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 stimulat ed by serotonin (5-HT), acting via 5-HT2 and possibly 5-HT3 receptors and by acetylcholine or carbachol, acting via muscarinic M1 and M3 rec eptors. Serotoninergic neurons have been described as tonically inhibi ting cortical acetylcholine release. We studied the effects of subchro nic pretreatment with high doses of D-fenfluramine (10 mg/kg, i.p., da ily for 4 days), which releases 5-HT and blocks its reuptake, on 5-HT- and carbachol-stimulated PI breakdown, as measured by [H-3]inositolmon ophosphate ([H-3]IP1) accumulation in cortical miniprisms. This pretre atment decreased 5-HT-stimulated [H-3]IP1 accumulation, suggesting tha t a prolonged increase of 5-HT in the synaptic cleft reduces the activ ity of the transducing system used by postsynaptic 5-HT receptors. Car bachol-stimulated PI breakdown was unaltered by pretreatment with D-fe nfluramine. Pretreatment with a single dose of p-chloroamphetamine (5 mg/kg), a serotoninergic neurotoxin, which depleted cortical 5-HT by 8 5%, did not change [H-3]IP1 accumulation after stimulation by 5-HT or by the muscarinic agonist carbachol. Subchronic pretreatment, which de pleted cortical 5-HT by 90%, decreased both 5-HT- and carbachol-stimul ated [H-3]IP1 accumulation. The mechanism by which p-chloroamphetamine , but not D-fenfluramine, diminishes the PI response to carbachol migh t involve impairment of the tonic serotoninergic inhibition of acetylc holine release.