Comparison of the effects of benzodiazepines and other anticonvulsant drugs on synthesis and utilization of 5-HT in mouse brain.

Acute administration of clonazepam (0.5-8.0 mg/kg, i.p.), diazepam (2-32 mg/kg, i.p.), chlordiazepoxide (1-40 mg/kg, i.p.) or diphenylhydantoin (5-320 mg/kg, i.p.), caused a dose-related elevation of the concentrations of, 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and tryptophan in whole mouse brain. Carbamazepine (5-100 mg/kg, i.p.), and phenobarbitone (10-80 mg/kg, i.p.) raised the concentrations of 5-HT and 5-HIAA in the brain, whereas flurazepam (5-80 mg/kg, i.p.) only elevated the level of 5-HIAA. After administration of L[G-3H]tryptophan (25 microCi, s.c.), clonazepam (4 mg/kg), diazepam (32 mg/kg, i.p.), chlordiazepoxide (40 mg/kg) or diphenylhydantoin (40 mg/kg), but not carbamazepine (50 mg/kg), flurazepam (40 mg/kg) or phenobarbitone (80 mg/kg), increased the content of labelled tryptophan in brain. However, administration of drugs did not alter the incorporation of the label into [3H]5-HT, suggesting that the synthesis of 5-HT was unaffected. When incorporation of [3H]tryptophan into [3H]5-HT was complete and the pool of labelled 5-HT was decreasing, clonazepam, diazepam, chlordiazepoxide and diphenylhydantoin elevated the content of [3H]5-HT in brain. Flurazepam, phenobarbitone and carbamazepine were without apparent effect. Calculation of the rate of utilization of 5-HT (Km) showed that all drugs, apart from flurazepam, reduced the utilization of 5-HT. Using the rate of disappearance of 5-HT after inhibition of tryptophan hydroxylase by p-chlorophenylalanine (PCPA), all drugs, except flurazepam, diphenylhydantoin and phenobarbitone, decreased the utilization of 5-HT. The major action of the anticonvulsant drugs on the function of 5-HT in brain appears to be a decrease in the utilization of 5-HT without altering synthesis.