Synaptosomal uptake of norepinephrine and 5-hydroxytryptamine and synthesis of catecholamines during benzodiazepine treatment.

Abstract

Administration of diazepam (10 mg/kg, sc) acutely or for 22 consecutive days decreased spontaneous locomotor activity and presumably the release of norepinephrine and dopamine as evidenced by increased levels of these amines in crude synaptosomes and low levels of their metabolites, 4-hydroxy-3-methoxyphenylglycol in brain and homovanillic acid in striatum of rats. Acute or chronic diazepam elevated the levels of synaptosomal 5-hydroxytryptamine by 21 and 50%, respectively, suggesting that the release of this indoleamine was also diminished. Whereas a single injection of diazepam failed to alter the synaptosomal uptake of 5-[3H]hydroxytryptamine or rate of synthesis of this indoleamine, repeated exposure for 22 days enhanced it by 31 and 28%, respectively. Acute diazepam treatment also enhanced 5-hydroxyindoleacetic acid levels in hypothalamus, pons–medulla, and midbrain of rats. The endogenous level of tryptophan in P2 pellet also was increased (by 117%) in chronic diazepam-treated rats. Diazepam given acutely or chronically failed to change the rate of catecholamine synthesis. However, discontinuation of diazepam for 48 h in rats previously treated for 20 days significantly increased locomotor activity and synaptosomal catecholamine synthesis above the values of 'treated' as well as normal control animals. Despite their increased synthesis, the synaptosomal levels of norepinephrine and dopamine in 'withdrawn' groups were decreased to 46 and 62%, respectively. This could presumably be due to a compensatory release of these monoamines and partly to altered uptake of norepinephrine which was diminished by 24%. Additionally, the levels of homovanillic acid in striatum and 4-hydroxy-3-methoxyphenylglycol in brain were enhanced to 196 and 193%, respectively, taking the values of chronically exposed rats as 100%. Withdrawal of rats from diazepam decreased the rate of synthesis of 5-hydroxytryptamine and the level of 5-hydroxytryptamine within the crude synaptosomes; the latter could be attributed to enhanced release and impeded uptake of this indoleamine. The view gains support from enhanced levels of the metabolite 5-hydroxyindoleacetic acid seen in several brain areas of withdrawn rats.Our data suggest that diazepam exerts its central effects on mood and behaviour by impairing the release of catecholamines and 5-hydroxytryptamine. It is also suggested that enhanced release and decreased uptake of these monoamines may, in part, be responsible for the hyperexcitability seen during the 'rebound' phase in anxious patients withdrawn from benzodiazepine therapy.