Effects of subchronic pretreatment with D-fenfluramine or p-chloroamphetamine on [3H]inositolmonophosphate accumulation in rat cortical miniprisms.
Phosphatidylinositol (PI) breakdown in rat cerebral cortex is stimulated by serotonin (5-HT), acting via 5-HT2 and possibly 5-HT3 receptors and by acetylcholine or carbachol, acting via muscarinic M1 and M3 receptors. Serotoninergic neurons have been described as tonically inhibiting cortical acetylcholine release. We studied the effects of subchronic pretreatment with high doses of D-fenfluramine (10 mg/kg, i.p., daily for 4 days), which releases 5-HT and blocks its reuptake, on 5-HT-and carbachol-stimulated PI breakdown, as measured by [3H]inositolmonophosphate ([3H]IP1) accumulation in cortical miniprisms. This pretreatment decreased 5-HT-stimulated [3H]IP1 accumulation, suggesting that a prolonged increase of 5-HT in the synaptic cleft reduces the activity of the transducing system used by postsynaptic 5-HT receptors. Carbachol-stimulated PI breakdown was unaltered by pretreatment with D-fenfluramine. Pretreatment with a single dose of p-chloroamphetamine (5 mg/kg), a serotoninergic neurotoxin, which depleted cortical 5-HT by 85%, did not change [3H]IP1 accumulation after stimulation by 5-HT or by the muscarinic agonist carbachol. Subchronic pretreatment, which depleted cortical 5-HT by 90%, decreased both 5-HT- and carbachol-stimulated [3H]IP1 accumulation. The mechanism by which p-chloroamphetamine, but not D-fenfluramine, diminishes the PI response to carbachol might involve impairment of the tonic serotoninergic inhibition of acetylcholine release.
Erfurth
A
A
Department of Brain and Cognitive Sciences, Wurtman Lab., Massachusetts Institute of Technology, Cambridge 02139.
Gardier
A M
AM
Ribeiro
E
E
Wurtman
R J
RJ
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D005277:Fenfluramine / Q000494:pharmacology*; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007295:Inositol Phosphates / Q000378:metabolism*; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D013268:Stimulation, Chemical; D014316:Tritium; D010133:p-Chloroamphetamine / Q000494:pharmacology*
D007295:Inositol Phosphates; D014316:Tritium; D005277:Fenfluramine; D012701:Serotonin; D010133:p-Chloroamphetamine; D002217:Carbachol