title: Amygdala FAAH and anandamide: mediating protection and recovery from stress.
abstract: A long-standing literature linking endocannabinoids (ECBs) to stress, fear, and anxiety has led to growing interest in developing novel anxiolytics targeting the ECB system. Following rapid on-demand biosynthesis and degradation upon neuronal activation, the ECB N-arachidonoylethanolamide (anandamide, AEA) is actively degraded by the serine hydrolase enzyme, fatty acid amide hydrolase (FAAH). Exposure to stress rapidly mobilizes FAAH to deplete the signaling pool of AEA and increase neuronal excitability in a key anxiety-mediating region--the basolateral amygdala (BLA). Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior. Additionally, inhibition of FAAH facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing AEA-CB1 (cannabinoid type 1) receptor signaling and synaptic plasticity in the BLA. These preclinical findings propose restoring deficient BLA AEA levels by pharmacologically inhibiting FAAH as a mechanism to therapeutically mitigate the effects of traumatic stress.
authors: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health, Bethesda, MD, USA. Electronic address: ozge.gunduzcinar@nih.gov.
authors: Ozge
authors: O
authors: Gunduz-Cinar
authors: Matthew N
authors: MN
authors: Hill
authors: Bruce S
authors: BS
authors: McEwen
authors: Andrew
authors: A
authors: Holmes
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000679:Amygdala / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D001008:Anxiety Disorders / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D001095:Arachidonic Acids / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology; D013315:Stress, Psychological / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide
keywords: 2-AG; anxiety; depression; endocannabinoid; fear; post-traumatic stress disorder