title: Differential effects of M1 and 5-hydroxytryptamine1A receptors on atypical antipsychotic drug-induced dopamine efflux in the medial prefrontal cortex.
abstract: Systemic administration of the M(1) receptor agonists N-desmethylclozapine (NDMC) and 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC260584) increase dopamine (DA) efflux in rat medial prefrontal cortex (mPFC). This increase is blocked by systemic administration of both telenzepine, a preferential M(1) receptor antagonist, and N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635), a 5-hydroxytryptamine(1A) receptor antagonist. The present study sought to determine whether DA efflux in the mPFC induced by the atypical antipsychotic drugs clozapine, risperidone, and olanzapine is also mediated by M(1) receptor stimulation and, specifically, to determine whether these effects are mediated M(1) receptors in the mPFC through use of in vivo microdialysis in awake, freely moving Sprague-Dawley rats. Telenzepine (3 mg/kg) significantly attenuated clozapine- (20 mg/kg), olanzapine- (10 mg/kg), and risperidone- (1.0 mg/kg) induced increases in mPFC DA efflux. Local mPFC perfusion of NDMC, AC260584, clozapine, risperidone, or olanzapine (10-500 microM), significantly increased DA efflux in the mPFC. Local mPFC perfusion of telenzepine (0.1 microM) prevented increases in mPFC DA efflux induced by systemic administration of AC260584 (10 mg/kg), NDMC (20 mg/kg), and clozapine (10 mg/kg), but not by risperidone (1.0 mg/kg) or olanzapine (10 mg/kg). However, local mPFC perfusion of WAY-100635 (0.1 microM) prevented mPFC DA efflux induced by clozapine, risperidone, and olanzapine, but not by AC260584 or NDMC. These results suggest that the AC260584-, NDMC-, and clozapine-induced DA efflux in the mPFC is mediated directly by mPFC M(1) receptors.
authors.affiliation: Psychiatry Department, Vanderbilt University School of Medicine, 1601 23rd Ave. South, 3035, Nashville, TN 37212, USA. zhu.li@vanderbilt.edu
authors.forename: Zhu
authors.initials: Z
authors.lastname: Li
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Prus
authors.forename: Jin
authors.initials: J
authors.lastname: Dai
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000187:drug effects*; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D018727:Muscarinic Antagonists; D010879:Piperazines; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D012702:Serotonin Antagonists; C046338:telenzepine; D044282:Receptor, Serotonin, 5-HT1A; D010890:Pirenzepine; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D004298:Dopamine