To study interactions between DA and 5-HT neurochemical systems in the DA D1 supersensitized induction of oral activity in neonatal 6-hydroxydopamine (6-OHDA) lesioned rats, the effects of a variety of 5-HT receptor agonists and antagonists were determined. At 3 days after birth rats were treated with desipramine HCl (20 mg/kg i.p., base form) 1 h before 6-OHDA HBr (100 micrograms, salt form, in each lateral ventricle). When these rats were studied as adults it was determined that the striatal content of DA, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) was reduced by 98%, while the striatal content of 5-HT was elevated by 75%. The Bmax and Kd for [3H]SCH 23390 and [3H]spiperone binding to striatal homogenates was unaltered in the lesioned rats. However, oral activity responses to a D1 agonist (SKF 38393), D2 antagonist (spiperone) and 5-HT1C agonist [1-(3-chlorophenyl)piperazine] were enhanced several fold in the lesioned rats. Several other agonists and antagonists that act at 5-HT1A, 5-HT1B, 5-HT2 and 5-HT3 receptors did not produce an altered response in the lesioned rats, nor were these substances effective in attenuating m-CPP-enhanced oral activity responses. The DA D1 receptor antagonist, SCH 23390 HCl (0.30 mg/kg i.p.), did not attenuate the response to m-CPP 2HCl (1.0 mg/kg i.p.). However, the 5-HT receptor antagonist, mianserin HCl (1.0 mg/kg s.c.) did effectively attenuate the oral activity response to SKF 38393 HCl (1.0 mg/kg i.p.). These findings indicate that there is supersensitization of both DA D1 and 5-HT1C receptors in neonatal 6-OHDA-lesioned rats, and that a D1 agonist acts via the 5-HT1C receptors. Therefore, induction of oral activity by DA agonists occurs through a serotoninergic neurochemical system.