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A deeper insight into how GABA-B receptor agonism via baclofen may affect alcohol seeking and consumption: lessons learned from a human laboratory investigation

Molecular Psychiatry volume 26, pages 545–555 (2021)Cite this article

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Abstract

Previous studies suggest that GABA-B receptor agonism may represent an effective pharmacological approach to treat addictive disorders. Baclofen is a selective GABA-B receptor agonist which has been investigated as a potential treatment for alcohol use disorder. However, research is needed to understand the biobehavioral mechanisms underlying baclofen’s effect on alcohol use. In the present randomized, double-blind, placebo-controlled study, thirty-four alcohol-dependent individuals were randomized to receive baclofen (30 mg/d) or placebo for a week, and then participated in a laboratory experiment consisting of three procedures: alcohol cue-reactivity, priming, and self-administration. During the experiment, craving and other subjective responses to alcohol were assessed, and blood samples were collected for pharmacokinetic measurements. The effects of baclofen on the relationships between different alcohol-related laboratory parameters were investigated. Baclofen pharmacokinetic parameters and their correlations with behavioral measures were also examined. Results showed that baclofen disrupted the link between alcohol priming and self-administration, as indicated by significant interaction effects between drug condition (baclofen vs. placebo) and some of the priming variables (alcohol craving: F3,9 = 6.03, p = 0.01; alcohol sedation: F3,6 = 7.16, p = 0.01) on the total amount of alcohol self-administered. Considerable interindividual variability in baclofen pharmacokinetic parameters was observed. Maximum plasma concentrations of baclofen negatively correlated with cue-induced alcohol craving (r = −0.57, p = 0.03) and priming-induced ratings of ‘like more’ (r = −0.59, p = 0.02). In conclusion, baclofen may work by dissociating the link between an initial drink (priming) and subsequent alcohol consumption (self-administration). Considerable pharmacokinetic variability is an important factor to take into account when employing baclofen as a treatment for alcohol use disorder.

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Acknowledgements

This work was supported by: (1) NIH intramural funding ZIA-AA000218 (Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology; PI: Dr. Lorenzo Leggio), jointly supported by the NIAAA Division of Intramural Clinical and Biological Research and the NIDA Intramural Research Program; and (2) Brain and Behavior Research Foundation (BBRF; formerly NARSAD) grant #17325 (PI: Dr. Lorenzo Leggio). We thank the clinical and research staff involved in data collection and support in the joint NIAAA/NIDA Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, in the NIAAA clinical program of the Division of Intramural Clinical and Biological Research, at the NIH Clinical Center (Nursing, Nutrition, and Pharmacy Departments), and in the Clinical Pharmacokinetics Research Laboratory at the University of Rhode Island. The authors would like to express their gratitude to the participants who took part in this study.

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  1. Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA

    Mehdi Farokhnia, Sara L. Deschaine, Lisa A. Farinelli, Mary R. Lee & Lorenzo Leggio

  2. Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA

    Armin Sadighi & Fatemeh Akhlaghi

  3. Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, USA

    Lorenzo Leggio

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Farokhnia, M., Deschaine, S.L., Sadighi, A. et al. A deeper insight into how GABA-B receptor agonism via baclofen may affect alcohol seeking and consumption: lessons learned from a human laboratory investigation. Mol Psychiatry 26, 545–555 (2021). https://doi.org/10.1038/s41380-018-0287-y

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