A relationship between the renin angiotensin system and the dopaminergic system has been described in the striatum. Until now, the role of the angiotensin II type 2 (AT₂) receptor in this interaction remained to be elucidated. The present study examined the outcome of direct AT₂ receptor stimulation on dopamine (DA) release and synthesis by means of the recently developed non-peptide AT₂ receptor agonist, compound 21 (C21). The effects of AT₂ receptor agonism on the release of DA and its major metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and on the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, were investigated using in vivo microdialysis. Local administration of C21 (0.1 and 1 mM) resulted in a decrease of the extracellular DOPAC levels, whereas extracellular DA concentrations remained unaltered, suggesting a reduced synthesis of DA. This effect was mediated by the AT₂ receptor since the decrease could be blocked by the AT₂ receptor antagonist PD123319 (1 mM). Interestingly, the effects could be reproduced by local (10 nM) as well as systemic (0.3 and 3 mg/kg i.p.) administration of the AT₁ receptor antagonist, candesartan. TH-activity as assessed by accumulation of extracellular levels of L-DOPA after inhibition of amino acid decaroboxylase with NSD-1015, were also reduced after local administration of C21 (0.1 and 1 mM) and candesartan (10 nM). Together, these data suggest that the AT₂ receptor in the striatum is involved in the modulation of DA synthesis rather than DA release, possibly via interaction with the AT₁ receptor.