Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies
- 13 December 2006
- journal article
- research article
- Published by Springer Science and Business Media LLC in Neuropsychopharmacology
- Vol. 32 (7), 1540-1549
- https://doi.org/10.1038/sj.npp.1301279
Abstract
There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT2 antagonist and as a partial agonist to dopamine D2 and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried out using: brain D2 and 5-HT2 receptor occupancy; animal models predictive of antipsychotic efficacy (amphetamine-induced hyperlocomotion (AIL) and conditioned avoidance response (CAR) models); measures predictive of side effects (catalepsy and prolactin elevation); and molecular markers predictive of antipsychotic action (striatal Fos induction). NDMC (10–60 mg/kg/s.c.) showed high 5-HT2 (64–79%), but minimal D2 occupancy (<15% at 60 mg/kg) 1 h after administration. In contrast to other antipsychotics, NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens. However, like atypical antipsychotics, it showed no catalepsy, prolactin elevation, and minimal Fos in the dorsolateral striatum. It seems unlikely that NDMC would show efficacy as a stand-alone antipsychotic, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile (muscarinic agonism) may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens.This publication has 55 references indexed in Scilit:
- Developing Predictive Animal Models and Establishing a Preclinical Trials Network for Assessing Treatment Effects on Cognition in SchizophreniaSchizophrenia Bulletin, 2005
- N-Desmethylclozapine, a Major Metabolite of Clozapine, Increases Cortical Acetylcholine and Dopamine Release In Vivo Via Stimulation of M1 Muscarinic ReceptorsNeuropsychopharmacology, 2005
- Predictors of Clinical Outcome in Schizophrenic Patients Responding to ClozapineJournal of Clinical Psychopharmacology, 2003
- Clozapine, Olanzapine, Risperidone, and Haloperidol in the Treatment of Patients With Chronic Schizophrenia and Schizoaffective DisorderAmerican Journal of Psychiatry, 2002
- M1 Muscarinic Acetylcholine Receptors Activate Extracellular Signal-Regulated Kinase in CA1 Pyramidal Neurons in Mouse Hippocampal SlicesMolecular and Cellular Neuroscience, 2001
- Antagonism at 5-HT2A receptors potentiates the effect of haloperidol in a conditioned avoidance response task in ratsPharmacology Biochemistry and Behavior, 2001
- Effects of Desmethylclozapine on Fos Protein Expression in the Forebrain: In Vivo Biological Activity of the Clozapine MetaboliteNeuropsychopharmacology, 1998
- The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapineBritish Journal of Clinical Pharmacology, 1997
- Clozapine and N-desmethylclozapine are potent 5-HT1C receptor antagonistsEuropean Journal of Pharmacology: Molecular Pharmacology, 1993
- Regionally specific effects of atypical antipsychotic drugs on striatal Fos expression: The nucleus accumbens shell as a locus of antipsychotic actionMolecular and Cellular Neuroscience, 1992