Preservation of striatal cannabinoid CB1 receptor function correlates with the antianxiety effects of fatty acid amide hydrolase inhibition.
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.
Rossi
Silvia
S
Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
De Chiara
Valentina
V
Musella
Alessandra
A
Sacchetti
Lucia
L
Cantarella
Cristina
C
Castelli
Maura
M
Cavasinni
Francesca
F
Motta
Caterina
C
Studer
Valeria
V
Bernardi
Giorgio
G
Cravatt
Benjamin F
BF
Maccarrone
Mauro
M
Usiello
Alessandro
A
Centonze
Diego
D
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
D000581:Amidohydrolases; D014151:Anti-Anxiety Agents; D004791:Enzyme Inhibitors; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases