Daily treatment with diazepam differentially modifies sensitivity to the effects of γ-aminobutyric acid_A modulators on schedule-controlled responding in rhesus monkeys

The present study examined how daily treatment with the benzodiazepine (BZ) diazepam modifies the effects of positive modulators acting at different sites on the γ-aminobutyric acid_A (GABA_A) receptor complex and negative modulators acting at BZ sites on the receptor complex. GABA_A31 modulators were administered alone or in combination with acute or chronic diazepam to rhesus monkeys (n = 4) responding under a multiple fixed ratio (FR/FR) schedule of food presentation and stimulus-shock termination (SST). There was mutual antagonism between the rate-decreasing effects of diazepam (5.6 mg/kg, p.o.) and high efficacy BZ site negative modulators [ethyl β-carboline-3-carboxylate (β-CCE), methyl β-carboline-3-carboxylate (β-CCM) and methyl-6,7-dimethoxyl-4-ethyl-β-carboline-3-carboxylate (DMCM)]. Antagonism of β-CCE, β-CCM, and DMCM by diazepam was markedly reduced in monkeys receiving diazepam daily. In contrast, daily diazepam treatment enhanced the rate-decreasing effects of Ro 15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-α]-[1,4]benzodiazepine -3-carboxylate) and flumazenil. Chronic diazepam elicited cross-tolerance to the BZ triazolam and not to the barbiturate pentobarbital or the neuroactive steroid pregnanolone. These results suggest that tolerance to the rate-decreasing effects of BZs is not accompanied by cross-tolerance to positive GABA_A modulators acting at other sites on the receptor complex. Moreover, changes in sensitivity to negative GABA_A modulators during chronic diazepam treatment appeared to be related to negative efficacy and not clearly related to the precipitation of withdrawal for all drugs. These results indicate that changes in sensitivity to the behavioral effects of drugs that act at different sites on the GABA_A receptor complex might be especially useful for identifying and characterizing the functional consequences of GABA_A receptor heterogeneity.