Chlordiazepoxide reduces in vivo serotonin release in the basal ganglia of encéphale isolé but not anesthetized cats: evidence for a dorsal raphe site of action.

By using a push-pull cannula technique and an isotopic method for the estimation of [3H]serotonin continuously synthetized from [3H]tryptophan, the effects of a benzodiazepine, chlordiazepoxide, were investigated on the in vivo release of [3H]serotonin in the cat basal ganglia. Chlordiazepoxide injection (10 mg/kg i.p.) decreased striatal and nigral [3H]serotonin release and enhanced the [3H]amine release in the dorsal raphe. These changes were blocked by the continuous superfusion of the dorsal raphe with Ro 15-1788 (10(-5) M), a benzodiazepine receptor antagonist. Chlordiazepoxide (10(-5) M) applied to the dorsal raphe reduced nigral [3H]serotonin release while decreasing [3H]serotonin release locally in the dorsal raphe. Furthermore, the superfusion of serotonergic nerve terminals of the substantia nigra or the caudate nucleus with chlordiazepoxide (10(-5) M) never altered the local release of [3H]serotonin. These data strongly suggest that the (inhibitory) influences exerted by chlordiazepoxide on serotonergic transmission more likely involved cell bodies and/or dendrites rather than terminals of serotonergic neurons. Chlordiazepoxide-induced changes in [3H]serotonin release were only observed in "encéphale isolé" and not in halothane-anesthetized cats. Further experiments revealed that GABAergic neurons of the dorsal raphe could participate to such a differential reactivity of serotonergic cells to chlordiazepoxide. For instance, [3H]gamma-aminobutyric acid release in the dorsal raphe was enhanced by halothane anesthesia. These findings further suggest the possibility that the influence exerted by benzodiazepines on serotonergic transmission, perhaps through a gamma-aminobutyric acid-dependent process, can significantly be involved in the pharmacological actions of these drugs.