Muscarinic receptors as a target for drugs treating schizophrenia

The family of 5 muscarinic acetylcholine receptors belongs to the superfamily of G protein coupled neurotransmitter receptors that serve in part as regulators of synaptic function. Muscarinic receptors are anatomically positioned in cortical and subcortical areas and modulate dopaminergic and glutamatergic neurotransmission thought to be dysfunctional in schizophrenia. Neurochemical studies have shown that dopamine and muscarinic receptors reciprocally modulate one another. For example, the muscarinic agonist xanomeline increases extracellular levels of dopamine and Fos expression in cortical areas greater than subcortical areas, similar to effects of atypical antipsychotics. In electrophysiological studies, xanomeline with acute and chronic administration decreased firing of the mesocorticolimbic dopamine A10 tract, but not the motoric dopamine A9 tract. Behavioral investigations have shown that muscarinic agonists, like dopamine antagonists, inhibit conditioned-avoidance responding and dopamine-agonist-induced behaviors including hyperactivity, climbing behavior and disruption of prepulse inhibition, models for positive symptoms of schizophrenia. Transgenic knockout mice lacking M(4) receptors are hyperactive and hyper-responsive to dopamine D(1) agonists, suggesting a dynamic balance between the dopamine and M(4) receptors. Muscarinic agonists had activity in animal models of negative symptoms, cognitive dysfunction and affective disorders, symptoms that are prominent in schizophrenic patients. Consistent with effects in animal models, preliminary clinical investigation indicates that muscarinic agonists like xanomeline may be effective in the pharmacotherapy of schizophrenia. Thus, we hypothesize that a combined M(1) agonist to promote cognition and a M(4) agonist for antipsychotic-like effects would treat the symptom domains of schizophrenia without parasympathomimetic side effects.