Role of postsynaptic serotonin1A receptors in risperidone-induced increase in acetylcholine release in rat prefrontal cortex

Eur J Pharmacol. 2007 Mar 22;559(2-3):155-60. doi: 10.1016/j.ejphar.2006.12.007. Epub 2006 Dec 29.


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-HT1A receptor antagonist/dopamine D4 receptor agonist, but not by a low dose (0.1 mg/kg) of the antagonist which antagonizes preferentially presynaptic 5-HT1A 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 microM), the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (1 and 10 microM), and the dopamine D4 receptor antagonist 3-(4-(4-iodophenyl)piperazine-1-yl)methyl-1H-pyrrolo[2,3-b]pyridine (1 and 10 microM) 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-HT1A receptor activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism*
  • Animals
  • Antipsychotic Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Male
  • Microdialysis
  • Piperazines / pharmacology
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / drug effects*
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Risperidone / pharmacology*
  • Serotonin Antagonists / pharmacology*
  • Synapses / drug effects*
  • Synapses / metabolism
  • Time Factors


  • Antipsychotic Agents
  • Piperazines
  • Pyridines
  • Serotonin Antagonists
  • Receptor, Serotonin, 5-HT1A
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • Risperidone
  • Acetylcholine