Systemic administration of the M1 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 M1 receptor antagonist, and N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY-100635), a 5-hydroxytryptamine1A 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 M1 receptor stimulation and, specifically, to determine whether these effects are mediated M1 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 μM), significantly increased DA efflux in the mPFC. Local mPFC perfusion of telenzepine (0.1 μM) 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 μM) 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 M1 receptors.
|Original language||English (US)|
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Sep 21 2009|
ASJC Scopus subject areas
- Molecular Medicine