Fatty acid amide hydrolase inhibitors produce rapid anti-anxiety responses through amygdala long-term depression in male rodents

Background Pathological anxiety is the most common type of psychiatric disorder. The current first-line anti-anxiety treatment, selective serotonin/noradrenaline reuptake inhibitors, produces a delayed onset of action with modest therapeutic and substantial adverse effects, and long-term use of the fast-acting anti-anxiety benzodiazepines causes severe adverse effects. Inhibition of the fatty acid amide hydrolase (FAAH), the endocannabinoid N-arachidonoylethanolamine (AEA) degradative enzyme, produces anti-anxiety effects without substantial unwanted effects of cannabinoids, but its anti-anxiety mechanism is unclear. Methods We used behavioural, electro-physiological, morphological and mutagenesis strategies to assess the anti-anxiety mechanism of the FAAH inhibitors PF3845 and URB597. Results PF3845 exerts rapid and long-lasting anti-anxiety effects in mice exposed acutely to stress or chronically to the stress hormone corticosterone. PF3845-induced anti-anxiety effects and in vivo long-term depression (LTD) of synaptic strength at the prefrontal cortical input onto the basolateral amygdala neurons are abolished in mutant mice without CB1 cannabinoid receptors (CB1R) in brain astroglial cells, but are conserved in mice without CB1R in glutamatergic neurons. Blockade of glutamate N-methyl-d-aspartate receptors and of synaptic trafficking of glutamate AMPA receptors also abolishes PF3845-induced anti-anxiety effects in mice and LTD production in rats. URB597 produces similar anti-anxiety effects, which are abolished by blockade of LTD induction in mice. Limitations The determination of FAAH in which types of brain cells contribute to AEA degradation for the maintenance of amygdala interstitial AEA has yet to be determined. Conclusion We propose that the rapid anti-anxiety effects of FAAH inhibition are due to AEA activation of astroglial CB1R and subsequent basolateral amygdala LTD in vivo.