Effect of muscarinic receptor agonists xanomeline and sabcomeline on acetylcholine and dopamine efflux in the rat brain; comparison with effects of 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC260584) and N-desmethylclozapine.

We have demonstrated that the main metabolite of clozapine, N-desmethylclozapine, has a significant role in the ability of clozapine to improve some aspects of cognition in schizophrenia. Furthermore, there is also evidence to suggest that it is the muscarinic M1 receptor agonist effect of N-desmethylclozapine that underlies its cognitive effects. In the present study we examined the efficacy of two muscarinic receptor agonists xanomeline and sabcomeline to increase the efflux of acetylcholine and dopamine in rat medial prefrontal cortex and nucleus accumbens. Microdialysis in awake, freely moving rats was used to demonstrate that xanomeline at 10, but not 1 or 3 mg/kg (s.c.), significantly increased acetylcholine efflux in both the medial prefrontal cortex and nucleus accumbens. Sabcomeline, at 1 but not 0.1 or 0.5 mg/kg (s.c.), significantly increased acetylcholine efflux in the medial prefrontal cortex but not the nucleus accumbens. Both xanomeline and sabcomeline dose-dependently increased dopamine efflux in the medial prefrontal cortex but only high dose of xanomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) increased that in the nucleus accumbens. The acetylcholine and dopamine efflux induced by xamomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) were significantly blocked by the preferential muscarinic M1 receptor antagonist telenzepine (3 mg/kg, s.c.), but significantly potentiated by the atypical antipsychotic drug risperidone (0.1 mg/kg, s.c.), which does not have much affinity for muscarinic receptor(s). According to the analysis of net-AUC (area under the curve) values of acetylcholine and dopamine levels, the rank order of ability of these drugs to increase acetylcholine or dopamine levels is sabcomeline>xanomeline≈AC260584>N-desmethylclozapine. The present study suggests that the binding potency of muscarinic M1 receptors is greatly related to their ability to increase cortical acetylcholine and dopamine efflux, and that this may have some relevance for treatment of the cognitive deficit of schizophrenia.