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 M(1) 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 M(1) 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 approximately
AC260584>
N-desmethylclozapine. The present study suggests that the binding potency of
muscarinic M(1) 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.