Endocannabinoid system and D-serine interaction in the modulation of fear memory dynamics under stress

Background The inability to extinguish fear memory is a hallmark symptom of post-traumatic stress disorder (PTSD). The high levels of stress that characterize PTSD symptomatology contribute to maladaptive fear responses by disrupting extinction learning processes. Stress and fear share common neural circuits and corticolimbic structures involved in fear memory dynamics are highly sensitive to stress. The endocannabinoid system has emerged as a crucial modulator of stress related-behaviors and aversive memory. Particularly, research has shown that augmentation of anandamide signaling facilitates fear extinction. Notably, a similar effect has been reported for D-serine, a co-agonist of NMDA receptors. Interestingly, astroglial cannabinoid type-1 receptors have been shown to modulate hippocampal plasticity through regulation of astrocytic D-serine release. This study aimed at exploring the mechanisms underlying stress effects on fear extinction and the interaction between hippocampal anandamide and D-serine in the regulation of these effects. Methods Male rats trained on a contextual fear conditioning were subjected to a swim stress 30min before the extinction training session. Extinction recall was tested 24h later. Pharmacological manipulations of anandamide and D-serine signaling was performed via intra-CA1 infusions. Results Behavioral analyses revealed that stress impaired fear extinction, while administration of the anandamide hydrolysis inhibitor URB-597 or D-serine rescued extinction deficits. Furthermore, pharmacological inhibition of astrocytic D-serine synthesis with NCT-503 blocked the beneficial effects of URB-597. Conclusions Our results shed light on the mechanisms underlying stress detrimental effects on fear extinction suggesting that targeting the endocannabinoid system may offer therapeutic potential for stress-related psychopathologies.