Zimmer L, Riad M, Rbah L, Belkacem-Kahlouli A, Le Bars D, Renaud B, Descarries L
Laboratoire de Neuropharmacologie et Neurochimie, INSERM U512, Université Claude Bernard, Lyon, France.
Neuroimage. 2004 Jul;22(3):1421-6. doi: 10.1016/j.neuroimage.2004.03.020.
Enhancing cerebral serotonin (5-hydroxytryptamine, 5-HT) neurotransmission is a common property of antidepressant treatments and the basis for their efficacy. 5-HT1A receptors located on the cell body and dendrites of 5-HT neurons (autoreceptors) play a key role in this regard. Because they normally mediate an inhibition of neuronal firing, their desensitization is a prerequisite to the delayed enhancement of 5-HT neurotransmission upon treatment with monoamine oxidase (MAOI) inhibitors or specific serotonin reuptake inhibitors (SSRI). Using beta-sensitive microprobes in vivo, we measured a significant decrease (-30%) in binding sites for the 5-HT1A PET radioligand [18F]MPPF associated with an equivalent reduction (-34%) in the cell surface density of 5-HT1A receptor immunoreactivity (internalization), in the nucleus raphe dorsalis (autoreceptors), but not hippocampus (heteroreceptors), of rats given a single dose of the specific 5-HT1A receptor agonist, 8-OH-DPAT (0.5 mg/kg, iv). This effect was completely blocked by pretreatment with the selective 5-HT1A antagonist WAY 100635. Having ruled out that this decreased density of [18F]MPPF binding in the nucleus raphe dorsalis of 8-OH-DPAT-treated rats resulted from a local blood flow effect, we obtained autoradiographic evidence indicating that the total amount of specific binding of [18F]MPPF in tissue sections was unaffected by the 8-OH-DPAT treatment in either NRD or hippocampus. It was therefore concluded that the internalization of 5-HT1A autoreceptors accounted for the decreased binding in vivo of [18F]MPPF in the nucleus raphe dorsalis of rats treated with 8-OH-DPAT. Thus, PET imaging might provide a mean to measure 5-HT1A receptor internalization in human brain and thus assess responsiveness to antidepressant treatment.
增强大脑5-羟色胺（5-羟色胺，5-HT）神经传递是抗抑郁治疗的共同特性及其疗效的基础。位于5-HT神经元细胞体和树突上的5-HT1A受体（自身受体）在这方面起着关键作用。由于它们通常介导对神经元放电的抑制，其脱敏是在用单胺氧化酶（MAOI）抑制剂或特异性5-羟色胺再摄取抑制剂（SSRI）治疗后5-HT神经传递延迟增强的先决条件。使用体内β敏感微探针，我们测量了给予单剂量特异性5-HT1A受体激动剂8-OH-DPAT（0.5mg/kg，静脉注射）的大鼠中缝背核（自身受体）而非海马体（异源受体）中5-HT1A正电子发射断层扫描（PET）放射性配体[18F]MPPF的结合位点显著减少（-30%），这与5-HT1A受体免疫反应性的细胞表面密度同等降低（-34%）（内化）相关。这种效应被选择性5-HT1A拮抗剂WAY 100635预处理完全阻断。在排除了8-OH-DPAT处理的大鼠中缝背核中[18F]MPPF结合密度降低是由局部血流效应导致的可能性后，我们获得了放射自显影证据，表明在组织切片中[18F]MPPF的特异性结合总量在中缝背核或海马体中均不受8-OH-DPAT处理的影响。因此得出结论，5-HT1A自身受体的内化导致了用8-OH-DPAT处理的大鼠中缝背核中[18F]MPPF体内结合减少。因此，PET成像可能提供一种手段来测量人脑中5-HT1A受体的内化，从而评估对抗抑郁治疗的反应性。
