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.