Repeated administration of the synthetic cannabinoid AKB48 induces serotonergic neuroadaptation in male and female mice: behavioural and immunohistochemical evidence

Background and purpose: In the last years, Synthetic Cannabinoids (SCBs) have established themselves as one of the largest and most popular groups of Novel Psychoactive Substances (NPS), being frequently detected in biological samples of patients involved in intoxication and death cases. To date, compelling evidence on the potential interaction between SCBs and non-cannabinoid neurotransmission systems has emerged, with reference to a high-level overlap between endocannabinoid and serotoninergic system. Their long-term effect on serotoninergic pathways is still to be elucidated. Experimental approach: Using a behavioural and immunohistochemical approach, we investigated the neuroplasticity at 5-HT2A serotoninergic receptors and serotonin transporter in the cerebellum and cortex induced by repeated AKB48 administration in male and female mice. Further, pharmacological response to the serotoninergic compounds 2C-I or 25I-NBOMe has been studied. Key results: The repeated exposure to AKB48 results in a worsening effect on the visual sensorimotor, sensory gating, and motor reactivity response to synthetic hallucinogens, that appears to be generally more prolonged in male with respect to AKB48-treated female mice. Interestingly, the effect has been related to cerebellar and cortical neuroplasticity at serotoninergic neurotransmission system, that involves both 5-HT2A and SERT, that occurs more markedly and rapidly in female with respect to male mice. Conclusion and implications: This data highlight the interaction between SCBs and psychedelic drugs that may be relevant to their long-term effects and psychiatric sequelae potentially related to their consumption.