The aim of this study was to evaluate the effects of cannabidiol (CBD) on the behavioural and gene expression changes in a new animal model of spontaneous cocaine withdrawal. For this purpose, male CD-1 mice were exposed to progressive increasing doses of cocaine for 12 days (15 to 60 mg/kg/day, i.p.), evaluating spontaneous cocaine withdrawal 6 h after the last cocaine administration. The effects of CBD (10, 20, and 40 mg/kg, i.p.) were evaluated on cocaine withdrawal–induced alterations in motor activity, somatic signs, and anxiety-like behaviour. Furthermore, gene expression changes in dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the ventral tegmental area, and in cannabinoid receptors 1 (CNR1) and 2 (CNR2) in the nucleus accumbens, were analysed by real-time PCR. The results obtained in the study showed that mice exposed to the spontaneous cocaine withdrawal model presented increased motor activity, somatic withdrawal signs, and high anxiety-like behaviour. Interestingly, the administration of CBD normalized motor and somatic signs disturbances and induced an anxiolytic effect. Moreover, the administration of CBD blocked the increase of DAT and TH gene expression in mice exposed to the cocaine withdrawal, regulated the decrease of CNR1 and induced an additional upregulation of CNR2 gene expression. Thus, this model of spontaneous cocaine withdrawal induces clear behavioural and gene expression changes in mice. Interestingly, CBD alleviates these behavioural and gene expression alterations suggesting its potential for the management of cocaine withdrawal.

本研究的目的是评估大麻二酚（CBD）对自发可卡因戒断的新动物模型的行为和基因表达变化的影响。为此，雄性 CD-1 小鼠暴露于逐渐增加剂量的可卡因 12 天（15 至 60 mg/kg/天，腹膜内），评估最后一次可卡因给药后 6 小时的自发可卡因戒断情况。评估了 CBD（10、20 和 40 mg/kg，腹腔注射）对可卡因戒断引起的运动活动、躯体体征和焦虑样行为改变的影响。此外，通过实时PCR分析了腹侧被盖区的多巴胺转运蛋白（DAT）和酪氨酸羟化酶（TH）以及伏隔核中的大麻素受体1（CNR1）和2（CNR2）的基因表达变化。研究结果表明，暴露于自发可卡因戒断模型的小鼠表现出运动活动增加、躯体戒断症状和高度焦虑样行为。有趣的是，服用 CBD 可以使运动和躯体体征紊乱正常化，并产生抗焦虑作用。此外，CBD的施用阻断了可卡因戒断小鼠中DAT和TH基因表达的增加，调节CNR1的减少并诱导CNR2基因表达的额外上调。因此，这种自发的可卡因戒断模型会引起小鼠明显的行为和基因表达变化。有趣的是，CBD 减轻了这些行为和基因表达的改变，表明它在管理可卡因戒断方面的潜力。