D3 dopamine receptors and a missense mutation of fatty acid amide hydrolase linked in mouse and men: implication for addiction

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 45; no. 5; pp. 745 - 752
• Main Authors: Mansouri, Esmaeil, Nobrega, José N., Hill, Matthew N., Tyndale, Rachel F., Lee, Francis S., Hendershot, Christian S., Best, Laura M., Di Ciano, Patricia, Balsevich, Georgia, Sloan, Mathew E., Kish, Stephen J., Tong, Junchao, Le Foll, Bernard, Boileau, Isabelle
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.04.2020; Springer International Publishing
• Subjects: Addictions; Adult; Aged; Amidohydrolases - metabolism; Anandamide; Animals; Autoradiography; Brain - metabolism; Cannabis; Dopamine; Dopamine D3 receptors; Drug use; Fatty acids; Fatty-acid amide hydrolase; Female; Gene Knock-In Techniques; Gene polymorphism; Genetic diversity; Globus pallidus; Humans; Hybridization; Hydrolase; Male; Mice; Middle Aged; Missense mutation; mRNA; Mutation, Missense; Neostriatum; Obesity; Polymorphism; Polymorphism, Single Nucleotide; Positron emission tomography; Receptor mechanisms; Receptors, Dopamine D3 - genetics; Receptors, Dopamine D3 - metabolism; RNA, Messenger - metabolism; Substance-Related Disorders - enzymology; Substance-Related Disorders - genetics; Young Adult
• ISSN: 0893-133X; 1740-634X; 1740-634X
• DOI: 10.1038/s41386-019-0580-8

The endocannabinoid and dopaminergic systems have independently been implicated in substance use disorder and obesity. We investigated a potential interaction between genetically inherited variation in fatty acid amide hydrolase (FAAH, C385A), which metabolizes the cannabis-like endocannabinoid anandamide, and dopaminergic system, measured by dopamine receptor levels and mRNA. Binding of the dopamine D3 preferring probe [C-11]-(+)-PHNO was measured with positron emission tomography (PET) in 79 human subjects genotyped for the FAAH C385A polymorphism (36/79 AC + AA). Autoradiography with [H-3]-(+)-PHNO and in situ hybridization with a D3-specific S-35 riboprobe were carried out in 30 knock-in mice with the FAAH C385A polymorphism (20/30 AC + AA). We found that the FAAH genetic variant C385A was associated with significantly higher (+)-PHNO binding in both humans and in knock-in mice, and this effect was restricted to D3 selective brain regions (limbic striatum, globus pallidus, and ventral pallidum (9-14%; p < 0.04) in humans and Islands of Calleja (28%; p = 0.036) in mice). In situ hybridization with a D3-specific S-35 riboprobe in FAAH knock-in C385A mice confirmed significantly increased D3 receptor mRNA across examined regions (7-44%; p < 0.02). The association of reduced FAAH function with higher dopamine D3 receptors in human and mouse brain provide a mechanistic link between two brain systems that have been implicated in addiction-risk. This may explain the greater vulnerability for addiction and obesity in individuals with C385A genetic variant and by extension, suggest that a D3 antagonism strategy in substance use disorders should consider FAAH C385A polymorphism.