Munzar P, Laufert M D, Kutkat S W, Nováková J, Goldberg S R
Preclinical Pharmacology Laboratory, National Institutes of Health, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland, USA.
J Pharmacol Exp Ther. 1999 Oct;291(1):239-50.
Neurochemical studies indicate that methamphetamine increases central serotonin (5-HT) levels more markedly than other psychomotor stimulants such as amphetamine or cocaine. In the present study, we investigated 5-HT involvement in the discriminative stimulus effects of methamphetamine. In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine i.p. from saline under a fixed-ratio schedule of food presentation, the effects of selected 5-HT agonists, antagonists, and uptake inhibitors were tested. Fluoxetine (1.8-18.0 mg/kg) and clomipramine (3.0-18.0 mg/kg), selective serotonin uptake inhibitors, did not produce any methamphetamine-like discriminative stimulus effects when administered alone, but fluoxetine (5.6 mg/kg), unlike clomipramine (5.6 mg/kg), significantly shifted the methamphetamine dose-response curve to the left. Both 8-hydroxy-2-dipropylaminotetralin (0.03-0.56 mg/kg), a full agonist, and buspirone (1.0-10.0 mg/kg), a partial agonist at 5-HT(1A) receptors, partially generalized to the training dose of methamphetamine but only at high doses that decreased response rate. This generalization was antagonized by the coadministration of the 5-HT(1A) antagonist WAY-100635 (1.0 mg/kg). WAY-100635 (1.0 mg/kg) also partially reversed the leftward shift of the methamphetamine dose-response curve produced by fluoxetine. (+/-)-1-(2, 5-Dimethoxy-4-iodophenyl)-2-aminopropane (0.3 mg/kg), a 5-HT(2A/2C) agonist, shifted the methamphetamine dose-response curve to the left, and this leftward shift was antagonized by the coadministration of ketanserin (3.0 mg/kg), a 5-HT(2A/2C) antagonist. Ketanserin (3.0 mg/kg) also produced a shift to the right in the methamphetamine dose-response curve and completely reversed the leftward shift in the methamphetamine dose-response curve produced by fluoxetine. In contrast, tropisetron (1.0 mg/kg), a 5-HT(3) antagonist, produced a shift to the left of the methamphetamine dose-response curve, and this effect of tropisetron was antagonized by the coadministration of m-chlorophenyl-biguanide (1.8 mg/kg), a 5-HT(3) agonist. The present data suggest that the 5-HT system plays a modulatory role in the discriminative stimulus effects of methamphetamine. These effects appear to be mediated through 5-HT release and blockade of reuptake and subsequent activation of 5-HT(2A/2C) receptors, with limited involvement of other 5-HT receptor subtypes.
神经化学研究表明，甲基苯丙胺比其他精神运动兴奋剂如苯丙胺或可卡因更显著地提高中枢5-羟色胺（5-HT）水平。在本研究中，我们调查了5-HT在甲基苯丙胺辨别刺激效应中的作用。在斯普拉格-道利大鼠中，按照固定比率的食物呈现方式训练它们辨别腹腔注射1.0mg/kg甲基苯丙胺与生理盐水，测试了选定的5-HT激动剂、拮抗剂和摄取抑制剂的效果。选择性5-羟色胺摄取抑制剂氟西汀（1.8 - 18.0mg/kg）和氯米帕明（3.0 - 18.0mg/kg）单独给药时未产生任何类似甲基苯丙胺的辨别刺激效应，但氟西汀（5.6mg/kg）与氯米帕明（5.6mg/kg）不同，它使甲基苯丙胺剂量-反应曲线显著向左移动。8-羟基-2-二丙基氨基四氢萘（0.03 - 0.56mg/kg），一种完全激动剂，和丁螺环酮（1.0 - 10.0mg/kg），一种5-HT(1A)受体的部分激动剂，仅在高剂量时部分泛化到甲基苯丙胺的训练剂量，但高剂量会降低反应率。这种泛化被共同给予5-HT(1A)拮抗剂WAY-100635（1.0mg/kg）所拮抗。WAY-100635（1.0mg/kg）也部分逆转了氟西汀产生的甲基苯丙胺剂量-反应曲线的左移。(+/-)-1-(2,5-二甲氧基-4-碘苯基)-2-氨基丙烷（0.3mg/kg），一种5-HT(2A/2C)激动剂，使甲基苯丙胺剂量-反应曲线向左移动，这种左移被共同给予5-HT(2A/2C)拮抗剂酮色林（3.0mg/kg）所拮抗。酮色林（3.0mg/kg）也使甲基苯丙胺剂量-反应曲线向右移动，并完全逆转了氟西汀产生的甲基苯丙胺剂量-反应曲线的左移。相比之下，5-HT(3)拮抗剂托烷司琼（1.0mg/kg）使甲基苯丙胺剂量-反应曲线向左移动，托烷司琼的这种效应被共同给予5-HT(3)激动剂间氯苯基双胍（1.8mg/kg）所拮抗。目前的数据表明，5-HT系统在甲基苯丙胺的辨别刺激效应中起调节作用。这些效应似乎是通过5-HT释放、再摄取阻断以及随后5-HT(2A/2C)受体的激活介导的，其他5-HT受体亚型的参与有限。
