Addicting drugs utilize a synergistic molecular mechanism in common requiring adenosine and Gi-beta gamma dimers.
Addicting drugs utilize a synergistic molecular mechanism in common requiring adenosine and Gi-beta gamma dimers.
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成瘾药物利用共同的协同分子机制，需要腺苷和 Gi-β γ 二聚体。
DOI：
10.1073/pnas.2336093100
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发表时间：
2003
影响因子：
11.1
通讯作者：
Diamond,Ivan
中科院分区：
文献类型：
--
作者：
Yao,Lina;Fan,Peidong;Jiang,Zhan;Mailliard,WilliamS;Gordon,AdrienneS;Diamond,Ivan
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.
