The discriminative stimulus effects of muscimol in rats

To evaluate the discriminative stimulus effects of a direct-acting GABA(A) agonist, seven rats were trained to discriminate 1 mg/kg IP muscimol 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-isoxazolo [5, 4,c]-pyridin-3-ol) produced increases in muscimol lever responding and substituted for muscimol in all subjects. Unlike results with muscimol, the highest levels of muscimol lever responding following THIP administration were often produced at doses which also decreased rates of responding. The GABA(B) agonist baclofen and the indirect-acting GABA(A) agonists pentobarbital and midazolam produced substitution for muscimol in some subjects, but not in others. The non-competitive NMDA antagonist phencyclidine (PCP) produced mixed results in these rats, from partial to full substitution (both dose-dependently and exhibiting a lack of dose-dependence) in some animals and a complete failure to substitute in another. The selective GABA(A) antagonist bicuculline dose-dependently blocked the muscimol discriminative stimulus in 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 bicuculline, respectively, that the muscimol discrimination was mediated by actions at the GABA binding site on the GABA(A) receptor-ionophore complex. Results, also suggest that drug stimulus control by muscimol is weak compared to that of other types of GABA agonists previously studied using drug discrimination procedures in rodents.