title: Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum.
abstract: The role of acetylcholine (ACh) in the action of antipsychotic drugs (APDs) was studied by microdialysis, without AChesterase inhibition, to facilitate the interpretation of any observed drug effects. The atypical APDs, clozapine (2.5-20 mg/kg), olanzapine (10 mg/kg), risperidone (1 mg/kg), and ziprasidone (3 mg/kg) significantly increased ACh release in rat medial prefrontal cortex (mPFC), whereas the typical APDs, haloperidol (0.1-1 mg/kg), S(-)-sulpiride (10-25 mg/g), and thioridazine (5-20 mg/kg) did not. None of seven APDs increased ACh release in the nucleus accumbens or striatum at the doses effective in the mPFC. Thus, atypical and typical APDs may differ in the ability to increase cortical ACh release, a possible factor contributing to cognitive improvement in schizophrenia. After perfusion with neostigmine, an AChesterase inhibitor, clozapine, but not haloperidol, increased ACh release in all three aforementioned brain regions with an enhanced effect in the mPFC, indicating the importance of studying ACh release in the absence of AChesterase inhibition. Clozapine, and perhaps other atypical APDs, alone or in combination with an AChesterase inhibitor, may improve cognition in schizophrenia, and perhaps other cognitive disorders, e.g., early Alzheimer's disease, by enhancing cortical cholinergic transmission.
authors.affiliation: Departments of Psychiatry and Pharmacology, The Psychiatric Hospital at Vanderbilt, Vanderbilt University School of Medicine, 1601 23rd Avenue South, Nashville, TN 37212, USA.
authors.forename: Junji
authors.initials: J
authors.lastname: Ichikawa
authors.forename: Jin
authors.initials: J
authors.lastname: Dai
authors.forename: Ian A
authors.initials: IA
authors.lastname: O'Laughlin
authors.forename: Wiley L
authors.initials: WL
authors.lastname: Fowler
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
mesh_terms: D000109:Acetylcholine / Q000096:biosynthesis / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology*; D001569:Benzodiazepines; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D000077152:Olanzapine; D010095:Oxotremorine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000494:pharmacology; D012601:Scopolamine / Q000494:pharmacology; D013469:Sulpiride / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013881:Thioridazine / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D002800:Cholinesterase Inhibitors; D010879:Piperazines; D013844:Thiazoles; D001569:Benzodiazepines; D010890:Pirenzepine; D010095:Oxotremorine; C092292:ziprasidone; D013469:Sulpiride; D012601:Scopolamine; D000110:Acetylcholinesterase; D003024:Clozapine; D006220:Haloperidol; D018967:Risperidone; D013881:Thioridazine; D000077152:Olanzapine; D000109:Acetylcholine