Chronic URB597 treatment at adulthood reverted most depressive-like symptoms induced by adolescent exposure to THC in female rats.

We have recently shown that chronic THC administration in adolescent female rats induces subtle but lasting alterations in the emotional circuit ending in depressive-like behaviour at adulthood. Here we describe other relevant depressive-like symptoms present in these animals. Adult female rats pretreated with THC display passive coping strategy towards acute stressful situations as demonstrated by their behaviours in the first session of the forced swim test, develop a profound anhedonic state as demonstrated by the reduced consumption of palatable food and present a decrease in social functioning. Besides the emotional symptoms, adolescent exposure to THC induced a significant deficit in object recognition memory. Since it has been reported that deficits in adult hippocampal neurogenesis may underlie the cognitive dysfunction seen in depression, we then survey cell proliferation in the dentate gyrus of the hippocampus. Adolescent THC exposure significantly reduced the number of BrdU-positive cells in THC-treated rats as well as hippocampal volume. We suggest that this complex depressive-like phenotype is triggered by a long-lasting decrease in CB1 receptor functionality in specific brain regions. To test whether an increase in the endocannabinoid signalling could ameliorate the depressive phenotype, adult female rats pre-exposed to THC were injected with URB597 (0.3mg/kg ip) and then tested in behavioural assays. URB597 was able to reverse most depressive-like symptoms induced by adolescent THC exposure such as the passive coping strategy observed in THC exposed animals in the forced swim test as well as anhedonia and the reduced social activity. These results support a role for the endocannabinoid system in the neurobiology of depression and suggest the use of URB597 as a new therapeutic tool with antidepressant properties.