Assessment of the mixed discriminative stimulus effects of ethanol in a three-choice ethanol-dizocilpine-water discrimination in rats

Previous drug discrimination studies have elucidated the importance of the NMDA, GABA(A) and 5-HT₁ receptor systems in mediating the discriminative stimulus effects of ethanol. The present study used a three-choice drug discrimination paradigm in an attempt to determine whether the salient NMDA antagonistic effects were separable from other stimulus effects of ethanol. Adult Long-Evans rats (n = 7) were trained to discriminate ethanol (1.5 g/kg, intragastric (i.g.)), the uncompetitive NMDA antagonist dizocilpine (0.17 mg/kg, i.g.) or water (3.5 ml, i.g.) under a food-reinforced fixed-ratio 15 (FR15) schedule of reinforcement. Following training, substitution tests were conducted wth the GABA(A)/benzodiazepine (GABA(A)/BDZ) positive modulator pentobarbital (PB, 5.6-17 mg/kg, i.g.), the uncompetitive NMDA antagonist phencyclidine (PCP, 0.1-5.6 mg/kg, i.p.) and the 5-HT₁ agonist RU 24969 (0.1-3.0 mg/kg, i.p.). Complete substitution of PCP (ED₅₀, 0.9 mg/kg) for dizocilpine was found in all animals. Conversely, PB (ED₅₀, 10 mg/kg) substituted fully for ethanol in five of seven animals, whereas RU 24969 (ED₅₀, 1.4 mg/kg) completely substituted for ethanol in only three of seven animals tested. The results demonstrate that a three-choice discrimination using dizocilpine, ethanol and water as training conditions can be established in rats. By contrasting the discriminative stimulus effects of an uncompetitive NMDA antagonist to ethanol, the ethanol-like effects of pentobarbital and RU 24969 are attenuated compared to previous studies of two-choice ethanol water discrimination.