Modulatory function of cannabidiol on the extinction and reinstatement of methamphetamine-seeking behavior through the D2-like dopamine receptors in the dentate gyrus.

Methamphetamine (METH) is a serious health concern with no reliable pharmaceutical treatment. Cannabidiol (CBD), a non-psychoactive compound from the Cannabis sativa plant, has shown potential in reducing drug-seeking behaviors, although its underlying neurobiological mechanisms remain unclear. Evidence suggests that CBD may modulate the dopamine system to suppress such behaviors. Given that D2-like receptors are critically involved in reward-related neuroplasticity and have been implicated in the modulation of drug-seeking behaviors, they were selected as the primary target for investigating CBD's mechanism of action. To investigate the role of D2-like dopamine receptors (D2R) in the dentate gyrus (DG), this study examined CBD's effects on extinction and reinstatement of METH-induced conditioned place preference (CPP). During a 10-day extinction period, rats received intra-DG Sulpiride (0.25, 1, or 4 μg/0.5 μl per side), a D2R antagonist, prior to intracerebroventricular (ICV) CBD (10 μg/5 μl). On reinstatement day, separate groups received the same Sulpiride doses before CBD (50 μg/5 μl). Results showed that the highest Sulpiride dose (4 μg) significantly attenuated CBD's facilitation of extinction. Additionally, Sulpiride (1 and 4 μg) reversed CBD's suppression of reinstatement. These findings suggest that CBD shortens extinction duration and inhibits METH reinstatement, partially through interaction with D2-like receptors in the DG. However, Sulpiride blocked CBD's behavioral effects, which likely reflects an indirect mechanism-possibly via increased dopamine release-rather than a direct interaction with D2 receptors.