Ethanol inhibition of N-methyl-D-aspartate responses involves presynaptic G-aminobutyric Acid(B) receptors

Ethanol alters N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid subt ype A (GABA(A)) receptor-mediated neurotransmission. We have previously dem onstrated that GABA(B) receptor blockade uncovers ethanol enhancement of GA BA(A) responses in the hippocampus. Therefore, we evaluated in vivo and in vitro the role of GABA(B) receptors in ethanol-induced inhibition of neuron al activity as well as NMDA responses in the hippocampus, ventral tegmental area (VTA), and nucleus accumbens (NAcc), three brain areas with known sen sitivity to low doses of ethanol. In vivo, in situ microelectrophoretic app lication of ethanol enhanced inhibition of VTA GABA neuron firing rate by t he GABA(B) agonist baclofen and reduced inhibition of VTA GABA firing rate by the GABA(A) agonist muscimol. The GABA(B) antagonist CGP35348 blocked ba clofen- and ethanol-induced, but not muscimol-induced, reduction of NMDA-ac tivated firing of hippocampal hilar mossy cells, hilar interneurons, and VT A GABA neurons, as well as ethanol inhibition of NMDA receptor-sensitive, a mygdala-driven NAcc neurons. We performed in vitro studies in NAcc slices t o evaluate the mechanism of GABA(B) receptor-mediated ethanol inhibition of NMDA neurotransmission. In the presence of the non-NMDA receptor antagonis t 6-cyano-7-nitroquinoxaline-2,3-dione and the GABA(A) receptor antagonist bicuculline, superfusion of the GABA(B) antagonist CGP55845 blocked ethanol (66 mM) inhibition of evoked NMDA receptor-mediated excitatory postsynapti c potentials. However, CGP55845 did not significantly affect ethanol inhibi tion of NMDA currents produced by pressure application of NMDA or non-NMDA glutamatergic excitatory postsynaptic potentials evoked in the presence of the bicuculline and the NMDA antagonist DL-2-amino-5-phosphonovalerate. Tak en together, these findings suggest that the sensitivity of NMDA receptor-m ediated neurotransmission to ethanol is regulated by GABA(B) receptors, pos sibly at presynaptic sites.