Supersensitization of the Oral Response to SKF 38393 in Neonatal 6- Hydroxydopamine-Lesioned Rats Is Eliminated by Neonatal 5,7- Dihydroxytryptamine Treatment

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5-Hydroxytryptamine (5-HT) 5-HT(2c) receptors mediate the enhanced oral activity response to the dopamine (DA) D1 agonist, (±)-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine-7,8-diol (SKF 38393) in neonatal 6- hydroxydopamine (6-OHDA)-lesioned rats. To study the possible involvement of 5-HT fibers on this process, the effect of the 5-HT neurotoxin, 5,7- dihydroxytryptamine (5,7-DHT) was determined. Rats were treated at 3 days after birth with desipramine (20 mg/kg i.p., base) 1 hr before intracerebroventricular vehicle, 6-OHDA (134 μg, base) and/or 5,7-DHT (50 μg, base). Oral activity was observed at 7 weeks and later. In neonatal 6- OHDA-lesioned rats oral activity dose-effect responses were increased by SKF 38393, 1-(3-chlorophenyl)-piperazine (m-CPP) and pilocarpine-respective DA D1, 5-HT(2c) and muscarinic receptor agonists. Rats treated neonatally with 5,7-DHT had agonist-induced responses resembling that of the saline control group. However, in rats treated neonatally with both 5,7-DHT and 6-OHDA, oral activity responses were reduced at nearly all doses of SKF 38393 and pilocarpine vs. that of the 6-OHDA group. The response of the 5,7-DHT + 6- OHDA group to m-CPP was reduced at only the 1.0 mg/kg dose. Of a variety of stereotyped behaviors that were observed in separate test sessions, m-CPP- induced grooming activity was less in the 5,7-DHT + 6-OHDA group vs. the 6- OHDA group. SKF 38393-induced arousal, rearing activity and immobility were also reduced in the 5,7-DHT + 6-OHDA vs. 6-OHDA group. Striatal DA content was reduced >98%, whereas 5-HT content was elevated >2-fold in the 6-OHDA group. Striatal 5-HT content was reduced by >85% after 5,7-DHT. These findings indicate that neonatal 5-HT fiber destruction does not produce enhanced m-CPP-induced oral activity in rats. In contrast, this lesion appears to attenuate DA D1 and muscarinic receptor supersensitivity. These findings indicate that 5-HT fibers have an important influence on the process of DA D1 and muscarinic receptor supersensitivity.