Department of Veterinary Comparative Anatomy, Pharmacology and Physiology, WWAMI Medical Education Program, Washington State University, Spokane, WA 99202, USA.
Brain Behav Immun. 2011 May;25(4):767-76. doi: 10.1016/j.bbi.2011.02.002. Epub 2011 Feb 17.
Methamphetamine and modafinil exert their wake-promoting effects by elevating monoaminergic tone. The severity of hypersomnolence that occurs subsequent to induced wakefulness differs between these two agents. Microglia detects and modulates CNS reactions to agents such as D-methamphetamine that induce cellular stress. We therefore hypothesized that changes in the sleep/wake cycle that occur subsequent to administration of D-methamphetamine are modulated by cerebral microglia. In CD11b-herpes thymidine kinase transgenic mice (CD11b-TK(mt-30)), activation of the inducible transgene by intracerebroventricular (icv) ganciclovir results in toxicity to CD11b-positive cells (i.e. microglia), thereby reducing cerebral microglial cell counts. CD11b-TK(mt-30)and wild type mice were subjected to chronic icv ganciclovir or vehicle administration with subcutaneous mini-osmotic pumps. D-methamphetamine (1 and 2 mg/kg), modafinil (30 and 100 mg/kg) and vehicle were administered intraperitoneally to these animals. In CD11b-TK(mt-30) mice, but not wild type, icv infusion of ganciclovir reduced the duration of wake produced by D-methamphetamine at 2 mg/kg by nearly 1h. Nitric oxide synthase (NOS) activity, studied ex vivo, and NOS expression were elevated in CD11b-positive cerebral microglia from wild type mice acutely exposed to d-methamphetamine. Additionally, CD11b-positive microglia, but not other cerebral cell populations, exhibited changes in sleep-regulatory cytokine expression in response to d-METH. Finally, CD11b-positive microglia exposed to d-methamphetamine in vitro exhibited increased NOS activity relative to pharmacologically-naïve cells. CD11b-positive microglia from the brains of neuronal NOS (nNOS)-knockout mice failed to exhibit this effect. We propose that the effects of D-METH on sleep/wake cycles are mediated in part by actions on microglia, including possibly nNOS activity and cytokine synthesis.
冰毒和莫达非尼通过提高单胺能张力来发挥其促醒作用。这两种药物诱导清醒后发生的过度嗜睡的严重程度不同。小胶质细胞检测并调节中枢神经系统对 D-冰毒等诱导细胞应激的药物的反应。因此，我们假设 D-冰毒给药后睡眠/觉醒周期的变化受大脑小胶质细胞的调节。在 CD11b-单纯疱疹胸苷激酶转基因小鼠（CD11b-TK(mt-30)）中，通过侧脑室（icv）给予更昔洛韦激活诱导型转基因，导致 CD11b 阳性细胞（即小胶质细胞）毒性，从而减少大脑小胶质细胞计数。CD11b-TK(mt-30)和野生型小鼠接受慢性 icv 更昔洛韦或皮下微量渗透泵给药。这些动物接受 D-冰毒（1 和 2mg/kg）、莫达非尼（30 和 100mg/kg）和载体的腹腔内给药。在 CD11b-TK(mt-30)小鼠中，但不是在野生型小鼠中，icv 输注更昔洛韦使 D-冰毒（2mg/kg）引起的觉醒时间减少了近 1 小时。体外研究表明，急性暴露于 D-冰毒的野生型小鼠的 CD11b 阳性小胶质细胞中的一氧化氮合酶（NOS）活性和 NOS 表达升高。此外，与其他脑细胞群体相比，CD11b 阳性小胶质细胞对 D-METH 的反应表现出睡眠调节细胞因子表达的变化。最后，与药理学上未处理的细胞相比，体外暴露于 D-冰毒的 CD11b 阳性小胶质细胞表现出增加的 NOS 活性。来自神经元 NOS（nNOS）敲除小鼠大脑的 CD11b 阳性小胶质细胞未能表现出这种效应。我们提出，D-METH 对睡眠/觉醒周期的影响部分是通过对小胶质细胞的作用介导的，包括可能的 nNOS 活性和细胞因子合成。
