Studies on the interaction between cerebral 5-hydroxytryptamine and gamma-aminobutyric acid in the mode of action of diazepam in the rat.
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. The effect of manipulating cerebral gamma-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. Focal injection of picrotoxin (0.1 micrograms) into the region of the dorsal raphé nucleus reversed the decrease in cortical 5-HT turnover caused by diazepam. 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.
D000613:Aminobutyrates / Q000378:metabolism*; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D002415:Cats; D002540:Cerebral Cortex / Q000378:metabolism*; D003975:Diazepam / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D010852:Picrotoxin / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*
D000613:Aminobutyrates; D001569:Benzodiazepines; D003975:Diazepam; D010852:Picrotoxin; D012701:Serotonin