Sex-specific impact of repeated adolescent vapour exposure to JWH-018 on dopamine response, behaviour and pharmacokinetics across adolescence and adulthood

Background and Purpose: Alarming trends show that vaping e-cigarettes containing synthetic cannabinoid receptor agonists, such as JWH-018, is increasing among youth. However, the effects of these trends are unclear in both sexes. We therefore characterized the neuropharmacological effects of adolescent JWH-018 inhalation in male and female rats. Experimental Approach: Adolescent rats inhaled passively JWH-018 vapour (0.3 or 0.6 mg·ml−1 qd) for 21 days. During vapour exposure, JWH-018 and main metabolite plasma levels, body weight, locomotion and ultrasonic vocalizations were measured at different time points. During drug-free period, behavioural (withdrawal signs, anxiety and repetitive-like behaviour) and microdialysis (NAc shell/mPFC dopamine responsiveness to intraoral chocolate, taste reactivity) studies were performed 24 h and 7 days after last JWH-018 inhalation, respectively. Key Results: Repeated adolescent JWH-018 inhalation induced sex-dependent effects with (i) higher plasma levels in males; (ii) increased body weight gain and withdrawal signs in females; (iii) transient hypolocomotion in females and dose-dependent biphasic locomotion in males; (iv) higher taste aversion in male; (v) sex- and dose-dependent adaptive changes of NAc shell and mPFC dopamine to single/repeated chocolate exposure in early adulthood, as follows: in the NAc shell, either low or high dose decreased dopamine sensitivity to chocolate in males, low dose abolished habituation whereas high dose blunted dopamine responsiveness in females; in the mPFC, the low dose blunted responsiveness in male and induced habituation in females while the high dose induced habituation only in males. Conclusion and Implications: Using highly translational models, we showed that the impact of adolescent JWH-018 inhalation differs between sexes.