GABAergic TRANSMISSION MODULATES ETHANOL EXCITATION OF VENTRAL TEGMENTAL AREA DOPAMINE NEURONS

摘要

Activation of the dopaminergic (DA) neurons of the ventral tegmental area (VTA) by ethanol has been implicated in its rewarding and reinforcing effects. We previously demonstrated that ethanol enhances GABA release onto VTA-DA neurons via activation of 5-HT_(2C) receptors and subsequent release of calcium from intracellular stores. Here we demonstrate that excitation of VTA-DA neurons by ethanol is limited by an ethanol-enhancement in GABA release. In this study, we performed whole-cell voltage clamp recordings of miniature inhibitory postsynaptic currents (mlPSCs) and cell-attached recordings of action potential firing from VTA-DA neurons in midbrain slices from young Long Evans rats. Acute exposure to ethanol (75 mM) transiently enhanced the firing rate of VTA-DA neurons as well as the frequency of mlPSCs. Simultaneous blockade of both GABA_A and GABA_B receptors (Picrotoxin (75 muM) and SCH50911 (20 muM)) disin-hibited VTA-DA firing rate whereas a GABA_A agonist (musci-mol, 1 muM) strongly inhibited firing rate. In the presence of picrotoxin, ethanol enhanced VTA-DA firing rate more than in the absence of picrotoxin. Additionally, a sub-maximal concentration of muscimol together with ethanol inhibited VTA-DA firing rate more than muscimol alone. DAMGO (3 muM) inhibited mlPSC frequency but did not block the ethanol-enhancement in mlPSC frequency. DAMGO (1 and 3 muM) had no effect on VTA-DA firing rate. Naltrexone (60 muM) had no effect on basal or ethanol-enhancement of mlPSC frequency. Additionally, naltrexone (20 and 60 muM) did not block the ethanol-enhancement in VTA-DA firing rate. Overall, the present results indicate that the ethanol enhancement in GABA release onto VTA-DA neurons limits the stimulatory effect of ethanol on VTA-DA neuron activity and may have implications for the rewarding properties of ethanol.