Gilman T Lee, George Christina M, Vitela Melissa, Herrera-Rosales Myrna, Basiouny Mohamed S, Koek Wouter, Daws Lynette C
Department of Cellular & Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Addiction Research, Treatment & Training Center of Excellence, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Eur J Neurosci. 2018 May 24. doi: 10.1111/ejn.13968.
Originally, uptake-mediated termination of monoamine (e.g., serotonin and dopamine) signalling was believed to only occur via high-affinity, low-capacity transporters ("uptake ") such as the serotonin or dopamine transporters, respectively. Now, the important contribution of a second low-affinity, high-capacity class of biogenic amine transporters has been recognised, particularly in circumstances when uptake transporter function is reduced (e.g., antidepressant treatment). Pharmacologic or genetic reductions in uptake function can change locomotor, anxiety-like or stress-coping behaviours. Comparable behavioural investigations into reduced low-affinity, high-capacity transporter function are lacking, in part, due to a current dearth of drugs that selectively target particular low-affinity, high-capacity transporters, such as the plasma membrane monoamine transporter. Therefore, the most direct approach involves constitutive genetic knockout of these transporters. Other groups have reported that knockout of the low-affinity, high-capacity organic cation transporters 2 or 3 alters anxiety-like and stress-coping behaviours, but none have assessed behaviours in plasma membrane monoamine transporter knockout mice. Here, we evaluated adult male and female plasma membrane monoamine transporter wild-type, heterozygous and knockout mice in locomotor, anxiety-like and stress-coping behavioural tests. A mild enhancement of anxiety-related behaviour was noted in heterozygous mice. Active-coping behaviour was modestly and selectively increased in female knockout mice. These subtle behavioural changes support a supplemental role of plasma membrane monoamine transporter in serotonin and dopamine uptake, and suggest sex differences in transporter function should be examined more closely in future investigations.
最初，人们认为摄取介导的单胺（如血清素和多巴胺）信号终止仅通过高亲和力、低容量转运体（“摄取”）发生，例如血清素或多巴胺转运体。现在，人们已经认识到第二类低亲和力、高容量生物胺转运体的重要作用，特别是在摄取转运体功能降低的情况下（如抗抑郁治疗）。摄取功能的药理学或基因学降低可改变运动、焦虑样或应激应对行为。部分由于目前缺乏选择性靶向特定低亲和力、高容量转运体（如质膜单胺转运体）的药物，因此缺乏对低亲和力、高容量转运体功能降低的类似行为研究。因此，最直接的方法是对这些转运体进行组成型基因敲除。其他研究小组报告说，低亲和力、高容量有机阳离子转运体2或3的敲除会改变焦虑样和应激应对行为，但没有一个研究评估质膜单胺转运体敲除小鼠的行为。在这里，我们在运动、焦虑样和应激应对行为测试中评估了成年雄性和雌性质膜单胺转运体野生型、杂合子和敲除小鼠。在杂合子小鼠中发现焦虑相关行为有轻度增强。在雌性敲除小鼠中，主动应对行为适度且选择性增加。这些细微的行为变化支持质膜单胺转运体在血清素和多巴胺摄取中的补充作用，并表明在未来的研究中应更仔细地研究转运体功能的性别差异。
