Tardive dyskinesia (TD) is a movement disorder that appears after chronic use of drugs that block dopaminergic receptors such as antipsychotics. Besides the motor symptoms, patients with TD also present cognitive deficits. Neuroinflammatory mechanisms could be involved in the development of these symptoms. A previous study showed that cannabidiol (CBD), the major non-psychotomimetic compound of Cannabis sativa plant, prevents orofacial dyskinesia induced by typical antipsychotics by activating peroxisome proliferator-activated receptors gamma (PPARγ). Here, we investigated if CBD would also reverse haloperidol-induced orofacial dyskinesia and associated cognitive deficits. We also verified if these effects depend on PPARγ receptor activation. Daily treatment with haloperidol (3 mg/kg, 21 days) increased the frequency of vacuous chewing movements (VCM) and decreased the discrimination index in the novel object recognition test in male Swiss mice. CBD (60 mg/kg/daily) administered in the last 7 days of haloperidol treatment attenuated both behavioral effects. Furthermore, haloperidol increased IL-1β and TNF-α levels in the striatum and hippocampus while CBD reverted these effects. The striatal and hippocampal levels of proinflammatory cytokines correlated with VCM frequency and discrimination index, respectively. Pretreatment with the PPARγ antagonist GW9662 (2 mg/kg/daily) blocked the behavioral effects of CBD. In conclusion, these results indicated that CBD could attenuate haloperidol-induced orofacial dyskinesia and improve non-motor symptoms associated with TD by activating PPARγ receptors.

迟发性运动障碍 (TD) 是一种运动障碍，在长期使用阻断多巴胺能受体的药物（如抗精神病药）后出现。除了运动症状外，TD 患者还存在认知缺陷。神经炎症机制可能与这些症状的发展有关。先前的一项研究表明，大麻二酚 (CBD) 是大麻的主要非拟精神病化合物植物，通过激活过氧化物酶体增殖物激活受体 γ (PPARγ) 来预防典型抗精神病药物引起的口面部运动障碍。在这里，我们调查了 CBD 是否也会逆转氟哌啶醇引起的口面部运动障碍和相关的认知缺陷。我们还验证了这些影响是否依赖于 PPARγ 受体激活。每天用氟哌啶醇（3 mg/kg，21 天）治疗增加了空性咀嚼运动 (VCM) 的频率，并降低了雄性瑞士小鼠新物体识别测试中的辨别指数。在氟哌啶醇治疗的最后 7 天给予 CBD（60 mg/kg/天）减弱了两种行为影响。此外，氟哌啶醇增加了纹状体和海马中的 IL-1β 和 TNF-α 水平，而 CBD 恢复了这些作用。纹状体和海马的促炎细胞因子水平分别与 VCM 频率和辨别指数相关。用 PPARγ 拮抗剂 GW9662（2 mg/kg/天）预处理阻断了 CBD 的行为影响。总之，这些结果表明 CBD 可以通过激活 PPARγ 受体来减轻氟哌啶醇引起的口面部运动障碍并改善与 TD 相关的非运动症状。