title: Preservation of striatal cannabinoid CB1 receptor function correlates with the antianxiety effects of fatty acid amide hydrolase inhibition.
abstract: The endocannabinoid anandamide (AEA) plays a crucial role in emotional control, and inhibition of its degradation by the fatty acid amide hydrolase (FAAH) has a potent antianxiety effect. The mechanism by which the magnification of AEA activity reduces anxiety is still largely undetermined. By using FAAH mutant mice and both intraperitoneal and intracerebroventricular administration of the FAAH inhibitor (3'-(aminocarbonyl)[1,1'-biphenyl]-3-yl)-cyclohexylcarbamate (URB597), we found that enhanced AEA signaling reversed, via central cannabinoid CB1 receptors (CB1Rs), the anxious phenotype of mice exposed to social defeat stress. This behavioral effect was associated with preserved activity of CB1Rs regulating GABA transmission in the striatum, whereas these receptors were dramatically down-regulated by stress in control animals. The hypothalamic-pituitary-adrenal (HPA) axis was not involved in the antistress effects of FAAH inhibition, although the HPA axis is a biological target of endogenous AEA. We also provided some physiological indications that striatal CB1Rs regulating GABA synapses are not the receptor targets of FAAH inhibition, which rather resulted in the stimulation of striatal CB1Rs regulating glutamate transmission. Collectively, our findings suggest that preservation of cannabinoid CB1 receptor function within the striatum is a possible synaptic correlate of the antianxiety effects of FAAH inhibition.
authors.affiliation: Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.forename: Valentina
authors.initials: V
authors.lastname: De Chiara
authors.forename: Alessandra
authors.initials: A
authors.lastname: Musella
authors.forename: Lucia
authors.initials: L
authors.lastname: Sacchetti
authors.forename: Cristina
authors.initials: C
authors.lastname: Cantarella
authors.forename: Maura
authors.initials: M
authors.lastname: Castelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Cavasinni
authors.forename: Caterina
authors.initials: C
authors.lastname: Motta
authors.forename: Valeria
authors.initials: V
authors.lastname: Studer
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D003342:Corpus Striatum / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D043884:Receptor, Cannabinoid, CB1 / Q000502:physiology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D014151:Anti-Anxiety Agents; D004791:Enzyme Inhibitors; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases