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Dopamine dysfunction in stimulant use disorders: mechanistic comparisons and implications for treatment

Abstract

Dopamine system deficiencies and associated behavioral phenotypes may be a critical barrier to success in treating stimulant use disorders. Similarities in dopamine dysfunction between cocaine and methamphetamine use disorder but also key differences may impact treatment efficacy and outcome. This review will first compare the epidemiology of cocaine and methamphetamine use disorder. A detailed account of the pharmacokinetic and pharmacodynamic properties associated with each drug will then be discussed, with an emphasis on effects on the dopamine system and associated signaling pathways. Lastly, treatment results from pharmacological clinical trials will be summarized along with a more comprehensive review of the involvement of the trace amine-associated receptor on dopamine signaling dysfunction among stimulants and its potential as a therapeutic target.

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Fig. 1: Mechanistic comparisons of methamphetamine and cocaine and the implications for treatment.

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Acknowledgements

This work was supported in part by the Department of Veterans Affairs Clinical Sciences Research and Development Merit Review Program, I01 CX001558-01A1 (WFH); Department of Justice 2010-DD-BX-0517 (WFH); National Institute on Drug Abuse P50DA018165 (WFH), and R21 DA047602-01A1 (WFH); Oregon Clinical and Translational Research Institute, 1 UL1 RR024140 01 from the National Center for Research Resources, a component of the National Institutes of Health and National Institute of Health Roadmap for Medical Research (WFH) and National Institute on Alcohol Abuse and Alcoholism R21 AA020039 (WFH). MK was supported by Department of Veterans Affairs Clinical Sciences Research and Development Career Development Award CX001790, Oregon Health & Science University Collins Medical Trust Award APSYC0249, Medical Research Foundation of Oregon APSYC0250 and Center for Women’s Health Circle of Giving GPSYC0287A.

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Kohno, M., Dennis, L.E., McCready, H. et al. Dopamine dysfunction in stimulant use disorders: mechanistic comparisons and implications for treatment. Mol Psychiatry 27, 220–229 (2022). https://doi.org/10.1038/s41380-021-01180-4

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