Duncan G E, Little K Y, Kirkman J A, Kaldas R S, Stumpf W E, Breese G R
Brain and Development Research Center, University of North Carolina, Chapel Hill 27599.
Brain Res. 1992 Sep 25;591(2):181-97. doi: 10.1016/0006-8993(92)91699-f.
The neuroanatomical distribution of binding sites for [3H]imipramine and [3H]citalopram was assessed by in vitro autoradiography in select regions of the rat and human forebrain. To determine involvement of serotonin-containing terminals in the binding of [3H]imipramine and [3H]citalopram, binding of these compounds was measured in rats after destroying serotonin-containing neurons with 5,7-dihydroxytryptamine (5,7-DHT). Treatment with this neurotoxin decreased serotonin content by 90% and reduced [3H]citalopram binding to a similar extent. These results demonstrate that [3H]citalopram binding is a reliable marker for serotonin-containing terminals. Binding of [3H]imipramine was reduced by only 15-35% after 5,7-DHT treatment. These latter results suggest that only a small fraction of [3H]imipramine binding to brain sections is associated with serotonergic terminals under standard conditions used in autoradiographic studies with the ligand. Dose-response effects of fluoxetine and desipramine on displacement of [3H]imipramine binding in forebrain regions indicate that the ligand labels predominantly high capacity, low affinity binding sites. To determine the utility of the rat brain as a model for [3H]imipramine and [3H]citalopram binding in the human brain, binding of the ligands was compared in human and rat hypothalamus, amygdala, and hippocampus. The pharmacological characteristics of [3H]imipramine and [3H]citalopram binding were similar in the rat and human brain. However, substantial species differences were observed in topographic patterns of [3H]imipramine binding within the hippocampus and hypothalamus. The distribution of [3H]citalopram binding sites within the amygdala and hypothalamus were also strikingly different in rats compared to humans. This work provides the first demonstration that marked species differences exist in the topography of serotonergic innervation and in the distribution of [3H]imipramine binding sites within the rat and human brain regions examined.
通过体外放射自显影技术，在大鼠和人类前脑的特定区域评估了[3H]丙咪嗪和[3H]西酞普兰结合位点的神经解剖分布。为了确定含5-羟色胺的终末在[3H]丙咪嗪和[3H]西酞普兰结合中的作用，在用5,7-二羟基色胺（5,7-DHT）破坏含5-羟色胺的神经元后，测量了大鼠体内这些化合物的结合情况。用这种神经毒素处理可使5-羟色胺含量降低90%，并使[3H]西酞普兰结合减少到类似程度。这些结果表明，[3H]西酞普兰结合是含5-羟色胺终末的可靠标记。5,7-DHT处理后，[3H]丙咪嗪的结合仅减少了15%-35%。后一组结果表明，在使用该配体进行放射自显影研究的标准条件下，与脑切片结合的[3H]丙咪嗪中只有一小部分与5-羟色胺能终末相关。氟西汀和地昔帕明对前脑区域[3H]丙咪嗪结合置换的剂量反应效应表明，该配体主要标记高容量、低亲和力的结合位点。为了确定大鼠脑作为人类脑[3H]丙咪嗪和[3H]西酞普兰结合模型的实用性，比较了人类和大鼠下丘脑、杏仁核和海马体中配体的结合情况。[3H]丙咪嗪和[3H]西酞普兰结合的药理学特征在大鼠和人类脑中相似。然而，在海马体和下丘脑内，[3H]丙咪嗪结合的地形模式存在显著的物种差异。与人类相比，大鼠杏仁核和下丘脑内[3H]西酞普兰结合位点的分布也明显不同。这项工作首次证明，在所检查的大鼠和人类脑区域中，5-羟色胺能神经支配的地形以及[3H]丙咪嗪结合位点的分布存在明显的物种差异。
