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Protective role of endocannabinoid signaling in an animal model of haloperidol-induced tardive dyskinesia
Pharmacology Biochemistry and Behavior ( IF 3.3 ) Pub Date : 2021-04-29 , DOI: 10.1016/j.pbb.2021.173193
Jivago Röpke 1 , Talita H Ferreira-Vieira 2 , Lia P Iglesias 1 , Laila Asth 1 , Fabíola M Ribeiro 2 , Fabrício A Moreira 1
Affiliation  

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.



中文翻译:

内源性大麻素信号在氟哌啶醇诱导的迟发性运动障碍动物模型中的保护作用

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。

更新日期:2021-05-04
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