Adult Cellular Neuroadaptations Induced by Adolescent THC Exposure in Female Rats Are Rescued by Enhancing Anandamide Signaling

Background: In rodent models, chronic exposure to cannabis' psychoactive ingredient, Delta(9)-tetrahydrocannabinol, during adolescence leads to abnormal behavior in adulthood. In female rats, this maladaptive behavior is characterized by endophenotypes for depressive-like and psychotic-like disorders as well as cognitive deficits. We recently reported that most depressive-like behaviors triggered by adolescent Delta(9)-tetrahydrocannabinol exposure can be rescued by manipulating endocannabinoid signaling in adulthood with the anandamide-inactivating enzyme FAAH inhibitor, URB597. However, the molecular mechanisms underlying URB597's antidepressant-like properties remain to be established.Methods: Here we examined the impact of adult URB597 treatment on the cellular and functional neuroadaptations that occurred in the prefrontal cortex and dentate gyrus of the hippocampus upon Delta(9)-tetrahydrocannabinol during adolescence through biochemical, morphofunctional, and electrophysiological studies.Results: We found that the positive action of URB597 is associated with the rescue of Delta(9)-tetrahydrocannabinol-induced deficits in endocannabinoid-mediated signaling and synaptic plasticity in the prefrontal cortex and the recovery of functional neurogenesis in the dentate gyrus of the hippocampus. Moreover, the rescue property of URB597 on depressive-like behavior requires the activity of the CB1 cannabinoid receptor.Conclusions: By providing novel insights into the cellular and molecular mechanisms of URB597 at defined cortical and hippocampal circuits, our results highlight that positive modulation of endocannabinoid-signaling could be a strategy for treating mood alterations secondary to adolescent cannabis use