Cocaine Disrupts Histamine H3 Receptor Modulation of Dopamine D1 Receptor Signaling: σ1-D1-H3 Receptor Complexes as Key Targets for Reducing Cocaine's Effects
Cocaine Disrupts Histamine H3 Receptor Modulation of Dopamine D1 Receptor Signaling: σ1-D1-H3 Receptor Complexes as Key Targets for Reducing Cocaine's Effects
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DOI：
10.1523/jneurosci.4147-13.2014
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发表时间：
2014-03-05
影响因子：
5.3
通讯作者：
McCormick, Peter J.
中科院分区：
文献类型：
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作者：
Moreno, Estefania;Moreno-Delgado, David;McCormick, Peter J.
可卡因的一般作用在分子水平上还没有得到很好的理解。已知的是多巴胺D-1受体起着重要作用。在这里，我们表明，一个关键的机制可能是可卡因的组胺H-3受体介导的抑制D-1受体功能的阻滞。这种阻断需要sigma（1）受体，并在可卡因与sigma（1）-D-1-H-3受体复合物结合时发生。可卡因介导的破坏留下未受抑制的D-1受体，其激活G（s），自由募集β-抑制蛋白，增加p-ERK 1/2水平，并在过度激活时诱导细胞死亡。使用转染细胞的体外试验和使用可卡因沿着急性治疗或自我给药的大鼠以及σ 1受体缺失的小鼠的离体实验，我们表明，通过拮抗剂阻断σ 1受体可以恢复H-3受体介导的D-1受体信号传导的保护性制动，并防止D-1受体信号传导升高导致的细胞死亡。这些发现表明，σ R-1拮抗剂与H-3受体激动剂的联合治疗可用于降低可卡因的某些作用。
The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D-1 receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H-3 receptor-mediated inhibition of D-1 receptor function. This blockade requires the sigma(1) receptor and occurs upon cocaine binding to sigma(1)-D-1-H-3 receptor complexes. The cocaine-mediated disruption leaves an uninhibited D-1 receptor that activates G(s), freely recruits beta-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of sigma(1) receptor, we show that blockade of sigma(1) 1 receptor by an antagonist restores the protective H-3 receptor-mediated brake on D-1 receptor signaling and prevents the cell death from elevated D-1 receptor signaling. These findings suggest that a combination therapy of sigma R-1 antagonists with H-3 receptor agonists could serve to reduce some effects of cocaine.