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Abstract

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.

Document Type

Article

Publication Date

2025

Notes/Citation Information

© 2025 The Authors. Published by American Chemical Society

Digital Object Identifier (DOI)

https://doi.org/10.1021/acsptsci.5c00391

Funding Information

This work was supported by the National Institutes of Health (NIH grants R01 DA056646, U18 DA052319, U01 DA051079, UG3/UH3 NS134920, UH2/UH3 DA041115, R01 DA035552, R01 DA032910, and R01 DA013930).

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