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首页> 外文期刊>The European Journal of Neuroscience >Opposite function of dopamine D1 and N-methyl-D-aspartate receptors in striatal cannabinoid-mediated signaling.
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Opposite function of dopamine D1 and N-methyl-D-aspartate receptors in striatal cannabinoid-mediated signaling.

机译：在纹状体大麻素介导的信号传导中，多巴胺D1和N-甲基-D-天冬氨酸受体的功能相反。

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It is well established that the cannabinoid and dopamine systems interact at various levels to regulate basal ganglia function. Although it is well known that acute administration of cannabinoids to mice can modify dopamine-dependent behaviors, the intraneuronal signaling pathways employed by these agents in the striatum are not well understood. Here we used knockout mouse models to examine the regulation of striatal extracellular-signal-regulated kinases 1 and 2 (ERK1/2) signaling by behaviorally relevant doses of cannabinoids. This cellular pathway has been implicated as a central mediator of drug reward and synaptic plasticity. In C57BL/6J mice, acute administration of the cannabinoid agonists, (-)-11-hydroxydimethylheptyl-Delta8-tetrahydrocannabinol (HU-210) and delta-9-tetrahydrocannabinol (Delta(9) -THC), promoted a dose- and time-dependent decrease in the phosphorylation of ERK1/2 in dorsal striatum. Co-administration of the CB1 cannabinoid receptor antagonist N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3 -carboxamide(AM251) with HU-210 prevented ERK1/2 inactivation, indicating a requirement for activation of this receptor. In dopamine D1 receptor knockout animals treated with HU-210, the magnitude of the HU-210-dependent decrease in striatal ERK1/2 signaling was greater than in wild-type controls. In contrast, HU-210 administration to N-methyl-D-aspartate receptor knockdown mice was ineffective at promoting striatal ERK1/2 inactivation. Genetic deletion of other potential ERK1/2 mediators, the dopamine D2 receptors or beta-arrestin-1 or -2, did not affect the HU-210-induced modulation of ERK1/2 signaling in the striatum. These results support the hypothesis that dopamine D1 receptors and N-methyl-D-aspartate receptors act in an opposite manner to regulate striatal CB1 cannabinoid receptor signal transduction.
机译：众所周知，大麻素和多巴胺系统在各种水平上相互作用以调节基底神经节功能。尽管众所周知，向小鼠急性施用大麻素可以改变多巴胺依赖性行为，但这些药物在纹状体中所利用的神经内信号通路尚不十分清楚。在这里，我们使用基因敲除小鼠模型通过行为相关剂量的大麻素来检查纹状体细胞外信号调节激酶1和2（ERK1 / 2）信号的调节。该细胞途径被认为是药物奖励和突触可塑性的主要介质。在C57BL / 6J小鼠中，大麻素激动剂（-）-11-羟二甲基庚基-Delta8-四氢大麻酚（HU-210）和Delta-9-四氢大麻酚（Delta（9）-THC）的急性给药促进了剂量和时间依赖性纹状体中ERK1 / 2磷酸化的减少。 CB1大麻素受体拮抗剂N-（哌啶-1-基）-5-（4-碘苯基）-1-（2,4-二氯苯基）-4-甲基-1H-吡唑-3-羧酰胺（AM251）的共同给药用HU-210阻止ERK1 / 2失活，表明需要激活该受体。在用HU-210处理的多巴胺D1受体敲除动物中，纹状体ERK1 / 2信号转导的HU-210依赖性下降幅度大于野生型对照。相反，向N-甲基-D-天冬氨酸受体敲低小鼠施用HU-210不能有效促进纹状体ERK1 / 2失活。其他潜在的ERK1 / 2介质，多巴胺D2受体或β-arrestin-1或-2的遗传缺失并不影响HU-210诱导的纹状体中ERK1 / 2信号传导的调节。这些结果支持了多巴胺D1受体和N-甲基-D-天冬氨酸受体以相反方式调节纹状体CB1大麻素受体信号转导的假设。

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