Ethanol drug discrimination in rats: substitution with GABA agonists and NMDA antagonists

Both enhancement of GABAergic neurotransmission and antagonism of glutamatergic neurotransmission involving the NMDA receptor have been implicated in the acute effects of ethanol. In this study, rats were trained to discriminate 1000mg/kg ethanol from saline. This dose of ethanol was consistently discriminated from saline but had no effects on overall rates of responding. Substitution tests were conducted with a number of GABA agonists and NMDA antagonists. Both midazolam and pentobarbital exhibited substantial substitution for ethanol at doses that moderately decreased response rates. However, muscimol and baclofen completely failed to substitute for ethanol, as did a combination of a fixed dose of muscimol with increasing doses of baclofen. The non-competitive NMDA antagonists PCP, dizocilpine and ketamine substituted fully for ethanol, but only at doses that also substantially suppressed rates of responding. The competitive NMDA antagonists, CPPene and NPC 17742, partially substituted for ethanol. The levels of substitution for ethanol among the indirect GABA agonists and the non-competitive NMDA antagonists indicate that the discriminative stimulus effects of ethanol, at least at a 1000mg/kg dose, may involve both GABAergic and glutamatergic systems.