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.