Development of a Ghrelin Deacylase to Attenuate Drug Reward and Associated Effects of Methamphetamine

All addictive substances directly or indirectly interact with the dopamine reward system to alter the brain’s dopamine receptor activities. It is essential for a truly effective addiction medication to attenuate substance reward and normalize the brain’s physiological functions. Conventional pharmacological intervention approaches to the treatment of substance addiction usually aim to develop and deliver a potential therapeutic agent to the brain to directly block or decrease actions of the substance or its therapeutic target in the brain. However, it is a grand challenge to attenuate the substance reward without affecting the normal physiological functions of brain receptors or transporters. Here, we show that peripheral ghrelin deacylation using a ghrelin deacylase identified in this study can effectively attenuate the pharmacological and rewarding effects of methamphetamine, a representative psychostimulant, in rodents through an interesting pharmacological mechanism without interacting with the ghrelin receptor or the dopamine receptor (because the ghrelin deacylase is not expected to cross the blood–brain barrier). In further animal behavioral studies, ghrelin deacylase administration significantly attenuated rat self-administration of methamphetamine, suggesting that ghrelin deacylase may serve as a promising therapeutic candidate for addiction treatment.