Supersensitization of the Oral Response to SKF 38393 in Neonatal 6-OHDA- Lesioned Rats Is Mediated Through a Serotonin System

Document Type

Article

Publication Date

1-1-1992

Description

To study possible interactions between dopamine (DA) and serotonin (5-HT) neurochemical systems in the D-1 supersensitized induction of oral activity in neonatal 6-hydroxydopamine (6-OHDA) lesioned rats, the effects of a series of 5-HT agonists and antagonists were determined. At 3 days after birth rats were treated with desipramine HCl (20 mg/kg i.p., base form, 1 hr) and 6-OHDA HBr (100 μg, salt form, in each lateral ventricle). Rats were observed individually as adults, once a minute every 10 min over a 1-hr period after challenge with a DA or 5-HT receptor agonist. The respective 5-HT(1A) and 5- HT(1B) agonists, (±)-8-hydroxydipropylaminotetralin (0.50 mg/kg s.c.) and CGS 12066B maleate (7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2- alquinoxaline], 1:2 maleate salt; 3.0 mg/kg i.p.), did not increase oral activity. The mixed 5-HT(1C) and 5-HT2 receptor agonist, m- chlorophenylpiperazine (m-CPP), produced a slight increase in oral activity in control rats and a marked increase in oral activity in 6-OHDA-lesioned rats. In the 6-OHDA group the peak effect of 76.5 ± 4.1 oral movements occurred with an m-CPP 2-HCl dose of 4.0 mg/kg. Pindolol (1.0 mg/kg i.p.), ketanserin tartrate (5 mg/kg i.p.) and MDL-72222 (3-tropanyl-3,5- dichlorobenzoate; 10 mg/kg s.c.), antagonists with high affinity for 5- HT(1A,1B), 5-HT2 and 5-HT3 receptors, respectively, did not attenuate m-CPP actions. However, mianserin HCl (1.0 mg/kg s.c.), an antagonist with high affinity for 5-HT(1C) and 5-HT2 receptors, attenuated the oral response to m-CPP. Although the supersensitized oral response of neonatal 6-OHDA-lesioned rats to m-CPP was not attenuated by the DA D-1 receptor antagonist, SCH 23390 HCl [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine hydrochloride; 0.30 mg/kg i.p.], the enhanced response of the D-1 agonist, SKF 38393 HCl [(±)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine- 7,8-diol hydrochloride; 1.0 mg/kg i.p.], was attenuated by mianserin (1.0 mg/kg i.p.). Striatal DA content was reduced by 98.6%, whereas 5-HT content was elevated by 77% in the 6-OHDA group. These findings demonstrate that neonatal 6-OHDA destruction of central DA-containing neurons is associated with supersensitized 5-HT receptors, probably of the 5-HT(1C)subtype. Moreover, induction of oral activity by DA agonists is mediated via a serotoninergic system.

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