Adolescent female rats are resistant to the affective and cognitive impacts of Δ9-tetrahydrocannabinol exposure despite long-lasting molecular and neuronal disturbances in the hippocampal-hypothalamic network.

Rationale: Chronic cannabis during adolescence is associated with long-lasting pathological outcomes, and these effects can be remarkably different between the sexes. Preclinical studies in rodents demonstrated that sustained exposure to Δ9-tetrahydrocannabinol (THC), induces sex-specific pathophysiological outcomes. Thus, while males exhibit higher vulnerability to schizophrenia-like manifestations and cognitive impairments, females show greater susceptibility to emotional dysregulations and selective memory deficits.

Objective: This study aimed to explore the long-lasting impact of adolescent THC exposure in female rats and to identify mechanisms underlying these potential THC-related effects.

Methods: We treated adolescent female rats from postnatal day (PND) 35 to 45 with increasing doses of THC. At adulthood (PND 75), we carried out a battery of behavioral tasks to assess locomotion, sensorimotor gating deficits, memory impairments, and anxiety. Furthermore, we examined molecular biomarkers in several local brain regions relevant to THC-related pathology as well as the neuronal activity states of putative glutamatergic cells in the dorsal and ventral subiculum and their associated oscillatory patterns.

Results: We report that adolescent female rats exposed to THC gained weight slower than controls during the treatment period. In adulthood, they did not exhibit any observable behavioral abnormalities in the chosen tests. However, we observed long-lasting adaptations in estrogen receptor-α (ERα) and fatty acid amid hydrolase (FAAH) expression levels in the hypothalamus and hippocampus and enduring alterations in hippocampal oscillatory patterns.

Conclusions: These findings provide evidence that female rats exhibit sex-specific adaptations following adolescent THC exposure, which may confer protection against long-term behavioural abnormalities consistently observed in male cohorts.