Effects of typical and atypical antipsychotics and receptor selective compounds on acetylcholine efflux in the hippocampus of the rat.

Abstract

Some atypical antipsychotic drugs appear to improve cognitive function in schizophrenia and since acetylcholine (ACh) is of importance in cognition, we used in vivo microdialysis to examine the effects of antipsychotics administered acutely (SC or IP) at pharmacologically comparable doses on ACh outflow in the hippocampus of the rat. The atypical antipsychotics olanzapine and clozapine produced robust increases in ACh up to 1500% and 500%, respectively. The neuroleptics haloperidol, thioridazine, and chlorpromazine, as well as the atypical antipsychotics risperidone and ziprasidone produced modest increases in ACh by about 50-100%. Since most atypical antipsychotics affect a variety of monoaminergic receptors, we examined whether selective ligands for some of these receptors affect hippocampal ACh. Antagonists for the 5-HT(2A) (MDL 100,907), the 5-HT(2C) (SB 242,084), the 5-HT(6) (Ro 04-6790), the D(2) (raclopride) receptors, and the alpha(1)-adrenoceptors (prazosin) modestly increased ACh by about 50%. The 5-HT(1A) agonist R-(+)-8-OH-DPAT and the alpha(2)-adrenoceptor antagonist yohimbine significantly increased ACh by about 100% and 50%, respectively. Thus, olanzapine and clozapine increased ACh to a greater extent than other tested antipsychotics, explaining perhaps their purported beneficial effect in cognitive function in schizophrenia. It appears that selective activity at each of the monoaminergic receptors studied is not the sole mechanism underlying the olanzapine and clozapine induced increases in hippocampal ACh.

• Authors: Sudabeh Shirazi-Southall, Dana Ellen Rodriguez, George G Nomikos
• Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 26 Issue 5 Pg. 583-94 (May 2002) ISSN: 0893-133X [Print] England
• PMID: 11927183 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Adrenergic alpha-Antagonists
• Antipsychotic Agents
• Dialysis Solutions
• Dopamine Antagonists
• Piperazines
• Serotonin Antagonists
• Thiazoles
• Benzodiazepines
• Pirenzepine
• ziprasidone
• Clozapine
• Haloperidol
• Risperidone
• Thioridazine
• Olanzapine
• Acetylcholine
• Chlorpromazine

Topics

• Acetylcholine (metabolism)
• Adrenergic alpha-Antagonists (pharmacology)
• Animals
• Antipsychotic Agents (pharmacology)
• Benzodiazepines
• Chlorpromazine (administration & dosage)
• Clozapine (administration & dosage)
• Dialysis Solutions (metabolism)
• Dopamine Antagonists (pharmacology)
• Extracellular Space (metabolism)
• Haloperidol (administration & dosage)
• Hippocampus (drug effects, metabolism)
• Injections, Intraperitoneal
• Injections, Subcutaneous
• Male
• Microdialysis
• Olanzapine
• Piperazines (administration & dosage)
• Pirenzepine (administration & dosage, analogs & derivatives)
• Rats
• Rats, Wistar
• Risperidone (administration & dosage)
• Serotonin Antagonists (pharmacology)
• Thiazoles (administration & dosage)
• Thioridazine (administration & dosage)