Lower brain fatty acid amide hydrolase in treatment-seeking patients with alcohol use disorder: a positron emission tomography study with [C-11]CURB.

Pablo Rusjan, Isabelle Boileau, Stephen J Kish, Junchao Tong, Sylvain Houle, Markus Heilig, Christian S Hendershot, Alan A Wilson, Rachel F Tyndale, Laura M Best, Dina Lagzdins, Vincenzo De Luca, Lin Lin, Richard P Bazinet, Esmaeil Mansouri, Bernard Le Foll, Belinda Williams

Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 2021;45(8):1289-1296

PMID: 31910433

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Abstract

The endocannabinoid enzyme, fatty acid amide hydrolase (FAAH), has been proposed as a therapeutic target for alcohol use disorder (AUD) and co-morbid psychiatric illnesses. Investigating this target in the living human brain and its relationship to clinical outcome is a critical step of informed drug development. Our objective was to establish whether brain FAAH levels are low in individuals with AUD and related to drinking behavior. In this pilot study, treatment-seeking patients with AUD completed two PET scans with the FAAH radiotracer [C-11]CURB after 3-7 days (n = 14) and 2-4 weeks (n = 9) of monitored abstinence. Healthy controls (n = 25) completed one scan. FAAH genetic polymorphism (rs324420) and blood concentrations of anandamide and other N-acylethanolamines metabolized by FAAH were determined and AUD symptoms assessed. In AUD, brain FAAH levels were globally lower than controls during early abstinence (F(1,36) = 5.447; p = 0.025)) and FAAH substrates (anandamide, oleoylethanolamide, and N-docosahexaenoylethanolamide) were significantly elevated (30-67%). No significant differences in FAAH or FAAH substrates were noted after 2-4 weeks abstinence. FAAH levels negatively correlated with drinks per week (r = -0.57, p = 0.032) and plasma concentrations of the three FAAH substrates (r > 0.57; p < 0.04)). Our findings suggest that early abstinence from alcohol in AUD is associated with transiently low brain FAAH levels, which are inversely related to heavier alcohol use and elevated plasma levels of FAAH substrates. Whether low FAAH is an adaptive beneficial response to chronic alcohol is unknown. Therapeutic strategies focusing on FAAH inhibition should consider the possibility that low FAAH during early abstinence may be related to drinking.

Address: Addiction Imaging Research Group, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada.; Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada.; Institute of Medical Sciences, University of Toronto, Toronto, Canada.; Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada.; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada.; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.; Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.; Family and Community Medicine, University of Toronto, Toronto, ON, Canada.; Nutritional Sciences, University of Toronto, Toronto, ON, Canada.; Group for Suicide Studies, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada.; Biobehavioral Alcohol Research Lab, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada.; Division of Neuro and Inflammation Sciences (NIV), Center for Social and Affective Neuroscience (CSAN), Department of Clinical and Experimental Medicine (IKE), Liköping University, Likoping, Sweden.; Human Brain Lab, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada.; Preclinical Imaging, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada.; Addiction Imaging Research Group, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada. [email protected].; Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada. [email protected].; Institute of Medical Sciences, University of Toronto, Toronto, Canada. [email protected].; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada. [email protected].; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. [email protected].; Human Brain Lab, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, Canada. [email protected].

DOI: 10.1038/s41386-020-0606-2

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MeSH Terms: Alcoholism, Amidohydrolases, Brain, Carbon Radioisotopes, Endocannabinoids, Humans, Pilot Projects, Positron-Emission Tomography