The present study was undertaken to compare the abilities of the dopaminergic agonists apomorphine, bromocriptine, and lergotrile to inhibit the synthesis of dopamine (DA) in terminals of nigrostriatal and mesolimbic DA neurons. The in vivo synthesis of DA was estimated by measuring the rate of accumulation of dihydroxyphenylalanine (DOPA) in terminals of nigrostriatal (striatum) and mesolimbic (nucleus accumbens, olfactory tubercle) neurons 30 min after the administration of NSD 1015, a decarboxylase inhibitor. The activation of DA autoreceptors in these regions was evaluated by measuring the abilities of the DA agonists to inhibit DA synthesis in brain regions of rats pretreated with gamma-butyrolactone (GBL). Apomorphine (0.03-1.0 mg/kg for 45 min) and bromocriptine (0.1-10 mg/kg for 90 min) produced dose-dependent decreases in the rate of DA synthesis in all three brain regions of both vehicle- and GBL-treated rats. A time course of the effects of the highest dose of bromocriptine (10 mg/kg), however, demonstrated dramatic regional differences in the ability of this drug to inhibit DA synthesis in saline-versus GBL-pretreated rats. Bromocriptine inhibited the GBL-induced increase in DA synthesis for 6 hours in all regions examined. In the striatum of saline-treated rats the decrease in DA synthesis was evident only at 1.5 hours after bromocriptine administration, while in the nucleus accumbens and olfactory tubercle DA synthesis remained inhibited for 6 hours. By contrast, lergotrile reduced DA synthesis to a similar extent in all three regions for at least 6 hours in both vehicle- and GBL-treated rats. These results suggest that there is no regional difference in the ability of bromocriptine to inhibit DA synthesis via DA autoreceptor mechanisms, but there appear to be differences in postsynaptic DA receptor-mediated mechanisms which regulate nigrostriatal versus mesolimbic DA neurons.