Vol. 294, Issue 2, 637-647, August 2000

Ethanol Inhibition of N-Methyl-D-aspartate Responses Involves Presynaptic -Aminobutyric Acid_B Receptors¹

Scott C. Steffensen, Zhiguo Nie, Jose R. Criado and George R. Siggins

Department of Neuropharmacology and Alcohol Research Center, The Scripps Research Institute, La Jolla, California

Ethanol alters N-methyl-D-aspartate (NMDA) and -aminobutyric acid subtype A (GABA_A) receptor-mediated neurotransmission. We have previously demonstrated that GABA_B receptor blockade uncovers ethanol enhancement of GABA_A responses in the hippocampus. Therefore, we evaluated in vivo and in vitro the role of GABA_B receptors in ethanol-induced inhibition of neuronal activity as well as NMDA responses in the hippocampus, ventral tegmental area (VTA), and nucleus accumbens (NAcc), three brain areas with known sensitivity to low doses of ethanol. In vivo, in situ microelectrophoretic application of ethanol enhanced inhibition of VTA GABA neuron firing rate by the GABA_B agonist baclofen and reduced inhibition of VTA GABA firing rate by the GABA_A agonist muscimol. The GABA_B antagonist CGP35348 blocked baclofen- and ethanol-induced, but not muscimol-induced, reduction of NMDA-activated firing of hippocampal hilar mossy cells, hilar interneurons, and VTA GABA neurons, as well as ethanol inhibition of NMDA receptor-sensitive, amygdala-driven NAcc neurons. We performed in vitro studies in NAcc slices to evaluate the mechanism of GABA_B receptor-mediated ethanol inhibition of NMDA neurotransmission. In the presence of the non-NMDA receptor antagonist 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 postsynaptic potentials. However, CGP55845 did not significantly affect ethanol inhibition 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. Taken together, these findings suggest that the sensitivity of NMDA receptor-mediated neurotransmission to ethanol is regulated by GABA_B receptors, possibly at presynaptic sites.