Differential effects of spinal 5-HT1A receptor activation and 5-HT2A/2C receptor desensitization by chronic haloperidol.
The effects of 7- and 21-day haloperidol treatment on the spinal serotonergic system were examined in vivo in acutely spinalized adult rats. Intravenous administration of a selective 5-HT(2A/2C) receptor agonist, (+/-)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride (0.1 mg/kg) significantly increased the excitability of spinal motoneurones as reflected by increased monosynaptic mass reflex amplitude. This was significantly reduced in rats treated with haloperidol (1 mg/kg/day, i.p.) for 7 and 21 days. Administration of a 5-HT(1A/7) receptor agonist, (+/-)-8-Hydroxy dipropylaminotetraline hydrobromide (0.1 mg/kg, i.v.) significantly inhibited the monosynaptic mass reflex. This inhibition was greatly prolonged in haloperidol treated animals. These results demonstrate that the effects of haloperidol on the activation and desensitization of 5-HT(1A) and 5-HT(2A/2C) receptors respectively, may be mediated via intracellular mechanisms shared by these receptors with dopamine D(2) receptors in the mammalian spinal cord. The above serotonergic mechanisms may be partly responsible for haloperidol-induced extrapyramidal motor dysfunction.
Gajendiran
Mahadevan
M
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Science University of Tokyo, 12 Ichigaya, Funagawara-machi, Shinjuku-ku, Tokyo 162, Japan. gajendiran.mahadevan@Vanderbilt.edu
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D004594:Electrophysiology; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D012023:Reflex, Monosynaptic / Q000187:drug effects; D058825:Serotonin 5-HT1 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*
D000662:Amphetamines; D014150:Antipsychotic Agents; D017448:Receptors, Dopamine D2; D058825:Serotonin 5-HT1 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D017366:Serotonin Receptor Agonists; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D006220:Haloperidol; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine