Igari Moe, Shen Hao-Wei, Hagino Yoko, Fukushima Setsu, Kasahara Yoshiyuki, Lesch Klaus-Peter, Murphy Dennis L, Hall Frank Scott, Uhl George R, Ikeda Kazutaka, Yaegashi Nobuo, Sora Ichiro
Departments of aBiological Psychiatry bGynecology and Obstetrics, Tohoku University Graduate School of Medicine, Sendai cDepartment of Molecular Psychiatry, Tokyo Institute of Psychiatry, Tokyo, Japan dDepartment of Psychiatry und Psychotherapy, University of Wurzburg, Wurzburg, Germany eClinical Neuropharmacology Section, Laboratory of Clinical Science, National Institute on Mental Health, Intramural Research Program, Bethesda fMolecular Neurobiology Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland, USA.
Behav Pharmacol. 2015 Feb;26(1-2):167-79. doi: 10.1097/FBP.0000000000000120.
Repeated administration of methamphetamine (METH) enhances acute locomotor responses to METH administered in the same context, a phenomenon termed as 'locomotor sensitization'. Although many of the acute effects of METH are mediated by its influences on the compartmentalization of dopamine, serotonin systems have also been suggested to influence the behavioral effects of METH in ways that are not fully understood. The present experiments examined serotonergic roles in METH-induced locomotor sensitization by assessing: (a) the effect of serotonin transporter (SERT; Slc6A4) knockout (KO) on METH-induced locomotor sensitization; (b) extracellular monoamine levels in METH-treated animals as determined by in-vivo microdialysis; and (c) effects of serotonin (5-HT) receptor antagonists on METH-induced behavioral sensitization, with focus on effects of the 5-HT1B receptor antagonist SB 216641 and a comparison with the 5-HT2 receptor antagonist ketanserin. Repeated METH administration failed to induce behavioral sensitization in homozygous SERT KO (SERT-/-) mice under conditions that produced substantial sensitization in wild-type or heterozygous SERT KO (SERT+/-) mice. The selective 5-HT1B antagonist receptor SB 216641 restored METH-induced locomotor sensitization in SERT-/- mice, whereas ketanserin was ineffective. METH-induced increases in extracellular 5-HT (5-HTex) levels were substantially reduced in SERT-/- mice, although SERT genotype had no effect on METH-induced increases in extracellular dopamine. These experiments demonstrate that 5-HT actions, including those at 5-HT1B receptors, contribute to METH-induced locomotor sensitization. Modulation of 5-HT1B receptors might aid therapeutic approaches to the sequelae of chronic METH use.
重复给予甲基苯丙胺（METH）会增强在相同环境下给予METH时的急性运动反应，这种现象被称为“运动敏化”。尽管METH的许多急性效应是由其对多巴胺区室化的影响介导的，但也有人提出血清素系统以尚未完全理解的方式影响METH的行为效应。本实验通过评估以下方面来研究血清素能在METH诱导的运动敏化中的作用：（a）血清素转运体（SERT；Slc6A4）基因敲除（KO）对METH诱导的运动敏化的影响；（b）通过体内微透析测定METH处理动物的细胞外单胺水平；（c）血清素（5-HT）受体拮抗剂对METH诱导的行为敏化的影响，重点关注5-HT1B受体拮抗剂SB 216641的作用，并与5-HT2受体拮抗剂酮色林进行比较。在能使野生型或杂合子SERT基因敲除（SERT+/-）小鼠产生显著敏化的条件下，重复给予METH未能在纯合子SERT基因敲除（SERT-/-）小鼠中诱导行为敏化。选择性5-HT1B拮抗剂受体SB 216641恢复了SERT-/-小鼠中METH诱导的运动敏化，而酮色林则无效。尽管SERT基因型对METH诱导的细胞外多巴胺增加没有影响，但METH诱导的细胞外5-HT（5-HTex）水平增加在SERT-/-小鼠中显著降低。这些实验表明，包括5-HT1B受体处的作用在内的5-HT作用有助于METH诱导的运动敏化。调节5-HT1B受体可能有助于治疗慢性使用METH的后遗症。
