Role of postsynaptic serotonin 1A receptors in risperidone-induced increase in acetylcholine release in rat prefrontal cortex

Abstract

Most atypical antipsychotic drugs increase acetylcholine release in the prefrontal cortex, but the detailed mechanism is still unknown. The present study examined the role of serotonin (5-HT) 1A receptors in risperidone-induced increases in acetylcholine release in rat prefrontal cortex. Systemic administration of risperidone at doses of 1 and 2 mg/kg increased acetylcholine release in the prefrontal cortex in a dose-dependent manner. This increase was antagonized by systemic administration of high doses (1 and 3 mg/kg) of N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}- N-(2-pyridinyl)cyclohexanecarboxamide (WAY100635), a 5-HT 1A receptor antagonist/dopamine D 4 receptor agonist, but not by a low dose (0.1 mg/kg) of the antagonist which antagonizes preferentially presynaptic 5-HT 1A autoreceptors. Furthermore, local application of WAY100635 into the prefrontal cortex also attenuated risperidone-induced increases in acetylcholine release. WAY100635 alone did not affect acetylcholine release in the prefrontal cortex. On the other hand, local application of risperidone (3 and 10 μM), the 5-HT 1A receptor agonist 8-hydroxy-2-(di- n-propylamino)tetralin (1 and 10 μM), and the dopamine D 4 receptor antagonist 3-(4-(4-iodophenyl)piperazine-1-yl)methyl-1 H-pyrrolo[2,3- b]pyridine (1 and 10 μM) into the cortex did not affect acetylcholine release in the prefrontal cortex. These results suggest that risperidone increases acetylcholine release in the prefrontal cortex through a complex mechanism which is enhanced by prefrontal 5-HT 1A receptor activation.