Laruelle M, Iyer R N, al-Tikriti M S, Zea-Ponce Y, Malison R, Zoghbi S S, Baldwin R M, Kung H F, Charney D S, Hoffer P B, Innis R B, Bradberry C W
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06516, USA.
Synapse. 1997 Jan;25(1):1-14. doi: 10.1002/(SICI)1098-2396(199701)25:1<1::AID-SYN1>3.0.CO;2-H.
The competition between endogenous transmitters and radiolabeled ligands for in vivo binding to neuroreceptors might provide a method to measure endogenous transmitter release in the living human brain with noninvasive techniques such as positron emission tomography (PET) or single photon emission computerized tomography (SPECT). In this study, we validated the measure of amphetamine-induced dopamine release with SPECT in nonhuman primates. Microdialysis experiments were conducted to establish the dose-response curve of amphetamine-induced dopamine release and to document how pretreatment with the dopamine depleter alpha-methyl-para-tyrosine (alpha MPT) affects this response. SPECT experiments were performed with two iodinated benzamides, [123I]IBZM and [123I]IBF, under sustained equilibrium condition. Both radio-tracers are specific D2 antagonists, but the affinity of [123I]IBZM (KD-0.4 nM) is lower than that of [123I]IBF (KD 0.1 nM). With both tracers, we observed a prolonged reduction in binding to D2 receptors following amphetamine injection. [123I]IBZM binding to D2 receptors was more affected than [123I]IBF by high doses of amphetamine, indicating that a lower affinity increases the vulnerability of a tracer to endogenous competition. With [123I]IBZM, we observed an excellent correlation between reduction of D2 receptor binding measured with SPECT and peak dopamine release measured with microdialysis after various doses of amphetamine. Pretreatment with alpha MPT significantly reduced the effect of amphetamine on [123I]IBZM binding to D2 receptors, confirming that this effect was mediated by intrasynaptic dopamine release. Together, these results validate the use of this SPECT paradigm as a noninvasive measurement of intrasynaptic dopamine release in the living brain.
内源性递质与放射性标记配体在体内竞争结合神经受体，这可能为利用正电子发射断层扫描（PET）或单光子发射计算机断层扫描（SPECT）等非侵入性技术测量活体人脑中内源性递质释放提供一种方法。在本研究中，我们在非人灵长类动物中用SPECT验证了苯丙胺诱导的多巴胺释放的测量方法。进行了微透析实验以建立苯丙胺诱导的多巴胺释放的剂量反应曲线，并记录多巴胺耗竭剂α-甲基-对-酪氨酸（αMPT）预处理如何影响该反应。在持续平衡条件下，用两种碘化苯甲酰胺[123I]IBZM和[123I]IBF进行SPECT实验。两种放射性示踪剂都是特异性D2拮抗剂，但[123I]IBZM（KD-0.4 nM）的亲和力低于[123I]IBF（KD 0.1 nM）。使用这两种示踪剂，我们观察到注射苯丙胺后与D2受体的结合持续减少。高剂量苯丙胺对[123I]IBZM与D2受体结合的影响比对[123I]IBF的影响更大，表明较低的亲和力增加了示踪剂对内源性竞争的敏感性。使用[123I]IBZM，我们观察到SPECT测量的D2受体结合减少与微透析测量的不同剂量苯丙胺后多巴胺释放峰值之间具有良好的相关性。用αMPT预处理显著降低了苯丙胺对[123I]IBZM与D2受体结合的影响，证实该效应是由突触内多巴胺释放介导的。总之，这些结果验证了这种SPECT范式作为活体脑中突触内多巴胺释放的非侵入性测量方法的应用。
