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1.4 Neurophysiology and Neurochemistry

Figure 1.4-14 Endogenous cannabinoids. At least five endocannabinoids exist in the mammalian brain, each differing in affinity for CB1 and CB2 can- nabinoid receptors. All are derived from the essential omega-6 fatty acid, arachidonic acid, which is also a substrate in the formation of prostaglandins and leukotrienes. (From Sadock BJ, Sadock VA, Ruiz P. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry . 9 th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:111.)

Inactivation of Endocannabinoids.  Neurotransmitters are typically inactivated either by reuptake from the neurons that release them or by degradation by highly specific enzymes, such as the example of acetylcholine being hydrolyzed by acetylcho- linesterase. At least two enzymes exist to target the destruction of endocannabinoids and attenuate their neurotransmission. Fatty acid amide hydrolase (FAAH) converts anandamide to ara- chidonic acid and ethanolamine (Fig. 1.4-15). FAAH is found in regions of the brain where CB1 receptors are predominant and localizes to postsynaptic neurons where anandamide is made. Rapid degradation of anandamide in part explains its relatively

low potency compared to THC. Confirming a role of FAAH in anandamide inactivation, knockout mice without FAAH exhibit a 15-fold increase of anandamide, but not 2-AG. These mice have greater behavioral responses to exogenous anandamide, owing to its decreased degradation. The endocannabinoid 2-AG is inactivated by FAAH, but also by a monoacylglycerol lipase (MAGL) located in presynaptic neurons. Pharmacologic inhibitors of FAAH have analgesic effects and reduce anxiety in animal models, but do not have the unde- sirable effects of THC such as immobility, lowered body tem- perature, or greater appetite. Such a pharmacological strategy