Abstract
Background: In rodent models, chronic exposure to cannabis' psychoactive ingredient, Ä9-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 Ä9-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 Ä9-Tetrahydrocannabinol during adolescence through biochemical, morphofunctional, and electrophysiological studies. Results: We found that the positive action of URB597 is associated with the rescue of Ä9-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.
Original language | English (US) |
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Pages (from-to) | 1014-1024 |
Number of pages | 11 |
Journal | International Journal of Neuropsychopharmacology |
Volume | 21 |
Issue number | 11 |
DOIs | |
State | Published - Nov 1 2018 |
Externally published | Yes |
Keywords
- Depressive-like behavior
- URB597
- adolescent THC
- endocannabinoid-mediated LTD
- newborn neuron
ASJC Scopus subject areas
- Pharmacology
- Psychiatry and Mental health
- Pharmacology (medical)