Tardive dyskinesia (TD) is a side effect associated with the long-term use of certain antipsychotics. Considering the modulatory role of the endocannabinoid system upon dopaminergic neurotransmission, the present study tested the hypothesis that increasing endocannabinoid (anandamide and 2-arachidonoylglycerol) levels attenuates haloperidol-induced TD (vacuous chewing movements, VCMs) in male Wistar rats. The animals received administration of chronic haloperidol (38 mg/kg; 29 days) followed by acute FAAH (URB597, 0.1–0.5 mg/kg) or MAGL (JZL184, 1–10 mg/kg) inhibitors before VCM quantification. The underlying mechanisms were evaluated by pre-treatments with a CB₁ receptor antagonist (AM251, 1 mg/kg) or a TRPV₁ channel blocker (SB366791, 1 mg/kg). Moreover, CB₁ receptor expression was evaluated in the striatum of high-VCM animals. As expected, haloperidol induced VCMs only in a subset of rats. Either FAAH or MAGL inhibition reduced VCMs. These effects were prevented by CB₁ receptor antagonism, but not by TRPV1 blockage. Remarkably, CB₁ receptor expression was increased high-VCM rats, with a positive correlation between the levels of CB₁ expression and the number of VCMs. In conclusion, increasing endocannabinoid levels results in CB₁ receptor-mediated protection against haloperidol-induced TD in rats. The increased CB₁ receptor expression after chronic haloperidol treatment suggests a counter-regulatory protective mechanism.

迟发性运动障碍 (TD) 是与长期使用某些抗精神病药相关的副作用。考虑到内源性大麻素系统对多巴胺能神经传递的调节作用，本研究检验了以下假设：增加内源性大麻素（anandamide 和 2-花生四烯酸甘油）水平会减弱雄性 Wistar 大鼠中氟哌啶醇诱导的 TD（空洞咀嚼运动，VCM）。在 VCM 量化之前，动物接受了慢性氟哌啶醇（38 毫克/千克；29 天），然后是急性 FAAH（URB597，0.1-0.5 毫克/千克）或 MAGL（JZL184，1-10 毫克/千克）抑制剂。通过用 CB ₁受体拮抗剂（AM251，1 毫克/千克）或 TRPV ₁通道阻滞剂（SB366791，1 毫克/千克）进行预处理来评估潜在机制。此外，CB ₁在高 VCM 动物的纹状体中评估受体表达。正如预期的那样，氟哌啶醇仅在一部分大鼠中诱导 VCM。FAAH 或 MAGL 抑制都减少了 VCM。这些作用被 CB ₁受体拮抗作用阻止，但不能被 TRPV1 阻断阻止。值得注意的是，高VCM大鼠CB ₁受体表达增加，CB ₁表达水平与VCM数量呈正相关。总之，增加内源性大麻素水平导致 CB ₁受体介导的对大鼠氟哌啶醇诱导的 TD 的保护。长期氟哌啶醇治疗后CB ₁受体表达增加表明存在反调节保护机制。