Effects of Selective Monoamine Oxidase Inhibitors on the In Vivo Release and Metabolism of Dopamine in the Rat Striatum

Abstract

Brain microdialysis was used to examine the in vivo efflux and metabolism of dopamine (DA) in the rat striatum following monoamine oxidase (MAO) inhibition. Relevant catecholamines and indoleamines were quantified by HPLC coupled with a electrochemical detection system. The MAO‐B inhibitor selegiline only affected DA deamination at a dose shown to inhibit partially type A MAO. Alterations in DA and metabolite efflux were not observed when using the MAO‐B‐selective dose of 1 mg/kg of selegiline. At 10 mg/kg, selegiline reduced the efflux of DA metabolites to ∼70% of basal values without affecting DA efflux. K⁺‐and veratrine‐stimulated DA efflux was not affected by selegiline. Experiments using amphetamine and the DA uptake inhibitor nomifensine demonstrated that the effect of selegiline on DA metabolism was unlikely to be mediated either by inhibition of DA uptake or by an indirect effect of its metabolite amphetamine. The possibility that the effect of selegiline is mediated via a nonspecific inhibition of MAO is discussed. In contrast, the MAO‐A inhibitor clorgyline inhibited basal DA metabolism and increased basal and de‐polarisation‐induced DA efflux. A 1 mg/kg dose of clorgyline reduced basal DA metabolite efflux (40–60% of control values) without affecting DA efflux. At 10 mg/kg of clorgyline, DA efflux increased to 253 ± 19% of basal values, whereas efflux of DA metabolites was reduced to between 15 and 26% of control values. The release of DA induced by K⁺ and vera‐trine was not affected by 1 mg/kg of clorgyline but was increased by ∼200% following pretreatment with 10 mg/kg of clorgyline. The nonselective MAO inhibitor pargyline caused similar but more pronounced alterations in these parameters. For example, using a 75 mg/kg dose of pargyline, efflux of DA increased maximally to 310 ± 20% of basal values, and the release of DA induced by K⁺ and veratrine was increased by ∼300% following pargyline pretreatment. These data suggest that DA metabolism is mediated principally by MAO‐A in the rat striatum. However, under conditions of MAO‐A inhibition, a component of metabolism mediated by the type B enzyme becomes apparent.