Objective It is well documented that ethanol exposure alters GABA (γ-aminobutyric acid)-releasing synapses, and ethanol addiction is associated with endogenous opioid system.Emerging evidence indicates that opioids block long-term potentiation in the fast inhibitory GABAA receptor synapses (LTPGABA) onto dopamine-containing neurons in the ventral tegmental area (VTA), a brain region essential for reward-seeking behavior.However, how ethanol affects LTPGABA is not known.The present study is to explore the effects of ethanol on long-term potentiation of GABAergic synapses in the ventral tegrnental area.Methods Using whole-cell patch clamp methods we recorded evoked IPSCs from DA neurons in acute coronal midbrain slices of young Sprague-Dawley rats.Results We report here that in acute midbrain slices from rats, clinically relevant concentrations of ethanol applied both in vitro and in vivo prevents LTPGABA, which is reversed, respectively, by in vitro and in vivo administration of naloxone, a mu-opioid receptor (MOR) antagonist.Furthermore, the blockade of LTPGABA induced by a brief in vitro ethanol treatment is mimicked by DAMGO ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin), a MOR agonist.Paired-pulse ratios are similar in slices, 24 h after in vivo injection with either saline or ethanol.Sp-cAMPS, a stable cAMP analog, and pCPT-cGMP, a cGMP analog, potentiate GABAA-mediated inhibitory postsynaptic currents in slices from ethanol-treated rats, indicating that a single in vivo ethanol exposure does not maximally increase GABA release.Instead, ethanol produces a long-lasting inability to generate LTPGABA.Conclusion Ethanol blocks long-term potentiation of GABAergic synapses in the ventral tegmental area involving MORs.These neuroadaptations to ethanol might contribute to early stage of addiction.