Departamento de Neurofarmacología Experimental, Instituto de Investigaciones Biológicas Clemente Estable, Avenida Italia 3318, 11600, Montevideo, Uruguay.
Phytoplant Research S.L., Córdoba, Spain.
Neurotox Res. 2020 Aug;38(2):478-486. doi: 10.1007/s12640-020-00218-9. Epub 2020 May 15.
In the last years, clinical and preclinical researchers have increased their interest in non-psychotomimetic cannabinoids, like cannabidiol (CBD), as a strategy for treating psychostimulant use disorders. However, there are discrepancies in the pharmacological effects and brain targets of CBD. We evaluated if CBD was able to prevent the locomotor sensitization elicited by cocaine and caffeine co-administration. The effect of CBD on putative alterations in the metabolic activity of the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), and its respective subregions (cingulated, prelimbic, and infralimbic cortices, and NAc core and shell) associated to the behavioral response, was also investigated. Rats were intraperitoneally and repeatedly treated with CBD (20 mg/kg) or its vehicle, followed by the combination of cocaine and caffeine (Coc+Caf; 5 mg/kg and 2.5 mg/kg, respectively) or saline for 3 days. After 5 days of withdrawal, all animals were challenged with Coc+Caf (day 9). Locomotor activity was automatically recorded and analyzed by a video-tracking software. The metabolic activity was determined by measuring cytochrome oxidase-I (CO-I) staining. Locomotion was significantly and similarly increased both in Veh-Coc+Caf- and CBD-Coc+Caf-treated animals during the pretreatment period (3 days); however, on day 9, the expression of the sensitization was blunted in CBD-treated animals. A hypoactive metabolic response and a hyperactive metabolic response in mPFC and NAc subregions respectively were observed after the behavioral sensitization. CBD prevented almost all these changes. Our findings substantially contribute to the understanding of the functional changes associated with cocaine- and caffeine-induced sensitization and the effect of CBD on this process.
在过去的几年中，临床和临床前研究人员对非致幻大麻素（如大麻二酚，CBD）越来越感兴趣，将其作为治疗精神兴奋剂使用障碍的策略。然而，CBD 的药理学效应和大脑靶点存在差异。我们评估了 CBD 是否能够预防可卡因和咖啡因联合给药引起的运动敏化。还研究了 CBD 对内侧前额叶皮层（mPFC）和伏隔核（NAc）代谢活性的潜在改变，以及其与行为反应相关的各自亚区（扣带、前脑叶和下脑叶皮质以及 NAc 核心和壳）的改变。大鼠腹膜内和重复接受 CBD（20 mg/kg）或其载体治疗，随后接受可卡因和咖啡因（Coc+Caf；分别为 5 mg/kg 和 2.5 mg/kg）或生理盐水组合处理 3 天。戒断 5 天后，所有动物均接受 Coc+Caf 挑战（第 9 天）。运动活动通过视频跟踪软件自动记录和分析。代谢活性通过测量细胞色素氧化酶-I（CO-I）染色来确定。在预处理期（3 天），Veh-Coc+Caf-和 CBD-Coc+Caf 处理的动物的运动均显著且相似地增加；然而，在第 9 天，CBD 处理的动物的敏化表达减弱。行为敏化后，mPFC 和 NAc 亚区分别观察到代谢反应活性降低和代谢反应活性增加。CBD 几乎阻止了所有这些变化。我们的研究结果大大有助于理解与可卡因和咖啡因诱导的敏化相关的功能变化，以及 CBD 对这一过程的影响。
