Abstract
Utilizing behavioral, biochemical and electrophysiological methods, central effects of the monoamine oxidase-B inhibitor deprenyl (selegiline) were analyzed. Administration of deprenyl (3-30 mg/kg, i.p.) caused a dose-dependent increase in the spontaneous locomotor activity. In the striatum, deprenyl (10 and 30 mg/kg) changed the dopa accumulation following 3-hydroxybenzylhydrazine hydrochloride in a biphasic manner. Deprenyl slightly decreased the firing rate of dopamine-containing neurons in substantia nigra, zona compacta. However, increases in locomotor activity and dopa accumulation induced by deprenyl were almost totally prevented by pretreatment with the microsomal liver enzyme inhibitor proadifen hydrochloride (50 mg/kg, i.p., 30 min), indicating that metabolites of the drug are of pharmacological significance for deprenyl's central actions. Furthermore, administration of l-methamphetamine, a major metabolite of deprenyl, affected spontaneous locomotor activity and striatal dopa formation and the firing rate of dopamine-containing neurons in the substantia nigra within the same magnitude as deprenyl itself when given in doses relevant to the formation of l-methamphetamine from deprenyl. However, unlike the effect of deprenyl, the l-methamphetamine-induced increase in locomotor activity and striatal dopa formation was not antagonized by pretreatment with proadifen hydrochloride. The data suggest that the stimulatory effect on locomotor activity and dopamine synthesis is not related to a monoamine oxidase-B blocking action of the drug or to a putative effect on DA reuptake, but rather to effects of metabolites of the drug (e.g., l-methamphetamine). It is proposed that metabolites of deprenyl should not be disregarded to account for the clinical benefits of the drug.
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