Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.
Pharmacol Biochem Behav. 2021 Jul;206:173193. doi: 10.1016/j.pbb.2021.173193. Epub 2021 Apr 29.
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 CB receptor antagonist (AM251, 1 mg/kg) or a TRPV channel blocker (SB366791, 1 mg/kg). Moreover, CB 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 CB receptor antagonism, but not by TRPV1 blockage. Remarkably, CB receptor expression was increased high-VCM rats, with a positive correlation between the levels of CB expression and the number of VCMs. In conclusion, increasing endocannabinoid levels results in CB receptor-mediated protection against haloperidol-induced TD in rats. The increased CB receptor expression after chronic haloperidol treatment suggests a counter-regulatory protective mechanism.
迟发性运动障碍（TD）是与某些抗精神病药物长期使用相关的副作用。鉴于内源性大麻素系统对多巴胺能神经传递的调节作用，本研究检验了这样一种假设，即增加内源性大麻素（大麻素和 2-花生四烯酸甘油）水平可减轻氟哌啶醇诱导的雄性 Wistar 大鼠 TD（空嚼运动，VCMs）。动物接受慢性氟哌啶醇（38mg/kg；29 天）给药，随后在 VCM 定量前给予 FAAH（URB597，0.1-0.5mg/kg）或 MAGL（JZL184，1-10mg/kg）抑制剂。通过预先给予 CB 受体拮抗剂（AM251，1mg/kg）或 TRPV 通道阻滞剂（SB366791，1mg/kg）来评估潜在机制。此外，还评估了高 VCM 动物纹状体中的 CB 受体表达。正如预期的那样，氟哌啶醇仅在一小部分大鼠中引起 VCMs。FAAH 或 MAGL 的抑制均可减少 VCMs。这些作用被 CB 受体拮抗作用所阻止，但不能被 TRPV1 阻断所阻止。值得注意的是，CB 受体表达在高 VCM 大鼠中增加，CB 表达水平与 VCMs 的数量之间存在正相关。总之，增加内源性大麻素水平可导致 CB 受体介导的对大鼠氟哌啶醇诱导 TD 的保护。慢性氟哌啶醇治疗后 CB 受体表达增加表明存在一种代偿性保护机制。
