ALTERATIONS IN BRAIN 5‐HYDROXY‐TRYPTAMINE METABOLISM DURING THE ‘WITHDRAWAL’ PHASE AFTER CHRONIC TREATMENT WITH DIAZEPAM AND BROMAZEPAM

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Abstract
1 Daily administration of diazepam or bromazepam (10 mg/kg) for 22 days significantly increased the activity of mid-brain tryptophan hydroxylase by 36% and 39%, respectively. The concentration of tryptophan was also enhanced in the mid-brain region of rats subjected to benzodiazepine treatment. 2 Chronic therapy with either of the two anti-anxiety agents enhanced the endogenous levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in cerebral cortex, hypothalamus, pons-medulla, mid-brain and striatum. 3 Whereas diazepam treatment decreased (13%) the activity of monoamine oxidase in mid-brain, bromazepam failed to exert any effect, suggesting that the observed elevation in 5-hydroxyindoleacetic acid levels is not associated with enhanced deamination of 5-hydroxytryptamine. 4 Discontinuation of treatment for 48 h significantly decreased the activity of mid-brain tryptophan hydroxylase to levels that were significantly lower than those seen for benzodiazepine-treated and normal rats. The concentrations of mid-brain tryptophan and 5-hydroxytryptamine were also reduced in various brain regions examined. 5 Withdrawal from diazepam or bromazepam therapy further augmented the levels of brain 5-hydroxyindoleacetic acid. 6 The results demonstrate that the depressant effects on behaviour of these agents are accompanied by increased metabolism of 5-hydroxytryptamine in the brain. Withdrawal from these minor tranquillizers, on the other hand, reduces the synthesis of this indoleamine.