Waeber C, Palacios J M
Preclinical Research, Sandoz Pharma Ltd., CH-4002 Basel, Switzerland.
Brain Res Mol Brain Res. 1994 Jul;24(1-4):199-209. doi: 10.1016/0169-328x(94)90133-3.
Previous autoradiographic studies have shown that serotonin 5-HT2 receptors are homogeneously distributed in the human striatum. While these studies were done using antagonist radioligands such as [3H]ketanserin, we describe here a heterogeneous distribution of 5-HT2 binding sites in the human striatum, using [3H]LSD and [125I]DOI as ligands. Beside their agonist properties, these compounds belong to the family of psychedelic drugs. The localization of their binding sites in the dorsal striatum is very similar to that of striosomes, as visualized by acetylcholinesterase histochemistry or [3H]flunitrazepam labelling. This heterogeneous distribution seems to be a peculiarity of the human and guinea-pig brain, for it is not found in the monkey, cat, pig, and cow. In the rat striatum, a weak patchniness was seen, but corresponded to 5-HT1C binding sites. The density of [125I]DOI binding sites over striosomes presents large variations, which can neither be correlated with parameters such as age, gender and post-mortem delay nor with the effects of neurodegenerative disorders, with the exception of Huntington's disease, at late stages of the disease. The drug binding profile of [125I]DOI binding sites in the striosomes is identical to that of matrix binding sites. It is also fully comparable to the pharmacological profile of cortical 5-HT2 sites reported using [3H]ketanserin as a radioligand, with the exception of the higher affinity displayed by agonists for [125I]DOI binding sites. Interestingly, biphasic displacement curves yield a better fit for spiperone, cinanserin and ketanserin competitions. This biphasic profile can probably neither be accounted for by the presence of 5-HT1C sites nor by the existence of multiple affinity states. Taken together, these data suggest that a heterogeneous population of 5-HT2 receptors is present on the cell bodies or dendrites of striosomal neurons. These receptors provide an additional anatomical substrate to explain the psychedelic action of indoleamine (LSD) and phenylethylamine (DOI, DOM) drugs.
先前的放射自显影研究表明，5-羟色胺5-HT2受体在人类纹状体中呈均匀分布。虽然这些研究是使用拮抗剂放射性配体如[3H]酮色林进行的，但我们在此描述了使用[3H]麦角酸二乙酰胺（LSD）和[125I] DOI作为配体时，人类纹状体中5-HT2结合位点的异质性分布。除了具有激动剂特性外，这些化合物还属于迷幻药家族。它们的结合位点在背侧纹状体中的定位与纹状体小体非常相似，这可通过乙酰胆碱酯酶组织化学或[3H]氟硝西泮标记观察到。这种异质性分布似乎是人类和豚鼠大脑的一个特点，因为在猴子、猫、猪和牛的大脑中未发现。在大鼠纹状体中，可见微弱的斑块状分布，但与5-HT1C结合位点相对应。纹状体小体上[125I] DOI结合位点的密度存在很大差异，这既不能与年龄、性别和死后延迟等参数相关联，也不能与神经退行性疾病的影响相关联，但亨廷顿病晚期除外。纹状体小体中[125I] DOI结合位点的药物结合谱与基质结合位点相同。它也与使用[3H]酮色林作为放射性配体报道的皮质5-HT2位点的药理学谱完全可比，只是激动剂对[125I] DOI结合位点显示出更高的亲和力。有趣的是，双相置换曲线对螺哌隆、西那色林和酮色林竞争的拟合效果更好。这种双相谱可能既不能由5-HT1C位点的存在来解释，也不能由多种亲和力状态的存在来解释。综上所述，这些数据表明，5-HT2受体的异质性群体存在于纹状体小体神经元的细胞体或树突上。这些受体为解释吲哚胺（LSD）和苯乙胺（DOI、DOM）药物的迷幻作用提供了额外的解剖学基础。
