Clozapine increases both acetylcholine and dopamine release in rat ventral hippocampus: Role of 5-HT1A receptor agonism

Young Chul Chung, Zhu Li, Jin Dai, Herbert Y. Meltzer, Junji Ichikawa

Research output: Contribution to journalArticlepeer-review

80 Scopus citations


Atypical antipsychotic drugs (APDs) such as clozapine, but not the typical APD haloperidol, improve some aspects of cognition in schizophrenia. This advantage has been attributed, in part, to the ability of the atypical APDs to markedly increase acetylcholine (ACh) and dopamine (DA) release in rat medial prefrontal cortex (mPFC), while producing a minimal effect in the nucleus accumbens (NAC) or striatum. The atypical APD-induced preferential release of DA, but not ACh, in the mPFC is partially inhibited by the selective 5-HT 1A antagonist WAY100635. However, little is known about these effects of atypical APDs in the ventral hippocampus (vHIP), another possible site of action of atypical APDs with regard to cognitive enhancement. The present study demonstrates that clozapine (10 mg/kg) comparably increases both ACh and DA release in the vHIP and mPFC. The increases in DA, but not ACh, release in both regions were partially attenuated by WAY100635 (0.2 mg/kg), which had no effect by itself on the release of either neurotransmitter in either region. Tetrodotoxin (TTX; 1 μM), a Na+ channel blocker, in the perfusion medium, eliminated the clozapine (10 mg/kg)-induced ACh and DA release in the vHIP, indicating their neuronal origin. Haloperidol produced a slight increase in ACh release in the vHIP at 1 mg/kg, and DA release in the mPFC at 0.1 mg/kg. In conclusion, clozapine increases ACh and DA release in the vHIP and mPFC, whereas haloperidol has minimal effects on the release of these two neurotransmitters in either region. These differences may contribute, at least in part, to the superior ability of clozapine, compared to haloperidol, to improve cognition in schizophrenia. 5-HT1A agonism is important to the ability of clozapine and perhaps other atypical APDs to increase DA, but not ACh, release in the vHIP, as well as the mPFC. The role of hippocampus in the cognitive effects of atypical APDs warrants more intensive study.

Original languageEnglish (US)
Pages (from-to)54-63
Number of pages10
JournalBrain research
Issue number1
StatePublished - Oct 8 2004


  • Clozapine
  • Dopamine and acetylcholine release
  • Haloperidol
  • Medial prefrontal cortex and ventral hippocampus

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology


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