Selective Targeting of Muscarinic Receptors: Novel Therapeutic Approaches for Psychotic Disorders

Cyrille      Sur; Gene   G.   Kinney

Abstract

Schizophrenia is a well recognized and debilitating psychiatric disorder composed of several symptoms. Despite the clinical efficacy of present typical and atypical antipsychotics to alleviate positive symptoms, negative symptoms and cognitive disorders are not optimally controlled. Thus, there is an unmet medical need to develop novel medications with improved tolerability and efficacy for the treatment of these symptoms. Clinical observations over the past four decades have accumulated to support a role of central muscarinic cholinergic neurotransmission in psychosis. Indeed, recent studies have shown that acetylcholine esterase inhibitors as well as weakly selective muscarinic agonists such as xanomeline improved neuropsychiatric symptoms and cognitive function in Alzheimers disease patients. Preclinically, a large body of studies has highlighted the involvement of muscarinic cholinergic signaling in cognition and psychosis. However the lack of truly selective drugs for the five muscarinic receptors has prevented an unambiguous determination of the role of each receptor subtypes in these behaviors. Recent progress in behavioral studies of mice deficient for the muscarinic receptors and in the discovery of selective muscarinic agonists have started to unravel the contribution of muscarinic receptor subtypes to complex behaviors. Accordingly, this review examines the potential of selectively targeting muscarinic receptor subtypes as a therapeutic approach for the treatment of psychotic disorders.

Keywords: schizophrenia, acetylcholine, central nervous system, cholinergic neurons, muscarinic acetylcholine receptors, g protein-coupled receptor

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