l‐3,4‐Dihydroxyphenylalanine‐Induced Dopamine Release in the Striatum of Intact and 6‐Hydroxydopamine‐Treated Rats: Differential Effects of Monoamine Oxidase A and B Inhibitors

Abstract: Administration of l‐DOPA (50 mg/kg) elicits a significant increase in extracellular dopamine in striata of rats treated with the catecholaminergic neurotoxin 6‐hydroxydopamine but not in striata of intact rats. To assess the role of dopaminergic nerve terminals in determining the effects of exogenous l‐DOPA on extracellular dopamine levels in striatum, we examined the relative contributions of monoamine oxidase A and monoamine oxidase B to the catabolism of dopamine synthesized from exogenous l‐DOPA. Extracellular concentrations of dopamine and its catabolite, 3,4‐dihydroxyphenylacetic acid, were monitored with in vivo dialysis in striata of intact rats and of rats with unilateral 6‐hydroxydopamine lesions of striatal dopamine. Clorgyline (2 mg/kg), an inhibitor of monoamine oxidase A, significantly increased dopamine and decreased 3,4‐dihydroxyphenylacetic acid in intact but not in dopamine‐depleted striata. Inhibition of monoamine oxidase B with either l‐deprenyl (1 mg/kg) or Ro 19‐6327 (1 mg/kg) did not significantly affect dopamine or 3,4‐dihydroxyphenylacetic acid in striata of intact or dopamine‐depleted rats. In intact rats, administration of clorgyline in conjunction with l‐DOPA produced a >20‐fold increase in dopamine and prevented the l‐DOPA‐induced increase in 3,4‐dihydroxyphenylacetic acid. Although both l‐deprenyl and Ro 19‐6327 administered in combination with l‐DOPA elicited a small but significant increase in dopamine, levels of 3,4‐dihydroxyphenylacetic acid were not affected. In rats pretreated with 6‐hydroxydopamine, clorgyline had no significant effect on the increases in dopamine and 3,4‐dihydroxyphenylacetic acid elicited by l‐DOPA. Furthermore, neither l‐deprenyl nor Ro 19‐6327 affected l‐DOPA‐induced increases in dopamine and 3,4‐dihydroxyphenylacetic acid in dopamine‐depleted striata. The present findings indicate that deamination by monoamine oxidase A is the primary mechanism for catabolism of striatal dopamine, both under basal conditions and after administration of exogenous l‐DOPA. Loss of dopaminergic terminals eliminates this action of monoamine oxidase A but does not enhance deamination by monoamine oxidase B. These data support a model in which exogenous l‐DOPA elicits enhanced extracellular accumulation of dopamine in the dopamine‐depleted striatum because some transmitter synthesis occurs at nondopaminergic sites and the dopamine terminals that normally take up and catabolize this pool of transmitter are absent.