Evaluating Novel Muscarinic Acetylcholine Receptor Potentiators for the Treatment of Cognitive Deficits in Schizophrenia

Abstract

Current antipsychotic medications (APDs) for schizophrenia primarily treat positive symptoms (hallucinations, delusions) yet are largely ineffective in treating the negative (anhedonia, social withdrawal, apathy) and cognitive symptoms (attention, memory, executive function). Overall functional outcome in patients with schizophrenia has been positively linked to cognitive function, suggesting that novel treatments to improve cognition may provide greater efficacy compared to currently available APDs. Accumulating evidence suggests that modulation of the muscarinic cholinergic system represents a potential target for developing novel APDs for the treatment of multiple symptoms associated with schizophrenia. Of the five different subtypes of muscarinic acetylcholine receptors (mAChRs), M1 and M4 mAChRs subtypes demonstrate substantial promise for antipsychotic-like potential. The recent development and characterization of several allosteric potentiators with subtype selectivity for M1 or M4 allows for investigation in preclinical models of antipsychotic-like activity and/or enhancement of cognitive function. Through these studies, we further our understanding of the interaction between mAChRs and dopamine and glutamate systems that are implicated in the pathophysiology of schizophrenia.