Generalisation of ethanol with drug mixtures containing a positive modulator of the GABA(A) receptor and an NMDA antagonist.

Ethanol is thought to produce its discriminative stimulus effect by actions on two or more neurotransmitter systems. To test this idea further, rats were trained to discriminate mixtures of two drugs from vehicle in two-lever procedures with food reinforcers presented on a tandem variable-interval fixed ratio schedule. After drug-appropriate responding with the training mixtures reached 85%, generalisation to ethanol was examined in extinction tests. Rats trained to discriminate a mixture of chlordiazepoxide (5.0 mg/kg, s. c.) plus dizocilpine (0.08 mg/kg, i.p.) yielded a mean of 76% drug-appropriate responding when tested with ethanol (3.0 g/kg, i.g. ). However, when rats were trained with an 8.0 mg/kg dose of pentobarbitone in a mixture with 0.08 mg/kg of dizocilpine, the same dose of ethanol produced only 33% drug-appropriate responding. After retraining with pentobarbitone (12 mg/kg) plus dizocilpine (0.04 mg/kg), ethanol (3.0 g/kg, i.g.) produced 75% drug-appropriate responding. Pentobarbitone and dizocilpine administered alone produced full, dose-related generalisation, but there was no generalisation to (+)-amphetamine (0.025-0.8 mg/kg, s.c.). Thus, ethanol substituted for mixtures in which the GABA(A)-modulatory component had equal or greater salience than the NMDA-antagonist component. Doses of ethanol that generalised with the drug mixtures always reduced overall rates of responding as compared with control rates. Nevertheless, these data provide further support for the hypothesis that ethanol produces a compound stimulus comprised of elements resembling the effects of positive modulators of GABA(A) receptors and those of NMDA antagonists.