The prevailing view is that enhancement of dopamine (DA) transmission in the mesolimbic system consisting of DA neurons in the ventral tegmental area (VTA) that project to the nucleus accumbens (NAc) 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. Thus, the most sensitive target for reward-relevant EtOH modulation of mesolimbic DA transmission and the involvement of α6*-nAChRs in the mesolimbic DA reward system remains to be elucidated. 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. This study investigated the acute and chronic effects of EtOH at this synapse. We demonstrate that EtOH markedly enhances CIN firing rate and that these effects are blocked by the α6-conotoxin MII (α-Ctx MII), knockout of accumbal α6*-nAChRs with α6-shRNA, and atypical GABA receptor antagonists. This study also investigated plasticity at this synapse. We demonstrate that a low frequency stimulation (LFS; 1 Hz, 240 pulses) causes inhibitory long-term depression at this synapse (CIN-iLTD) which is also blocked by α-Ctx MII, α6-shRNA, and atypical GABA receptor antagonists. We also show that CIN-iLTD is blocked in EtOH-dependent mice. Taken together, these findings suggest that EtOH affects the VTA GABAergic projection to CINs via α6*-nAChRs and that atypical GABA receptors also play a role.



College and Department

Life Sciences; Neuroscience



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alcohol, nicotine (NIC), cholinergic interneurons (CINs), nicotinic acetylcholine receptors (nAChRs), alpha6 (α6)