Gifford A N, Park M H, Kash T L, Herman L M, Park E H, Gatley S J, Volkow N D
Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
Naunyn Schmiedebergs Arch Pharmacol. 2000 Nov;362(4-5):413-8. doi: 10.1007/s002100000293.
The in vivo binding of positron emission tomography (PET) and single photon emission computer tomography (SPECT) radiotracers to dopamine D2 receptors in the striatum can be influenced by competition with endogenous dopamine. The present study was undertaken to determine if a similar inhibition of radiotracer binding to dopamine receptors could be observed following pharmacologically-evoked dopamine release in rat brain striatal slices. Striatal slices were incubated in a large volume of oxygenated Krebs saline and exposed to amphetamine or methamphetamine to evoke dopamine release within the slice. Amphetamine and methamphetamine, at concentrations up to 30 microM, reduced [3H]raclopride binding in the slices by 77% and 86%, respectively, with 50% inhibition at 1.6 microM amphetamine or 3.0 microM methamphetamine. Neither drug produced a significant effect on binding of [3H]SCH 23390 in the slices. This suggests that dopamine was able to interfere with radiotracer binding to D2 but not D1 receptors. The dopamine uptake blockers, cocaine and methylphenidate, had relatively little effect by themselves on [3H]raclopride binding but, by inhibiting amphetamine-induced dopamine release, significantly reduced inhibition of [3H]raclopride binding by a low (3 microM) amphetamine concentration. At a higher (30 microM) amphetamine concentration the inhibition of [3H]raclopride binding was not antagonized by uptake blockers and data obtained from homogenate binding experiments indicated a direct displacement of [3H]raclopride binding by amphetamine at this concentration. In conclusion the data obtained in the present study demonstrate that the effects of amphetamine on striatal radiotracer accumulation observed in PET and SPECT can also be observed in brain slices in vitro and, at least at low amphetamine concentrations, are mediated by competition with released dopamine.
正电子发射断层扫描（PET）和单光子发射计算机断层扫描（SPECT）放射性示踪剂与纹状体中多巴胺D2受体的体内结合可能会受到内源性多巴胺竞争的影响。本研究旨在确定在大鼠脑纹状体切片中，药物诱发多巴胺释放后，是否能观察到放射性示踪剂与多巴胺受体结合的类似抑制作用。将纹状体切片置于大量充氧的 Krebs 盐溶液中孵育，并暴露于苯丙胺或甲基苯丙胺以诱发切片内多巴胺释放。浓度高达30 microM 的苯丙胺和甲基苯丙胺分别使切片中[3H]雷氯必利的结合减少77%和86%，1.6 microM 苯丙胺或3.0 microM 甲基苯丙胺时抑制率达50%。两种药物对切片中[3H]SCH 23390的结合均无显著影响。这表明多巴胺能够干扰放射性示踪剂与D2受体的结合，但不能干扰与D1受体的结合。多巴胺摄取阻滞剂可卡因和哌醋甲酯本身对[3H]雷氯必利的结合影响相对较小，但通过抑制苯丙胺诱导的多巴胺释放，能显著降低低浓度（3 microM）苯丙胺对[3H]雷氯必利结合的抑制作用。在较高浓度（30 microM）的苯丙胺下，摄取阻滞剂不能拮抗[3H]雷氯必利结合的抑制作用，匀浆结合实验数据表明该浓度下苯丙胺可直接取代[3H]雷氯必利的结合。总之，本研究获得的数据表明，PET和SPECT中观察到的苯丙胺对纹状体放射性示踪剂积累的影响在体外脑切片中也能观察到，并且至少在低苯丙胺浓度下，是由与释放的多巴胺竞争介导的。
