Katz Jonathan L, Su Tsung-Ping, Hiranita Takato, Hayashi Teruo, Tanda Gianluigi, Kopajtic Theresa, Tsai Shang-Yi
Psychobiology and Cellular Pathobiology Sections, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, 21224, USA.
Pharmaceuticals (Basel). 2011;4(6):880-914. doi: 10.3390/ph4060880.
Sigma(1) receptors (σ(1)Rs) represent a structurally unique class of intracellular proteins that function as chaperones. σ(1)Rs 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 σ(2)R antagonist but not by a preferential σ(1)R 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.
西格玛-1受体（σ(1)Rs）是一类结构独特的细胞内蛋白，具有伴侣蛋白的功能。σ(1)Rs从线粒体相关膜转移至细胞核或细胞膜，并通过蛋白质-蛋白质相互作用影响多个靶点，包括离子通道、G蛋白偶联受体、脂质及其他信号蛋白。多项研究表明，σR拮抗剂可阻断兴奋剂诱导的行为效应，包括自主活动、敏化及急性毒性。奇怪的是，在位置条件反射实验中测试的σR拮抗剂可阻断兴奋剂的效应，但在自身给药实验中却不能，这表明这两种效应背后的机制存在根本差异。在先前经训练可自行注射可卡因的受试者中发现了σR激动剂的自身给药现象。σR激动剂的强化效应可被σR拮抗剂阻断。此外，还发现σR激动剂可增加伏隔核壳中的多巴胺浓度，该脑区被认为对滥用药物的强化效应很重要。尽管σR激动剂DTG对多巴胺的作用是在接近维持自身给药行为的剂量下获得的，但另一种激动剂PRE-084则需要更高剂量。DTG的作用可被非选择性或选择性的σ(2)R拮抗剂拮抗，但不能被选择性的σ(1)R拮抗剂拮抗。PRE-084对多巴胺的作用对σR拮抗剂不敏感。数据表明，σR激动剂的自身给药与多巴胺无关，并且根据可卡因既有由σRs介导的细胞内作用，又有通过传统研究机制介导的细胞外作用这一假设对这些发现进行了讨论。这些机制之间的共同激活和潜在相互作用，特别是那些涉及细胞内伴侣蛋白σRs的相互作用，可能导致兴奋剂药物产生有害的成瘾效应。
