EFFECT OF ALPHA-METHYLSEROTONIN ON SEROTONIN RECEPTOR-COUPLED PHOSPHOINOSITIDE BREAKDOWN IN RAT CEREBRAL-CORTEX

α-Methylserotonin, an analogue of serotonin formed in vivo from α-methyltryptophan, is able to stimulate phosphoinositide turnover (up to 190% of the basal rate) in slices of rat cerebral cortex in vitro. Desensitization of the cortical slices by α-methylserotonin or serotonin significantly decreases serotonin-stimulated (but not norepinephrine-stimulated) phosphoinositide turnover, thus indicating an interaction of α-methylserotonin with serotonin receptors. Ketanserin, a serotonin2-receptor antagonist, blocks α-methylserotonin-stimulated phosphoinositide turnover. This suggests that this action is mediated by serotonin2-receptors. The chronic administration to rats of p-chlorophenylalanine, which depletes stores of brain serotonin, increases serotonin-stimulated phosphoinositide turnover, as detected in vitro. In contrast to this, the chronic administration of α-methyltryptophan, which also depletes brain serotonin, does not increase the in vitro serotonin-stimulated phosphoinositide turnover. This suggests that accumulated α-methylserotonin formed in the brain substitutes for serotonin and prevents the up-regulation of serotonin-receptor-mediated phosphoinositide hydrolysis. The present study explains the molecular basis for the functional activity of α-methylserotonin in serotonergic neurons. © 1990.