EFFECTS OF NEGATIVE ALLOSTERIC MODULATORS OF GAMMA-AMINOBUTYRIC ACID(A) RECEPTORS ON COMPLEX BEHAVIORAL PROCESSES IN MONKEYS

A multiple schedule of repealed acquisition and performance of conditi onal discriminations was used to characterize the effects of two negat ive allosteric modulators of the gamma-aminobutyric acid (GABA(A)) rec eptor (ethyl beta-carboline-3-carboxylate [beta-CCE] and N-methyl-beta -carboline-3-carboxamide [FG-7142]), a hallucinogenic beta-carboline d erivative (harmine), a benzodiazepine receptor antagonist (flumazenil) and a positive allosteric modulator (alprazolam). In the acquisition component, subjects acquired a different discrimination each session. Acquisition of a discrimination was defined by a decrease in errors as the session progressed. In the performance component, the discriminat ion was the same each session. Responding in both components was maint ained by good presentation under a variable-ratio schedule. Incorrect responses in both components produced a 5-sec timeout. Alprazolam (0.1 -18 mg/kg), beta-CCE (0.01-0.32 mg/kg), FG-7142 (0.1-18 mg/kg) and har mine (0.1-1.8 mg/kg) all dose-dependently decreased response rate in b oth components. However, accuracy of responding was differentially aff ected by the drugs. Alprazolam selectively and dose-dependently increa sed percent errors in acquisition, whereas beta-CCE increased acquisit ion errors only at the highest doses tested in each subject. In contra st, FG-7142 and harmine had no effects on percent errors at doses that virtually eliminated responding. In ail cases, performance accuracy w as generally not affected. Flumazenil, at doses that had little or no effect (0.1 and 0.32 mg/kg) or occasionally decreased response rates ( 1 mg/kg) when administered alone, dose-dependently antagonized the rat e-decreasing and error increasing effects of beta-CCE, FG-7142 arid al prazolam. In contrast, flumazenil failed to antagonize the effects of harmine. Thus, the negative allosteric modulators only moderately disr upted acquisition in comparison with the positive allosteric modulator , but the effects of both types of modulator were antagonized by the b enzodiazepine antagonist flumazenil.