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

Bruna Cuccurazzu, Erica Zamberletti, Cristiano Nazzaro, Pamela Prini, Massimo Trusel, Mariagrazia Grilli, Daniela Parolaro, Raffaella Tonini, Tiziana Rubino

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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 languageEnglish (US)
Pages (from-to)1014-1024
Number of pages11
JournalInternational Journal of Neuropsychopharmacology
Issue number11
StatePublished - Nov 1 2018
Externally publishedYes


  • Depressive-like behavior
  • URB597
  • adolescent THC
  • endocannabinoid-mediated LTD
  • newborn neuron

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)


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