Pharmacological analysis of the heterogeneous discriminative stimulus effects of ethanol in rats using a three choice ethanol-dizocilpine-water discrimination

The present study used a three-choice operant drug discrimination procedure to determine if NMDA-mediated discriminative stimulus effects could be separated from other stimulus effects of 2.0 g/kg ethanol. Adult male Long-Evans rats (n = 7) were trained to discriminate dizocilpine (0.17 mg/kg; IG) from ethanol (2.0 g/kg; IG) from water (4.7 ml; IG) using food reinforcement. Substitution tests were conducted following administration of the GABA(A) positive modulators allopregnanolone (5.6-30.0 mg/kg; IP), diazepam (0.3-10.0 mg/kg; IP) and pentobarbital (1.0-21.0 mg/kg; IP), the non-competitive NMDA antagonist phencyclidine (0.3-10.0 mg/kg; IP), the 5-HT₁ agonists TFMPP (0.3-5.6 mg/kg; IP) and RU 24969 (0.3-3.0 mg/kg; IP), and isopropanol (0.10-1.25 g/kg; IP). Allopregnanolone, diazepam and pentobarbital substituted completely (>80%) for ethanol. Isopropanol partially (77%) substituted for ethanol. Phencyclidine substituted completely for dizocilpine. RU 24969 and TFMPP did not completely substitute for either training drug, although RU 24969 partially (62%) substituted for ethanol. Successful training of this three-choice discrimination indicates that the discriminative stimulus effects of 0.17 mg/kg dizocilpine were separable from those of 2.0 g/kg ethanol. The finding that attenuation of NMDA-mediated effects of ethanol occurred without altering significantly GABA(A)- and 5-HT₁-mediated effects suggests that the NMDA component may be independent of other discriminative stimulus effects of 2.0 g/kg ethanol.