Taylor Woodward, Brigham Young University
Life Sciences
The prevailing view is that enhancement of dopamine (DA) transmission in the mesocorticolimbic system, consisting of DA neurons in the ventral tegmental area (VTA) that innervate the nucleus accumbens (NAc), underlies the rewarding properties of alcohol and nicotine (NIC). Dopamine neurotransmission is regulated by inhibitory VTA GABA neurons. We have shown previously that VTA GABA neurons are excited by low-dose ethanol, but inhibited by moderate to high-dose ethanol. The aim of this study was to evaluate the role of []6 nicotinic cholinergic receptors (nAChRs) in ethanol effects on VTA GABA neurons as well as DA release in the NAc. In electrophysiology studies, superfusion of ethanol enhanced the frequency, but not amplitude, of mIPSCs recorded in acutely dissociated VTA GABA neurons from GAD GFP mice. The []6 nAChR antagonist []-conotoxin P1A did not affect mIPSCs, but prevented the ethanol (30 mM)-induced increase in mIPSC frequency. While microdialysis studies show that ethanol enhances DA release in the NAc, we and others have found that ethanol decreases DA release at terminals using fast scan cyclic voltammetry (FSCV). We have reported that ethanol inhibition of DA release at terminals in the NAc of ethanol-naïve animals is mediated by GABA. Using FSCV in the slice preparation, ethanol inhibited DA release in the NAc. Superfusion of the []6 nAChR antagonist []-conotoxin MII did not affect DA release, but prevented ethanol inhibition of DA release. Taken together, these findings suggest that ethanol enhancement of GABA inhibition of VTA GABA neurons is mediated by []6 nAChRs located on GABA terminals to other VTA neurons, affecting DA release in the NAc. Results from this study could provide a pharmacologic rationale for considering drugs that act selectively on nAChRs as therapeutic agents for the treatment of alcohol dependence and alcohol and NIC co-dependence.