Allosteric modulation of muscarinic receptors in alcohol and substance use disorders.

Alcohol and substance use disorders are chronic relapsing disorders, characterized by a compulsion to take drugs and loss of control in limiting intake. The impact of alcohol and substance abuse on morbidity and mortality is very high worldwide, and treatment options are inadequate at a population level. There is a need for the discovery and development of novel pharmacotherapies to treat alcohol and substance use disorders. The recent development of subtype selective muscarinic acetylcholine receptor (mAChR) allosteric modulators, is rapidly increasing our understanding of this system and revealing great promise for disease treatment. In this chapter, we will present and integrate the current literature regarding the role of mAChRs in drug and alcohol abuse with emerging evidence using novel allosteric modulators targeting specific mAChR subtypes. We will focus on the potential of M1, M4 and M5 mAChRs in the treatment of alcohol, psychostimulant and opioid dependence, using evidence from preclinical studies to predict their utility in treating different stages of the addiction cycle. Overall, preclinical evidence suggests allosteric modulation of mAChRs may provide promise as potential treatment options for alcohol and substance abuse in reducing consumption, facilitating abstinence and preventing relapse.