A Role for Sigma Receptors in Stimulant Self Administration and Addiction.
A Role for Sigma Receptors in Stimulant Self Administration and Addiction.
复制标题
DOI：
10.3390/ph4060880
复制
发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Tsai SY
中科院分区：
文献类型：
--
作者：
Katz JL;Su TP;Hiranita T;Hayashi T;Tanda G;Kopajtic T;Tsai SY
Sigma 1受体（σ 1 Rs）是一类结构独特的细胞内蛋白，具有分子伴侣的功能。σ 1 Rs从细胞膜转移到细胞核或细胞膜，并通过蛋白质-蛋白质相互作用影响几个靶点，包括离子通道、G蛋白偶联受体、脂质和其他信号蛋白。几项研究表明，σR拮抗剂阻断兴奋剂诱导的行为效应，包括走动活动、致敏和急性毒性。奇怪的是，刺激剂的作用已被σR拮抗剂阻断，而不是自我给药程序下测试的位置条件，这表明这两种作用的基础机制的根本差异。在先前接受过自我施用可卡因训练的受试者中发现了σR激动剂的自我施用。σR激动剂的增强作用可被σR拮抗剂阻断。此外，σR激动剂被发现增加多巴胺在核壳，一个大脑区域被认为是重要的滥用药物的强化效果的浓度。尽管σR激动剂DTG对多巴胺的作用是在接近维持自我给药行为的剂量下获得的，但PRE-084需要更高的剂量。DTG的作用可被非选择性或选择性σ 2 R拮抗剂所拮抗，而不被选择性σ 1 R拮抗剂所拮抗。PRE-084对多巴胺的作用对σR拮抗剂不敏感。这些数据表明，自我管理的σR激动剂是独立的多巴胺和研究结果进行了讨论的假设，即可卡因既有细胞内的行动介导的σ R，以及通过传统的研究机制介导的细胞外的行动。这些机制之间的共激活和潜在的相互作用，特别是那些涉及细胞内伴侣σRs的机制，可能导致刺激性药物的有害成瘾作用。
Sigma1 receptors (σ1Rs) represent a structurally unique class of intracellular proteins that function as chaperones. σ1Rs translocate from the mitochondria-associated membrane to the cell nucleus or cell membrane, and through protein-protein interactions influence several targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Several studies have demonstrated that σR antagonists block stimulant-induced behavioral effects, including ambulatory activity, sensitization, and acute toxicities. Curiously, the effects of stimulants have been blocked by σR antagonists tested under place-conditioning but not self-administration procedures, indicating fundamental differences in the mechanisms underlying these two effects. The self administration of σR agonists has been found in subjects previously trained to self administer cocaine. The reinforcing effects of the σR agonists were blocked by σR antagonists. Additionally, σR agonists were found to increase dopamine concentrations in the nucleus accumbens shell, a brain region considered important for the reinforcing effects of abused drugs. Although the effects of the σR agonist, DTG, on dopamine were obtained at doses that approximated those that maintained self administration behavior those of another agonist, PRE-084 required higher doses. The effects of DTG were antagonized by non-selective or a preferential σ2R antagonist but not by a preferential σ1R antagonist. The effects of PRE-084 on dopamine were insensitive to σR antagonists. The data suggest that the self administration of σR agonists is independent of dopamine and the findings are discussed in light of a hypothesis that cocaine has both intracellular actions mediated by σRs, as well as extracellular actions mediated through conventionally studied mechanisms. The co-activation and potential interactions among these mechanisms, in particular those involving the intracellular chaperone σRs, may lead to the pernicious addictive effects of stimulant drugs.