University of Florida, College of Medicine, Department of Neuroscience, Gainesville, FL 32611, United States.
University of Florida, College of Medicine, Department of Neuroscience, Gainesville, FL 32611, United States.
Pharmacol Ther. 2018 Jun;186:152-167. doi: 10.1016/j.pharmthera.2018.01.009. Epub 2018 Jan 31.
Methamphetamine (METH) abuse is a major public health issue around the world, yet there are currently no effective pharmacotherapies for the treatment of METH addiction. METH is a potent psychostimulant that increases extracellular dopamine levels by targeting the dopamine transporter (DAT) and alters neuronal activity in the reward centers of the brain. One promising therapeutic target for the treatment of METH addiction is the sigma-1 receptor (σR). The σR is an endoplasmic reticulum-localized chaperone protein that is activated by cellular stress, and, unique to this chaperone, its function can also be induced or inhibited by different ligands. Upon activation of this unique "chaperone receptor", the σR regulates a variety of cellular functions and possesses neuroprotective activity in the brain. Interestingly, a variety of σR ligands modulate dopamine neurotransmission and reduce the behavioral effects of METH in animal models of addictive behavior, suggesting that the σR may be a viable therapeutic target for the treatment of METH addiction. In this review, we provide background on METH and the σR as well as a literature review regarding the role of σRs in modulating both dopamine neurotransmission and the effects of METH. We aim to highlight the complexities of σR pharmacology and function as well as the therapeutic potential of the σR as a target for the treatment of METH addiction.
甲基苯丙胺（METH）滥用是全球范围内的一个主要公共卫生问题，但目前尚无有效的药物治疗方法来治疗 METH 成瘾。METH 是一种强效的精神兴奋剂，通过靶向多巴胺转运体（DAT）增加细胞外多巴胺水平，并改变大脑奖励中心的神经元活动。治疗 METH 成瘾的一个有前途的治疗靶点是西格玛-1 受体（σR）。σR 是一种内质网定位的伴侣蛋白，通过细胞应激激活，并且与这种伴侣蛋白不同，其功能也可以被不同的配体诱导或抑制。这种独特的“伴侣受体”激活后，σR 调节多种细胞功能，并在大脑中具有神经保护活性。有趣的是，各种 σR 配体调节多巴胺神经传递，并减少动物成瘾行为模型中 METH 的行为效应，这表明 σR 可能是治疗 METH 成瘾的一个可行的治疗靶点。在这篇综述中，我们提供了 METH 和 σR 的背景知识，以及关于 σRs 调节多巴胺神经传递和 METH 效应的文献综述。我们旨在强调 σR 药理学和功能的复杂性，以及将 σR 作为治疗 METH 成瘾的靶点的治疗潜力。
