Cannabidiol inhibits methamphetamine-induced dopamine release via modulation of the DRD1-MeCP2-BDNF-TrkB signaling pathway

Rationale Adaptive alteration of dopamine (DA) system in mesocorticolimbic circuits is an extremely intricate and dynamic process, which contributes to maintaining methamphetamine (METH)-related disorders. There are no approved pharmacotherapies for METH-related disorders. Cannabidiol (CBD), a major non-psychoactive constituent of cannabis, has received attention for its therapeutic potential in treating METH-related disorders. However, the major research obstacles of CBD are the yet to be clarified mechanisms behind its therapeutic potential. Recent evidence showed that DA system may be active target of CBD. CBD could be a promising dopaminergic medication for METH-related disorders. Objectives We investigated the role of the DA receptor D1 (DRD1)-methyl-CpG-binding protein 2 (MeCP2)-brain-derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling pathway in DA release induced by METH. Investigating the intervention effects of CBD on the DRD1-MeCP2-BDNF-TrkB signaling pathway could help clarify the underlying mechanisms and therapeutic potential of CBD in METH-related disorders. Results METH (400 μM) significantly increased DA release from primary neurons in vitro, which was blocked by CBD (1 μM) pretreatment. METH (400 μM) significantly increased the expression levels of DRD1, BDNF, and TrkB, but decreased the expression of MeCP2 in the neurons, whereas CBD (1 μM) pretreatment notably inhibited the protein changes induced by METH. In addition, DRD1 antagonist SCH23390 (10 μM) inhibited the DA release and protein change induced by METH in vitro. However, DRD1 agonist SKF81297 (10 μM) induced DA release and protein change in vitro, which was also blocked by CBD (1 μM) pretreatment. METH (2 mg/kg) significantly increased the DA level in the nucleus accumbens (NAc) of rats with activation of the DRD1-MeCP2-BDNF-TrkB signaling pathway, but these changes were blocked by CBD (40 or 80 mg/kg) pretreatment. Conclusions This study indicates that METH induces DA release via the DRD1-MeCP2-BDNF-TrkB signaling pathway. Furthermore, CBD significantly inhibits DA release induced by METH through modulation of this pathway.