotine in rodents, suggesting that they may be key mediators of nicotine's action in humans. However, which nAChR subtype(s) that is/are sufficient to activate these neurons is unknown. To test the hypothesis that nAChRs containing α6 subunits are sufficient to activate VTA DA neurons, we studied mice expressing hypersensitive, gain-of-function α6 nAChRs (α6L9'S mice). In voltage clamp recordings in brain slices from adult mice, 100 nM nicotine was sufficient to elicit inward currents in VTA DA neurons via α6β2* nAChRs. In addition, we found that low concentrations of nicotine could act selectively through α6β2* nAChRs to enhance the function of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) receptors on the surface of these cells. In contrast, α6β2* activation did not enhance N-methyl D-aspartic acid (NMDA) receptor function. Finally, AMPAR function was not similarly enhanced in brain slices from α6L9'S mice lacking α4 nAChR subunits, suggesting that α4α6β2* nAChRs are important for enhancing AMPAR function in VTA DA neurons. Together, these data suggest that activation of α4α6β2* nAChRs in VTA DA neurons is sufficient to support the initiation of cellular changes that play a role in addiction to nicotine. α4α6β2* nAChRs may be a promising target for future smoking cessation pharmacotherapy.