Fields J Z, Lee J M, Gordon J H, Wichlinski L J, Ritzmann R F
Research Service (151), Hines V.A. Hospital, Illinois 60141.
Neuropeptides. 1990 Aug;16(4):207-11. doi: 10.1016/0143-4179(90)90064-6.
In a previous study we showed that cyclo(leu-gly) (CLG) prevents the behavioural supersensitivity induced in the mesolimbic dopamine (DA) tract (in mice) by chronic haloperidol (HAL). In the current study, we evaluated the effects of CLG on supersensitivity to DA agonists in the nigrostriatal DA tract induced by chronic HAL (1.0 mg/kg, i.p. x 21 days--Experiment 1) or by acute injection of a high dose of apomorphine (APO) (Experiment 2). In Experiment 1 CLG was given at doses of either (a) 0 mg/kg/day (b) 1 mg/kg every third day (30 minutes prior to HAL), (c) 1 mg/kg every day, or (d) 8 mg/kg every third day. In Experiment 2 the dose of CLG was 8 mg/kg, s.c., given 24h after APO. Co-administration of CLG with HAL attenuated the development of HAL-induced supersensitivity in both paradigms (b) and (c) above, although the attenuation was significantly greater in (c) compared to (b). This biphasic dose response (D-R) curve for CLG in Experiment 1 indicates that a therapeutic window exists for CLG (bell-shaped D-R curve) and is similar to previous curves for CLG effects on the mesolimbic DA tract. In Experiment 2, CLG attenuated the DA receptor supersensitivity caused by acute high dose APO. The capacity of CLG to down-regulate DA receptors and attenuate dopaminergic supersensitivity in these experiments suggests a potential therapeutic use in the prevention of tardive and/or L-dopa-induced dyskinesias.
在先前的一项研究中，我们发现环（亮氨酸 - 甘氨酸）（CLG）可预防慢性氟哌啶醇（HAL）（在小鼠中）诱导的中脑边缘多巴胺（DA）通路的行为超敏反应。在当前研究中，我们评估了CLG对慢性HAL（1.0mg/kg，腹腔注射，共21天 - 实验1）或急性注射高剂量阿扑吗啡（APO）（实验2）诱导的黑质纹状体DA通路中对DA激动剂超敏反应的影响。在实验1中，CLG的给药剂量分别为：（a）0mg/kg/天；（b）每三天1mg/kg（在HAL给药前30分钟）；（c）每天1mg/kg；或（d）每三天8mg/kg。在实验2中，CLG的剂量为8mg/kg，皮下注射，在APO注射后24小时给药。在上述两种模式（b）和（c）中，CLG与HAL共同给药均减弱了HAL诱导的超敏反应的发展，尽管与（b）相比，（c）中的减弱作用明显更大。实验1中CLG的这种双相剂量反应（D - R）曲线表明CLG存在一个治疗窗（钟形D - R曲线），并且与先前CLG对中脑边缘DA通路作用的曲线相似。在实验2中，CLG减弱了急性高剂量APO引起的DA受体超敏反应。在这些实验中，CLG下调DA受体和减弱多巴胺能超敏反应的能力表明其在预防迟发性和/或左旋多巴诱导的运动障碍方面具有潜在的治疗用途。
