Effect of low-dose treatment with selegiline on dopamine transporter (DAT)expression and amphetamine-induced dopamine release in vivo

1 Chronic treatment with low doses of the selective monoamine oxidase (MAO) type B inhibitors selegiline [(-)-deprenyl] and rasagiline, causes elevati on in extracellular level of 3,4-dihydroxyphenylethylamine (dopamine) in th e rat striatum in vivo (Lamensdorf et al., 1996). The present study was car ried out to determine whether this effect of selegiline could be the result of an inhibition of the high-affinity dopamine neuronal transport process. 2 Changes in activity of the dopamine transporter (DAT) in vivo following s elegiline treatment were evaluated indirectly by microdialysis technique in the rat, from the change in striatal dopamine extracellular concentration following systemic amphetamine administration (4 mg kg(-1), i.p.). Striatal levels of the DAT molecule were determined by immunoblotting. Uptake of [H -3]-dopamine was determined in synaptosomes from selegiline-treated animals . 3 Amphetamine-induced increase in striatal extracellular dopamine level was attenuated by one day and by chronic (21 days) treatment with selegiline ( 0.25 mg kg(-1), s.c.). 4 Striatal levels of DAT were elevated after I and 21 days treatment with s elegiline, but were not affected by clorgyline, rasagiline, nomifensine or amphetamine. 5 The increase in DAT expression, and attenuation of amphetami ne-induced dopamine release, were not accompanied by a change in [H-3]-dopa mine uptake in synaptosomes of selegiline-treated animals. 6 The results su ggest that a reversible inhibition of dopamine uptake occurs following chro nic low dose selegiline treatment in vivo which may be mediated by an incre ase in endogenous MAO-B substrates such as 2-phenylethylamine, rather than by the inhibitor molecule or its metabolites. Increased DAT expression appe ars to be a special property of the selegiline molecule, since it occurs af ter one low dose of selegiline, and is not seen with other inhibitors of MA O-A or MAO-B. The new DAT molecules formed following selegiline treatment a ppear not to be functionally active.