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The effects of pharmacological modulation of striatal dopaminergic neurotransmission were studied in freely mobile rats by intracerebral microdialysis and HPLC to assay dopamine and dopamine metabolite levels and the rate of dopamine synthesis, in combination with observations of stereotypical behavior. Inhibition of catechol O-methyltransferase (COMT) with tolcapone led to increases in extracellular dopamine levels only when the baseline dopamine level was elevated by administration of L-3,4-dihydroxyphenylalanine in combination with the decarboxylation inhibitor carbidopa. Increases in dopamine levels in striatal dialysates by blockade of reuptake were enhanced by inhibition of metabolic degradation of dopamine by tolcapone, a selective catechol O-methyltransferase inhibitor. GBR-12909, a blocker of the dopamine transporter, increased extracellular dopamine and induced motor stereotypy. Both of these effects were potentiated by tolcapone. The rate of dopamine biosynthesis decreased when reuptake was inhibited. These data provide evidence for the key role of the dopamine transporter in maintaining neurochemical homeostasis at the synaptic level.