Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, 266021, China.
Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
Sci Rep. 2018 Jan 17;8(1):882. doi: 10.1038/s41598-018-19207-2.
Methamphetamine (MAP) is the most widely used psychostimulant in the world, but the exact mechanisms underlying MAP addiction are not yet fully understood. Recent studies have identified the distribution of TRPV1 in several brain regions that are related to drug addiction, including nucleus accumbens (NAc) and dorsal striatum (DSt). In the present study, we performed conditioned place preference (CPP) and self-administration tests to examine the effects of capsazepine (CPZ) and SB366791 (SB) on MAP reward. We found that both CPZ and SB significantly inhibited MAP-induced CPP and self-administration; in contrast, TRPV1 knock-out (KO) mice did not develop MAP-induced CPP. Real-time RT-PCR, Western blot and quantitative autoradiographic tests showed up-regulation of TRPV1 mRNA and protein expression in the NAc and/or DSt regions of mice exhibiting MAP-induced CPP. In addition, an in vivo microdialysis experiment showed that CPZ dramatically reduced dopamine (DA) levels in the NAc region of MAP-treated mice. Furthermore, attenuated dopamine transporter (DAT) binding levels in the NAc and DSt regions of MAP-induced CPP mice were reversed by CPZ. Together, these data suggest that TRPV1 plays an important role in MAP reward via the modulation of DA release and DAT density, thereby providing a novel therapeutic target for MAP addiction.
甲基苯丙胺（MAP）是世界上使用最广泛的苯丙胺类兴奋剂，但 MAP 成瘾的确切机制尚未完全阐明。最近的研究已经确定了 TRPV1 在与药物成瘾相关的几个脑区的分布，包括伏隔核（NAc）和背侧纹状体（DSt）。在本研究中，我们进行了条件位置偏好（CPP）和自我给药测试，以研究辣椒素（CPZ）和 SB366791（SB）对 MAP 奖赏的影响。我们发现 CPZ 和 SB 均显著抑制 MAP 诱导的 CPP 和自我给药；相比之下，TRPV1 敲除（KO）小鼠不会产生 MAP 诱导的 CPP。实时 RT-PCR、Western blot 和定量 autoradiographic 测试显示，在表现出 MAP 诱导的 CPP 的小鼠的 NAc 和/或 DSt 区域，TRPV1 mRNA 和蛋白表达上调。此外，体内微透析实验表明 CPZ 可显著降低 MAP 处理小鼠 NAc 区域的多巴胺（DA）水平。此外，CPZ 逆转了 MAP 诱导的 CPP 小鼠 NAc 和 DSt 区域多巴胺转运蛋白（DAT）结合水平的降低。总之，这些数据表明 TRPV1 通过调节 DA 释放和 DAT 密度在 MAP 奖赏中发挥重要作用，从而为 MAP 成瘾提供了一个新的治疗靶点。
