THE DISCRIMINATIVE STIMULUS EFFECTS OF MUSCIMOL IN RATS

To evaluate the discriminative stimulus effects of a direct-acting GAB A(A) agonist, seven rats were trained to discriminate 1 mg/kg IP musci mol from saline under a two-lever fixed ratio (FR) 20 schedule of food reinforcement. The direct GABA(A) agonist THIP (4,5,6,7-tetrahydro-is oxazolo [5, 4,c]-pyridin-3-ol) produced increases in muscimol lever re sponding and substituted for muscimol in all subjects. Unlike results with muscimol, the highest levels of muscimol lever responding followi ng THIP administration were often produced at doses which also decreas ed rates of responding. The GABA(B) agonist baclofen and the indirect- acting GABA(A) agonists pentobarbital and midazolam produced substitut ion for muscimol in some subjects, but not in others. The non-competit ive NMDA antagonist phencyclidine (PCP) produced mixed results in thes e rats, from partial to full substitution (both dose-dependently and e xhibiting a lack of dose-dependence) in some animals and a complete fa ilure to substitute in another. The selective GABA(A) antagonist bicuc ulline dose-dependently blocked the muscimol discriminative stimulus i n a majority of subjects. This study is the first report of successful training of a drug discrimination in rats using muscimol. Evidence is provided from substitution and antagonism testing with THIP and bicuc ulline, respectively, that the muscimol discrimination was mediated by actions at the GABA binding site on the GABA(A) receptor-ionophore co mplex. Results, also suggest that drug stimulus control by muscimol is weak compared to that of other types of GABA agonists previously stud ied using drug discrimination procedures in rodents.