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Role of the Serotonergic System in the Neurobiology of Alcoholism

Implications for Treatment

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Abstract

Preclinical studies have contributed greatly to our understanding of the neurochemical pathways associated with the development and maintenance of alcohol-seeking behaviour. These studies have demonstrated the important role of serotonin pathways, particularly as they relate to dopaminergic function, which mediates alcohol-induced reward associated with its abuse liability. Naturally, this has led to the study of serotonergic agents as treatments for alcoholism.

SSRIs do not appear to be effective treatment for a heterogeneous alcoholic group. However, they may be useful as treatment for late-onset alcoholics, or alcoholism complicated by comorbid major depression. Buspirone, a serotonin 5-HT1a partial agonist, does not appear to be an effective treatment for alcoholics without comorbid disease. Buspirone may, however, have some utility for treating alcoholics with comorbid anxiety disorder. The 5-HT2 antagonist ritanserin, at pharmacologically relevant clinical doses, does not appear to be an effective treatment for alcoholism. Ondansetron, a 5-HT3 antagonist, is an efficacious and promising medication for the treatment of early-onset alcoholism. Preliminary evidence suggests that combining the mu antagonist naltrexone with the 5-HT3 antagonist ondansetron promises to be more effective for treating alcoholism than either alone.

The differential treatment effect of SSRIs and ondansetron among various subtypes of alcoholic is intriguing. Future research is needed to understand more clearly the molecular genetic differences and the interactions of such differences with the environment that typify a particular alcoholic subtype. Such an understanding could enable us to make comfortable predictions as to which alcoholic subtype might respond best to a particular serotonergic agent, which could then be provided.

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Acknowledgements

This work was supported by grants #AA10522-05 and AA10522-0551 from the National Institute on Alcohol Abuse and Alcoholism. I would also like to thank the following colleagues affiliated with my group (alphabetical order) — Drs N. Ait-Daoud, M. Devous, J. Hensler, M. Javors, R. Lamb, and J. Roache — for their comments in developing this hypothesis for the differential effectiveness of specific serotonergic agents in treating alcoholic subtypes. I also am grateful to Mr Robert Cormier BA for his skilled assistance in the preparation of this manuscript. The author has no potential conflicts of interest directly related to the contents of this review.

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Johnson, B.A. Role of the Serotonergic System in the Neurobiology of Alcoholism. CNS Drugs 18, 1105–1118 (2004). https://doi.org/10.2165/00023210-200418150-00005

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