Short-acting cocaine and long-acting GBR-12909 both elicit rapid dopamine uptake inhibition following intravenous delivery.
Short-acting cocaine and long-acting GBR-12909 both elicit rapid dopamine uptake inhibition following intravenous delivery.
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DOI：
10.1016/j.neuroscience.2008.05.022
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发表时间：
2008-07-31
期刊：
影响因子：
3.3
通讯作者：
Jones, S. R.
中科院分区：
文献类型：
--
作者：
Espana, R. A.;Roberts, D. C. S.;Jones, S. R.
据报道，可卡因的奖励作用在服用后几秒钟内就发生了。大量证据表明，这些行动涉及可卡因抑制多巴胺（DA）转运蛋白的能力。我们最近表明，1.5 mg/kg静脉（i. v.）可卡因在5秒内抑制DA摄取。尽管有这些证据，但对于静脉注射可卡因和其他DA摄取抑制剂如何快速引起DA摄取抑制仍缺乏共识。目前的研究旨在更好地表征可卡因诱导的DA摄取抑制的开始，并将这些作用与高亲和力、长效DA转运蛋白抑制剂1-（2-双（4-氟苯基）-甲氧基）-乙基）-4-（3-苯基-丙基）哌嗪（GBR-12909）获得的作用进行比较。用在体快速扫描循环伏安法，我们表明，静脉注射可卡因（0.75，1.5和3.0毫克/公斤）显着抑制DA摄取在麻醉大鼠的延髓核在5秒内。DA摄取抑制在30秒达到峰值，并在约1小时内恢复到基线水平。可卡因的作用具有剂量依赖性，3.0 mg/kg剂量在早期时间点产生更大的摄取抑制，并显示出更长的恢复至基线的潜伏期。此外，血脑屏障渗透剂可卡因-甲碘对DA摄取或峰高没有影响，表明可卡因的全身外周效应对此处测量的CNS改变没有贡献。最后，我们表明，GBR-12909（0.75，1.5，和3.0毫克/公斤）也显着抑制DA摄取注射后5秒内，虽然峰值效应和恢复到基线显着延迟相比，可卡因，特别是在最高剂量。总之，这些观察结果表明，多巴胺摄取抑制剂的中枢作用在静脉给药后发生得非常迅速。
The rewarding effects of cocaine have been reported to occur within seconds of administration. Extensive evidence suggests that these actions involve the ability of cocaine to inhibit the dopamine (DA) transporter. We recently showed that 1.5 mg/kg intravenous (i.v.) cocaine inhibits DA uptake within 5 sec. Despite this evidence there remains a lack of consensus regarding how quickly i.v. cocaine and other DA uptake inhibitors elicit DA uptake inhibition. The current studies sought to better characterize the onset of cocaine-induced DA uptake inhibition and to compare these effects to those obtained with the high-affinity, long-acting DA transporter inhibitor, 1-(2-bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl)piperazine (GBR-12909). Using in vivo fast scan cyclic voltammetry, we showed that i.v. cocaine (0.75, 1.5, and 3.0 mg/kg) significantly inhibited DA uptake in the nucleus accumbens of anesthetized rats within 5 sec. DA uptake inhibition peaked at 30 sec and returned to baseline levels in approximately one hour. The effects of cocaine were dose-dependent, with the 3.0 mg/kg dose producing greater uptake inhibition at the early time points and exhibiting a longer latency to return to baseline. Further, the blood-brain barrier impermiant cocaine-methiodide had no effect on DA uptake or peak height, indicating that the generalized peripheral effects of cocaine do not contribute to the CNS alterations measured here. Finally, we show that GBR-12909 (0.75, 1.5, and 3.0 mg/kg) also significantly inhibited DA uptake within 5 sec post-injection, although the peak effect and return to baseline were markedly delayed compared to cocaine, particularly at the highest dose. Combined, these observations indicate that the central effects of dopamine uptake inhibitors occur extremely rapidly following i.v. drug delivery.
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