Hansen, Wade; Stockard, Alyssa; Anderson, Elizabeth; Yorgason, Jordan; Sudweeks, Sterling; Wu, Jie; Steffensen, Scott (Brigham Young University)
Faculty Advisor: Steffensen, Scott (Family, Home, and Social Sciences; Psychology); Yorgason, Jordan (Life Sciences, Physiology & Developmental Biology); Sudweeks, Sterling (Life Sciences, Physiology & Developmental Biology)
The prevailing view is that enhancement of dopamine (DA) transmission in the mesolimbic underlies the rewarding properties of ethanol (EtOH) and nicotine (NIC). Although the dogma is that EtOH enhancement of DA neural activity contributes to enhancement of DA transmission, DA neurons are not sensitive to rewarding levels of EtOH. However, VTA GABA neurons are sensitive to low-dose EtOH. We have shown previously that EtOH modulation of DA release in the NAc is mediated by α6-containing nicotinic receptors (α6*-nAChRs), that α6*-nAChRs mediate low-dose EtOH effects on VTA GABA neurons and EtOH preference, and α6*-nAChRs may be a molecular target for low-dose EtOH. The aim of this study was to evaluate EtOH effects on VTA GABAergic input to CINs and DA release in the NAc. Using DIO channel rhodopsin-2 (ChR2) viral injections into the VTA of VGAT Cre mice, we found that VTA GABA neurons send an inhibitory projection to CINs, replicating what has been demonstrated by others. Low-dose EtOH (IC50 = 10 mM) decreased optically-evoked IPSCs (oIPSCs) on CINs and enhanced (EC50 = 10 mM) CIN-mediated spontaneous DA release. Surprisingly, oIPSCs on CINs were not blocked by typical GABAA receptor (GABAAR) antagonists, but by GABAR rho-1 antagonists, suggesting involvement of atypical GABARs on CINs that are postsynaptic to VTA GABAergic input. The α6-conotoxin MII blocked the effects of EtOH on spontaneous DA release and optically-evoked DA release in choline acetyltransferase (ChAT) ChR2 mice. Chronic administration of NIC enhanced EtOH consumption in the drink-in-the-dark procedure and EtOH preference in the CPP procedure and concomitantly enhanced expression of α6*-nAChRs in VTA GABA neurons, without affecting other nAChR subunits. Taken together, these findings suggest that VTA GABA neuron inhibitory input to CINs is modulated by α6*-nAChRs and sensitive to low-dose EtOH, which may underlie the rewarding properties of EtOH.