Tetrabenazine inhibition of monoamine uptake and methamphetamine behavioral effects: locomotor activity, drug discrimination and self-administration.
Tetrabenazine inhibition of monoamine uptake and methamphetamine behavioral effects: locomotor activity, drug discrimination and self-administration.
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DOI：
10.1016/j.neuropharm.2011.05.033
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发表时间：
2011-09
影响因子：
4.7
通讯作者：
Bardo, M. T.
中科院分区：
文献类型：
--
作者：
Meyer, A. C.;Horton, D. B.;Neugebauer, N. M.;Wooters, T. E.;Nickell, J. R.;Dwoskin, L. P.;Bardo, M. T.
关键词：
丁苯那嗪（TBZ）是一种苯并喹嗪衍生物，可与囊泡单胺转运蛋白2（VMAT 2）高亲和力结合，抑制细胞溶质单胺的摄取。目前的研究旨在提供临床前证据，支持TBZ作为甲基苯丙胺滥用治疗的潜在用途。TBZ对纹状体和海马突触体中多巴胺转运体（DAT）和5-羟色胺转运体（SERT）功能的影响，以及对分离的纹状体突触囊泡中VMAT 2功能的影响。TBZ的影响（急性，0.1 - 3.0 mg/kg，皮下注射;重复，1.0 mg/kg，持续7天）对甲基苯丙胺致敏大鼠自发活动的影响。TBZ（0.1 - 3.0 mg/kg; s.c.）或载体降低甲基苯丙胺的辨别作用。TBZ（急性，0.1 - 1.0 mg/kg，s.c.;重复，0.1或1.0 mg/kg，持续7天），以特异性地减少甲基苯丙胺自我给药;为了比较，评估了另一组大鼠的TBZ对食物维持反应的影响。结果表明，TBZ是11倍更有效地抑制DAT比SERT，和2.5倍更有效地抑制VMAT 2比DAT。从行为研究的结果表明，最低剂量的TBZ瞬时增加甲基苯丙胺自我管理，而较高的TBZ剂量减少甲基苯丙胺自我管理。此外，TBZ在高剂量降低甲基苯丙胺运动敏化和歧视性刺激效应，以及食物维持的反应。因此，尽管作为一种有效的VMAT 2抑制剂，这些临床前结果表明，TBZ缺乏作为甲基苯丙胺诱导的强化抑制剂的行为特异性，降低了其作为甲基苯丙胺滥用的合适治疗的可行性。
Tetrabenazine (TBZ), a benzoquinolizine derivative, binds with high affinity to the vesicular monoamine transporter-2 (VMAT2), inhibiting uptake of cytosolic monoamines. The current study aimed to provide preclinical evidence supporting the potential use of TBZ as a treatment for methamphetamine abuse. Effects of TBZ on function of the dopamine transporter (DAT) and serotonin transporter (SERT) in striatal and hippocampal synaptosomes, respectively, and on VMAT2 function in isolated striatal synaptic vesicles were determined. Effect of TBZ (acute, 0.1 - 3.0 mg/kg, s.c.; repeated, 1.0 mg/kg for 7 days) on locomotor activity in methamphetamine-sensitized rats was assessed. Ability of TBZ (0.1 -3.0 mg/kg; s.c.) or vehicle to decrease the discriminative effect of methamphetamine also was determined. Ability of TBZ (acute, 0.1 - 1.0 mg/kg, s.c.; repeated, 0.1 or 1.0 mg/kg for 7 days) to specifically decrease methamphetamine self-administration was determined; for comparison, a separate group of rats was assessed for effects of TBZ on food-maintained responding. Results show that TBZ was 11-fold more potent inhibiting DAT than SERT, and 2.5-fold more potent inhibiting VMAT2 than DAT. Results from behavioral studies showed that the lowest dose of TBZ transiently increased methamphetamine self-administration, whereas higher TBZ doses decreased methamphetamine self-administration. Also, TBZ at high doses decreased methamphetamine locomotor sensitization and discriminative stimulus effects, as well as food-maintained responding. Thus, despite acting as a potent VMAT2 inhibitor, these preclinical results indicate that TBZ lacks behavioral specificity as an inhibitor of methamphetamine-induced reinforcement, diminishing its viability as a suitable treatment for methamphetamine abuse.
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DOI：
10.1186/1471-2210-6-6
发表时间：
2006-03-03
期刊：
BMC pharmacology
影响因子：
--
作者：
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通讯作者：
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DOI：
10.1017/s1461145705005249
发表时间：
2005-09-01
影响因子：
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作者：
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影响因子：
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通讯作者：
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影响因子：
11.2
作者：
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影响因子：
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