α4α6β2* Nicotinic Acetylcholine Receptor Activation on Ventral Tegmental Area Dopamine Neurons Is Sufficient to Stimulate a Depolarizing Conductance and Enhance Surface AMPA Receptor Function

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, it is unknown which nAChR subtypes are sufficient to activate these neurons. To test the hypothesis that nAChRs containing alpha 6 subunits are sufficient to activate VTA DA neurons, we studied mice expressing hypersensitive, gain-of-function alpha 6 nAChRs (alpha 6L9'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 alpha 6 beta 2* nAChRs. In addition, we found that low concentrations of nicotine could act selectively through alpha 6 beta 2* 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, alpha 6 beta 2* activation did not enhance N-methyl-D-aspartic acid receptor function. Finally, AMPA receptor (AMPAR) function was not similarly enhanced in brain slices from alpha 6L9'S mice lacking alpha 4 nAChR subunits, suggesting that alpha 4 alpha 6 beta 2* nAChRs are important for enhancing AMPAR function in VTA DA neurons. Together, these data suggest that activation of alpha 4 alpha 6 beta 2* nAChRs in VTA DA neurons is sufficient to support the initiation of cellular changes that play a role in addiction to nicotine. alpha 4 alpha 6 beta 2* nAChRs may be a promising target for future smoking cessation pharmacotherapy.