Studies on the interaction between cerebral 5‐hydroxytryptamine and γ‐aminobutyric acid in the mode of action of diazepam in the rat

Abstract

1 The effect of the benzodiazepine, diazepam, administered for 7 days in doses between 1.25 and 5 mg kg⁻¹ was studied on the turnover of 5-hydroxytryptamine (5-HT) in rat cerebral cortex. 5-HT turnover was assessed by calculating the ratio of the concentration of the major metabolite 5-hydroxyindoleacetic acid (5-HIAA) to that of 5-HT (i.e., 5-HIAA:5-HT). Diazepam (2.5 and 5 mg kg⁻¹ i.p. daily for 7 days) significantly reduced cerebral cortical 5-HT turnover. 2 The effect of manipulating cerebral γ-aminobutyric acid (GABA) mechanisms on this action of diazepam was studied. Treatment of animals with a subconvulsive dose of Picrotoxin (3 mg kg⁻¹ i.p.) reversed the fall in cortical 5-HT turnover seen following diazepam. In contrast, however, treatment with the GABA transaminase inhibitors, amino-oxyacetic acid (25 mg kg⁻¹) or ethanolamine-O-sulphate (250 mg kg⁻¹, 7 days) which elevated cerebral GABA concentrations, enhanced the reduction in cortical 5-HT turnover following diazepam. 3 Focal injection of picrotoxin (0.1 μg) into the region of the dorsal raphé nucleus reversed the decrease in cortical 5-HT turnover caused by diazepam. 4 The hypothesis that doses of diazepam which result in total plasma concentrations comparable to those observed in man produce a reduction in 5-HT turnover mediated via GABA neurones is discussed.