Inhibition of fatty acid amidohydrolase (FAAH), the enzyme responsible for the selective in vivo degradation of the endocannabinoid anandamide, elicits CB1 receptor-mediated anxiolytic, analgesic and cardiovascular depressor effects, without inducing behavioral effects that would indicate addictive potential. In an earlier collaborative study with Dr. Andrew Holmes'group, we used the novel FAAH inhibitor AM3506 to test its therapeutic potential in PTSD, using a mouse model of fear extinction. We found that AM3506 elevated anandamide levels in the amygdala, facilitated fear extinction and this effect was reversed by CB1 antagonist treatment, raising the possible therapeutic use of AM3506 in PTSD. These findings were published in 2012 in Molecular Psychiatry with Dr. Holmes as corresponding author. While doing this study, we found that a single dose of AM3506 caused complete inhibition of FAAH that lasted more than 48 hours, due to the irreversible (covalent) mechanism of blocking FAAH activity. However, the corresponding rise in brain anandamide levels was transient and lasted <2 hours. This suggested that in the absence of FAAH activity, anandamide can be metabolized by other enzymes, such as COX-2, as suggested by a recent study (Nat Neurosci 16:1291, 2013). We therefore extending this project, in continued collaboration with Dr. Holmes'group, to test whether a) combined treatment of mice with AM3506 and a novel, substrate-selective COX-2 inhibitor prolongs the elevation of tissue anandamide levels, and b) in that case whether it also potentiates extinction in a fear paradigm.

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National Institute on Alcohol Abuse and Alcoholism
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