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

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