N-arachidonoyl-serotonin, a dual FAAH and TRPV1 blocker, inhibits the retrieval of contextual fear memory: Role of the cannabinoid CB1 receptor in the dorsal hippocampus

• Published in: Journal of psychopharmacology (Oxford) 2017-06, Vol.31 (6), p.750-756
• Main Authors: Gobira, Pedro H, Lima, Isabel V, Batista, Luara A, de Oliveira, Antônio C, Resstel, Leonardo B, Wotjak, Carsten T, Aguiar, Daniele C, Moreira, Fabricio A
• Format: Article
• Language: English
• Subjects: Amidohydrolases - antagonists & inhibitors; Anandamide; Animals; Anxiety; Anxiolytics; Arachidonic Acids - pharmacology; Cannabinoid CB1 receptors; Capsaicin receptors; Drug therapy; Endocannabinoids - pharmacology; Fatty-acid amide hydrolase; Fear; Fear - drug effects; Fear conditioning; Freezing; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hydrolase; Injection; Male; Memory; Memory - drug effects; Mental disorders; Mice; Polyunsaturated Alkamides - pharmacology; Receptor mechanisms; Receptor, Cannabinoid, CB1 - metabolism; Rodents; Serotonin; Serotonin - analogs & derivatives; Serotonin - pharmacology; Tonic immobility; Transient receptor potential proteins; TRPV Cation Channels - antagonists & inhibitors
• ISSN: 0269-8811; 1461-7285
• DOI: 10.1177/0269881117691567

Anandamide, an endocannabinoid, inhibits aversive responses by activating the CB1 cannabinoid receptor. At high concentrations, however, anandamide may exert pro-aversive activities mediated by the transient receptor potential vanilloid type-1 channel (TRPV1). Accordingly, N-arachidonoyl-serotonin (AA-5-HT), a dual blocker of the anandamide-hydrolysing enzyme fatty acid amide hydrolase (FAAH) and the TRPV1 channel, induces anxiolytic-like effects. Here we tested the hypothesis that AA-5-HT inhibits the expression of contextual fear conditioning by facilitating CB1 receptor signalling in the dorsal hippocampus of mice. Intraperitoneal injection of AA-5-HT (0.1, 0.3, 1 mg/kg) inhibited the retrieval of contextual fear memory (freezing response). The effect of AA-5-HT (0.3 mg/kg) was prevented by systemic injection of the CB1 receptor antagonist, AM251 (1.0 mg/kg), and mimicked by simultaneous FAAH inhibition (URB597, 0.3 mg/kg) and TRPV1 blockage (SB366791, 1 mg/kg). Injection of AA-5-HT (0.125, 0.25, 0.5 nmol) into the dorsal hippocampus also reduced freezing. Finally, the effect of systemic AA-5-HT (0.3 mg/kg) was prevented by intra-hippocampal injection of AM251 (1 nmol). In conclusion, dual FAAH and TRPV1 blockage inhibits contextual fear memory by facilitating anandamide-induced CB1 receptor activation in the dorsal hippocampus. This approach may lead to new pharmacological treatments for traumatic memories and related psychiatric disorders.