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We have investigated the mechanisms by which acute ethanol inhibits the induction of long-term potentiation (LTP) in area CA1 of the rat hippocampal slice. In a previous report [Alcohol. Clin. Exp. Res. 21 (1997) 404] we demonstrated that ethanol produces only a modest inhibition of pharmacologically isolated N-methyl-D-aspartate receptors (NMDAR) in the CA1 region of the hippocampus. Moreover, this level of inhibition was not sufficient to account for ethanol's complete inhibition of LTP induction in this brain region. One possible explanation of these results is that we may have underestimated ethanol's ultimate effect on the NMDAR by focusing on pharmacologically isolated NMDAR responses. Ethanol might indirectly inhibit the NMDAR by, for example, potentiating the GABA(A)R. To explore this possibility, we first examined the effects of the GABA(A)R antagonist picrotoxin (PTX) and the allosteric GABA(A)R modulator flunitrazepam on NMDAR responses. We demonstrate that these modulators of GABA(A)R activity significantly affect the magnitude of synaptically evoked NMDAR responses. We next examined the effects of ethanol on NMDAR responses in the presence and absence of PTX. We see a significantly greater ethanol inhibition of the NMDAR when GABA(A)Rs are functional, i.e. in the absence of PTX. These data suggest that ethanol produces an inhibition of the NMDAR indirectly by affecting the GABA(A)R neurotransmission. Moreover, we found that ethanol inhibition of NMDAR activity, both directly through actions on the NMDAR, and indirectly, possibly through potentiation of GABA(A)R activity, is sufficient to account for ethanol's complete blockade of LTP induction.

Type

Journal article

Journal

Brain Res Mol Brain Res

Publication Date

19/10/2001

Volume

94

Pages

9 - 14

Keywords

Animals, Central Nervous System Depressants, Ethanol, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, GABA Antagonists, Long-Term Potentiation, Male, Memory, Organ Culture Techniques, Organophosphorus Compounds, Picrotoxin, Quinoxalines, Rats, Rats, Sprague-Dawley, Receptors, GABA-A, Receptors, N-Methyl-D-Aspartate, Synaptic Transmission