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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Addicting drugs utilize a synergistic molecular mechanism in common requiring adenosine and Gi-βγ dimers
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Addicting drugs utilize a synergistic molecular mechanism in common requiring adenosine and Gi-βγ dimers

机译：上瘾药物利用共同的协同分子机制共同需要腺苷和Gi-βγ二聚体

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摘要

The mesolimbic dopamine system and cAMP-dependent/protein kinase A (PKA) pathways are strongly implicated in addictive behaviors. Here we determine the role of dopamine D2 receptors (D2) in PKA signaling responses to δ-opioid (DOR) and cannabinoid (CB1) receptors. We find in NG108-15/D2 cells and in cultured primary neurons that a brief exposure to saturating concentrations of DOR and CB1 agonists increases cAMP, promotes PKA Cα translocation and increases cAMP-dependent gene expression. Activation of PKA signaling is mediated by Gi-βγ dimers. Importantly, subthreshold concentrations of DOR or CB1 agonists with D2 agonists, which are without effect when added separately, together activate cAMP/PKA signaling synergistically. There is also synergy between DOR or CB1 with ethanol, another addicting agent. In all instances, synergy requires adenosine activation of adenosine A2 receptors and is mediated by βγ dimers. Synergy by this molecular mechanism appears to confer hypersensitivity to opioids and cannabinoids while simultaneously increasing the sensitivity of D2 signaling when receptors are expressed on the same cells. This mechanism may account, in part, for drug-induced activation of medium spiny neurons in the nucleus accumbens.
机译：中脑边缘多巴胺系统和cAMP依赖/蛋白激酶A（PKA）途径与成瘾行为密切相关。在这里，我们确定了多巴胺D2受体（D2）在PKA对δ阿片类药物（DOR）和大麻素（CB1）受体的信号应答中的作用。我们在NG108-15 / D2细胞和培养的原代神经元中发现，短暂接触饱和浓度的DOR和CB1激动剂会增加cAMP，促进PKACα易位并增加cAMP依赖性基因表达。 PKA信号的激活是由Gi-βγ二聚体介导的。重要的是，单独添加时没有作用的亚阈浓度的DOR或CB1激动剂与D2激动剂一起协同激活cAMP / PKA信号传导。 DOR或CB1与另一种成瘾剂乙醇之间也存在协同作用。在所有情况下，协同作用都需要腺苷A2受体的腺苷活化，并由βγ二聚体介导。通过这种分子机制的协同作用似乎赋予了对阿片类药物和大麻素超敏性，同时当受体在同一细胞上表达时，同时增加了D2信号的敏感性。这种机制可能部分解释了伏隔核中药物诱导的中棘神经元的激活。

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