Ruboxistaurin Reduces Cocaine-Stimulated Increases in Extracellular Dopamine by Modifying Dopamine-Autoreceptor Activity.,ACS Chemical Neuroscience

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Ruboxistaurin Reduces Cocaine-Stimulated Increases in Extracellular Dopamine by Modifying Dopamine-Autoreceptor Activity.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2018-11-08 , DOI: 10.1021/acschemneuro.8b00259
Alexander G Zestos ₁ , Colleen Carpenter , Youngsoo Kim , Malcolm J Low , Robert T Kennedy , Margaret E Gnegy

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Cocaine is a highly abused drug, and cocaine addiction affects millions of individuals worldwide. Cocaine blocks normal uptake function at the dopamine transporter (DAT), thus increasing extracellular dopamine. Currently, no chemical therapies are available to treat cocaine abuse. Previous works showed that the selective inhibitors of protein kinase Cβ (PKCβ), enzastaurin and ruboxistaurin, attenuate dopamine overflow and locomotion stimulated by another psychostimulant drug, amphetamine. We now test if ruboxistaurin similarly affects cocaine action. Perfusion of 1 μM ruboxistaurin directly into the core of the nucleus accumbens via retrodialysis reduced cocaine-stimulated increases in dopamine overflow, measured using microdialysis sampling, with simultaneous reductions in locomotor behavior. Because cocaine activity is highly regulated by dopamine autoreceptors, we examined whether ruboxistaurin was acting at the level of the D2 autoreceptor. Perfusion of 5 μM raclopride, a selective D2-like receptor antagonist, before addition of ruboxistaurin, abrogated the effect of ruboxistaurin on cocaine-stimulated dopamine overflow and hyperlocomotion. Further, ruboxistaurin was inactive against cocaine-stimulated locomotor activity in mice with a genetic deletion in D2 receptors as compared to wild-type mice. In contrast, blockade or deletion of dopamine D2 receptors did not abolish the attenuating effect of ruboxistaurin on amphetamine-stimulated activities. Therefore, the inhibition of PKCβ reduces dopamine overflow and locomotor activity stimulated by both cocaine and amphetamine, but the mechanism of action differs for each stimulant. These data suggest that inhibition of PKCβ would serve as a target to reduce the abuse of either amphetamine or cocaine.

中文翻译：

Ruboxistaurin通过修饰多巴胺自身受体活性来减少可卡因刺激的细胞外多巴胺增加。

可卡因是一种高度滥用的药物，可卡因成瘾影响全球数以百万计的人。可卡因阻断了多巴胺转运蛋白（DAT）的正常摄取功能，从而增加了细胞外多巴胺。当前，没有化学疗法可用于治疗可卡因滥用。先前的研究表明，蛋白激酶Cβ（PKCβ），enzastaurin和ruboxistaurin的选择性抑制剂可减轻另一种精神刺激药物安非他明刺激的多巴胺溢出和运动。现在，我们测试ruboxistaurin是否同样影响可卡因的作用。通过微透析将1μM的ruboxistaurin直接灌注到伏隔核的核中，减少了可卡因刺激的多巴胺溢流的增加（使用微透析采样测量），同时降低了运动行为。因为可卡因的活性受到多巴胺自身受体的高度调节，所以我们检查了ruboxistaurin是否在D2自身受体的水平上起作用。在添加鲁贝司他林之前，灌注5μM雷克沙必利（一种选择性的D2样受体拮抗剂）可消除鲁贝司他林对可卡因刺激的多巴胺溢流和运动过度的影响。此外，与野生型小鼠相比，在具有D2受体基因缺失的小鼠中，ruboxistaurin对可卡因刺激的运动活性无活性。相反，多巴胺D2受体的阻滞或缺失并没有消除ruboxistaurin对苯丙胺刺激的活性的减弱作用。因此，对PKCβ的抑制作用降低了可卡因和苯丙胺刺激的多巴胺溢流和运动能力，但每种兴奋剂的作用机理不同。

更新日期：2018-11-01

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