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 acidA (GABAA) receptor complex and negative modulators acting at BZ sites on the receptor complex. GABAA31 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 GABAA modulators acting at other sites on the receptor complex. Moreover, changes in sensitivity to negative GABAA 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 GABAA receptor complex might be especially useful for identifying and characterizing the functional consequences of GABAA receptor heterogeneity.
|Original language||English (US)|
|Number of pages||9|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 2002|
ASJC Scopus subject areas
- Molecular Medicine