Enhanced oral activity is induced in neonatal 6-hydroxydopamine- (6-OHDA-) lesioned rats by systemic administration of the dopamine (DA) D1 receptor agonist SKF 38393 and serotonin (5-HT) 5-HT2A,2C agonist m-chlorophenylpiperazine (m-CPP). The DA D1 receptor antagonist SCH 23390 effectively attenuates the effect of SKF 38393 but not m-CPP. The 5-HT2antagonist mianserin attenuates the effects of both m-CPP and SKF 38393, suggesting that DA agonist effects are mediated by 5-HT neurochemical systems. To test whether DA and 5-HT agonist effects and interactions might occur within the neostriatum, rats were implanted with permanent injection cannulae, with tips in the ventral striatum. One group of rats was lesioned at 3 days after birth with 6-OHDA HBr (100 μg salt form, in each lateral ventricle; desipramine HCl pretreatment, 20 mg/kg IP, base form, 1 h), while controls received the vehicle in place of 6-OHDA. Cannulae were implanted when rats weighed 200-250 g. During a 1-h observation session SKF 38393 (5 nmol per side) produced 74.3±19.2 oral movements in intact rats and 310.7±97.0 oral movements in 6-OHDA-lesioned rats. m-CPP (10 nmol per side) produced 72.6±15.1 and 274.5±65.0 oral movements in these respective groups. These responses were several-fold greater than the 25.3±7.3 and 41.8±9.5 oral movements in the same groups after saline (0.5 μl per side) (P<0.05). Mianserin (6 nmol per side) alone had no effect on oral activity but attenuated responses to both SKF 38393 and m-CPP in intact and 6-OHDA-lesioned rats. These findings demonstrate that enhanced oral activity responses are produced by intrastriatal SKF 38393 and m-CPP in neonatal 6-OHDA-lesioned rats. Also, when the 5-HT2 receptor antagonist mianserin was administered intrastriatally, induction of oral activity by the DA D1 agonist SKF 38393 was attenuated. These findings indicate that ventral striatum represents at least one brain focus at which DA and 5-HT systems interact to modulate oral activity in rats.