Trace amine-associated receptor 1 (TAAR1) is activated by methamphetamine (MA) and modulates dopaminergic (DA) function. Although DA dysregulation is the hallmark of MA-induced neurotoxicity leading to behavioral and cognitive deficits, the intermediary role of TAAR1 has yet to be characterized. To investigate TAAR1 regulation of MA-induced neurotoxicity, Taar1 transgenic knock-out (KO) and wildtype (WT) mice were administered saline or a neurotoxic regimen of 4 i.p. injections, 2h apart, of MA (2.5, 5, or 10mg/kg). Temperature data were recorded during the treatment day. Additionally, striatal tissue was collected 2 or 7days following MA administration for analysis of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and tyrosine hydroxylase (TH) levels, as well as glial fibrillary acidic protein (GFAP) expression. MA elicited an acute hypothermic drop in body temperature in Taar1-WT mice, but not in Taar1-KO mice. Two days following treatment, DA and TH levels were lower in Taar1-KO mice compared to Taar1-WT mice, regardless of treatment, and were dose-dependently decreased by MA. GFAP expression was significantly increased by all doses of MA at both time points and greater in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5mg/kg. Seven days later, DA levels were decreased in a similar pattern: DA was significantly lower in Taar1-KO compared to Taar1-WT mice receiving MA 2.5 or 5mg/kg. TH levels were uniformly decreased by MA, regardless of genotype. These results indicate that activation of TAAR1 potentiates MA-induced hypothermia and TAAR1 confers sustained neuroprotection dependent on its thermoregulatory effects.

中文翻译：

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微量胺相关受体 1 对甲基苯丙胺诱导的神经毒性的调节。


痕量胺相关受体 1 (TAAR1) 被甲基苯丙胺 (MA) 激活并调节多巴胺能 (DA) 功能。尽管 DA 失调是 MA 诱导的神经毒性导致行为和认知缺陷的标志，但 TAAR1 的中介作用尚未得到表征。为了研究 TAAR1 对 MA 诱导的神经毒性的调节，对 Taar1 转基因敲除 (KO) 和野生型 (WT) 小鼠施用生理盐水或神经毒性方案，即 4 次腹膜内注射（间隔 2 小时）MA（2.5、5 或 10mg/kg） ）。在治疗当天记录温度数据。此外，MA 给药后 2 或 7 天收集纹状体组织，用于分析 DA、3,4-二羟基苯乙酸 (DOPAC)、高香草酸 (HVA) 和酪氨酸羟化酶 (TH) 水平以及胶质纤维酸性蛋白 (GFAP) ） 表达。 MA 引起 Taar1-WT 小鼠体温急剧降低，但 Taar1-KO 小鼠则不然。治疗两天后，无论进行何种治疗，Taar1-KO 小鼠的 DA 和 TH 水平均低于 Taar1-WT 小鼠，并且 MA 呈剂量依赖性降低。与接受 MA 2.5 或 5mg/kg 的 Taar1-WT 小鼠相比，所有剂量的 MA 在两个时间点均显着增加了 GFAP 表达，并且在 Taar1-KO 中更高。 7 天后，DA 水平以类似的模式下降：与接受 MA 2.5 或 5 mg/kg 的 Taar1-WT 小鼠相比，Taar1-KO 中的 DA 显着降低。无论基因型如何，MA 均会降低 TH 水平。这些结果表明，TAAR1 的激活增强了 MA 诱导的体温过低，并且 TAAR1 依赖于其体温调节作用而赋予持续的神经保护作用。