Young L T, Wong D F, Goldman S, Minkin E, Chen C, Matsumura K, Scheffel U, Wagner H N
Division of Nuclear Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205.
Synapse. 1991 Nov;9(3):188-94. doi: 10.1002/syn.890090305.
Competition by endogenous dopamine with the binding of D2 dopamine receptor ligands may be important in the interpretation of positron emission tomography (PET) neuroreceptor studies. PET studies with N-methylspiperone (NMSP) have revealed increased D2 dopamine receptors in schizophrenia, whereas studies with raclopride (RAC) have not detected such differences. This may be due, at least in part, to differences in competition with endogenous dopamine for ligand binding. To determine effects of endogenous dopamine on in vivo receptor binding, adult male rats were preinjected with amphetamine and reserpine prior to [3H]NMSP or [3H]RAC. Striatal to cerebellar ratios of ligand binding were determined. To approximate the conditions of a PET study, a kinetic model was employed to examine effects of pharmacologically increasing brain dopamine levels (amphetamine pretreatment) on PET ligand binding. In these experiments, tail veins and arteries were cannulated and kinetic parameters determined from normalized integral plots in rats treated with amphetamine prior to radioligand injection. Both [3H]NMSP (43.5%) and [3H]RAC (41.5%) binding were significantly decreased after amphetamine pretreatment, whereas after reserpine pretreatment [3H]RAC binding was increased (52.7%). Kinetic studies revealed a marked resistance of [3H]NMSP to competition with endogenous dopamine released by amphetamine. In contrast, kinetic parameters of [3H]RAC were markedly reduced at all time intervals. This suggests significant differences in competition with endogenous dopamine by [3H]NMSP and [3H]RAC, determined kinetically. These findings may have important implications for the interpretation of PET neuroreceptor studies.
内源性多巴胺与D2多巴胺受体配体结合的竞争可能在正电子发射断层扫描（PET）神经受体研究的解释中具有重要意义。用N-甲基螺哌隆（NMSP）进行的PET研究显示精神分裂症患者的D2多巴胺受体增加，而用雷氯必利（RAC）进行的研究未检测到这种差异。这可能至少部分归因于与内源性多巴胺在配体结合竞争方面的差异。为了确定内源性多巴胺对体内受体结合的影响，成年雄性大鼠在注射[3H]NMSP或[3H]RAC之前预先注射了苯丙胺和利血平。测定了纹状体与小脑的配体结合比率。为了接近PET研究的条件，采用动力学模型来研究药理学上增加脑多巴胺水平（苯丙胺预处理）对PET配体结合的影响。在这些实验中，将尾静脉和动脉插管，并从放射性配体注射前用苯丙胺处理的大鼠的标准化积分图中确定动力学参数。苯丙胺预处理后，[3H]NMSP（43.5%）和[3H]RAC（41.5%）的结合均显著降低，而利血平预处理后[3H]RAC的结合增加（52.7%）。动力学研究表明，[3H]NMSP对苯丙胺释放的内源性多巴胺竞争具有明显抗性。相比之下，[3H]RAC的动力学参数在所有时间间隔均显著降低。这表明通过动力学测定，[3H]NMSP和[3H]RAC与内源性多巴胺的竞争存在显著差异。这些发现可能对PET神经受体研究的解释具有重要意义。
