Discriminative stimulus effects of ethanol in rats using a three-choice ethanol-midazolam-water discrimination

Three-choice discrimination procedures are used to characterize how similar the discriminative stimulus effects of two drugs are in relation to each other. This procedure has suggested similarities between ethanol and ligands that positively modulate the γ-aminobutyric acid type A (GABA_A) receptor complex. As an extension to these studies, male Long-Evans rats were trained to discriminate midazolam (3.0 mg/kg, i.p.) from ethanol (1.0 g/kg, i.g.) from water (2.3 ml, i.g.) in a three-lever, food reinforced task. Substitution tests were conducted following administration of GABA _A-positive modulators, noncompetitive N-methyl-D-aspartate (NMDA) antagonists, 5-HT_1B agonists and isopropanol. Among the GABA _A-positive modulators, diazepam was the only drug that completely substituted for midazolam; both pentobarbital and the neurosteroid allopregnanolone showed partial midazolam substitution. The NMDA antagonist dizocilpine substituted for ethanol, while phencyclidine showed no substitution for either ethanol or midazolam. The serotonin agonists tested also showed no substitution for either ethanol or midazolam. Isopropanol was the only other drug that completely substituted for ethanol. These data extend previous findings from an ethanol-pentobarbital-water discrimination and further define training conditions that result in a conditional basis for the ethanol discrimination where only those drugs with pharmacological heterogeneous effects similar to ethanol produce a full ethanol-like effect.