5-HT1A and 5-HT2A receptors minimally contribute to clozapine-induced acetylcholine release in rat medial prefrontal cortex

Junji Ichikawa*, Jin Dai, Herbert Y. Meltzer

*Corresponding author for this work

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

The atypical antipsychotic drugs (APDs) clozapine, olanzapine, risperidone, and ziprasidone preferentially increase dopamine (DA) release in rat medial prefrontal cortex (mPFC). These effects have been shown to depend upon potent 5-HT2A relative to weak D2 antagonism, and 5-HT1A agonism as well. Atypical APDs also increase acetylcholine (ACh) release in the mPFC, but not the nucleus accumbens (NAC) or striatum (STR), whereas typical APDs such as haloperidol, S(-)-sulpiride and thioridazine do not produce either effect in the mPFC. This study examined the role of 5-HT1A agonism, 5-HT2A and D2 antagonism, and the combination thereof, in the ability of clozapine to increase ACh release in rat mPFC. R(+)-8-OH-DPAT (0.2 mg/kg), a 5-HT1A agonist, WAY100635 (0.2-0.5 mg/kg), a 5-HT1A antagonist, and DOI (0.6-2.5 mg/kg), a 5-HT2A/2C agonist, increased ACh release in the mPFC, whereas M100907 (0.03-1 mg/kg), a 5-HT2A antagonist, did not. DOI (2.5 mg/kg) and M100907 (0.1 mg/kg) had no effect on ACh release in the NAC or STR. WAY100635 and M100907 inhibited the ability of R(+)-8-OH-DPAT and DOI, respectively, to increase ACh release in the mPFC. WAY100635, which inhibits clozapine-induced DA release in the mPFC, failed to inhibit clozapine (20 mg/kg)-induced ACh release in that region. Similarly, the combination of M100907 and haloperidol (0.1 mg/kg), which enhances DA release in the mPFC, failed to increase ACh release in that region. These results suggest that 5-HT1A agonism and 5-HT2A antagonism, as well as DA release, contribute minimally to the ability of clozapine, and perhaps other atypical APDs, to increase ACh release in the mPFC.

Original languageEnglish (US)
Pages (from-to)34-42
Number of pages9
JournalBrain research
Volume939
Issue number1-2
DOIs
StatePublished - Jun 7 2002

Keywords

  • 5-HT receptor
  • 5-HT receptor
  • Acetycholine release
  • Clozapine
  • Haloperidol
  • Medial prefrontal cortex

ASJC Scopus subject areas

  • Neuroscience(all)

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