Cyclo (Leu-Gly) attenuates the striatal dopaminergic supersensitivity induced by chronic morphine.

Alcohol and drug research Pub Date : 1987-01-01
J M Lee, F DeLeon-Jones, J Z Fields, R F Ritzmann
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引用次数: 0

Abstract

Cyclo(Leu-Gly) (CLG), a diketopiperazine analog of Pro-Leu-Gly-NH2 (MIF), has direct effects on dopamine (DA) mediated behaviors as well as on D-2 DA receptors. Endogenous opioids, as well as morphine have also been implicated as neuromodulators of dopaminergic function. We studied these interactions in an animal model in which chronic morphine administration induces a dopaminergic supersensitivity that can be detected during the 48 hour (h) period following withdrawal of morphine. At 24 h following morphine withdrawal, there was a 3.5-fold increase in stereotypic behavior in rats following a challenge dose of apomorphine (APO) (0.5 mg/kg). By 48 h this effect had disappeared. Co-administration of CLG (8 mg/kg s.c.) with morphine attenuated the development of the behavioral supersensitivity to APO. D-2 DA receptor binding analysis indicated that parallel molecular changes occurred. There was a morphine-induced increase in the affinity (+167 percent) in antagonist (i.e. 3H-spiroperidol displaced by butaclamol) binding at 24 h after withdrawal. Co-administration of CLG with morphine attenuated these DA receptor changes at 24 hours which is consistent with the peptide's effect on stereotyped behavior. However, antagonist binding parameters did not parallel changes in behavior at 48 h. Agonist binding was then studied by examining DA displaceable 3H-spiroperidol (75 pM) binding to the D-2 DA receptor. Two receptor subpopulations D-2-HI and D-2-LO were revealed. Morphine caused an increase in the affinity for agonist binding to the D-2-HI site (83-fold increase). Affinity changes at the D-2-HI site correlated positively and strongly with the behavioral changes in all groups at both 24 and 48 h. We conclude that changes in agonist binding to D-2 DA receptors rather than antagonist binding is more consistent with the behaviors induced by morphine and CLG.

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Cyclo (Leu-Gly)可减弱慢性吗啡诱导的纹状体多巴胺能超敏反应。
Cyclo(Leu-Gly) (CLG)是Pro-Leu-Gly-NH2 (MIF)的二酮哌嗪类似物,对多巴胺(DA)介导的行为和D-2 DA受体有直接影响。内源性阿片样物质以及吗啡也被认为是多巴胺能功能的神经调节剂。我们在一个动物模型中研究了这些相互作用,在这个动物模型中,慢性吗啡给药诱导多巴胺能超敏感性,可以在吗啡停药后48小时(h)内检测到。戒断吗啡后24小时,阿波啡(APO)激发剂量(0.5 mg/kg)后,大鼠的刻板行为增加3.5倍。48小时后,这种效果消失了。CLG (8mg /kg s.c)与吗啡联用可减轻APO行为超敏反应的发生。D-2 DA受体结合分析表明发生了平行的分子变化。停药后24小时吗啡诱导拮抗剂(即3h -螺哌啶醇被丁他卡莫取代)结合的亲和力增加(+ 167%)。CLG与吗啡的联合使用在24小时内减弱了这些DA受体的变化,这与肽对刻板行为的影响是一致的。然而,拮抗剂结合参数在48小时后的行为变化并不平行。然后通过检测DA置换3h -螺哌啶醇(75 pM)与D-2 DA受体的结合来研究激动剂的结合。发现了两个受体亚群D-2-HI和D-2-LO。吗啡引起受体激动剂与D-2-HI位点结合的亲和力增加(增加83倍)。在24和48 h时,所有组的D-2- hi位点的亲和力变化与行为变化呈正相关。我们得出结论,与拮抗剂结合相比,激动剂与D-2 DA受体结合的变化更符合吗啡和CLG诱导的行为。
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Cyclo (Leu-Gly) attenuates the striatal dopaminergic supersensitivity induced by chronic morphine. Alcohol preference and regional brain monoamine contents of N/Nih heterogeneous stock rats. Toxicity of MDA (3,4-methylenedioxyamphetamine) considered for relevance to hazards of MDMA (Ecstasy) abuse. Alprazolam dependence in mice. Chronic cocaine administration induces opposite changes in dopamine receptors in the striatum and nucleus accumbens.
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