Murray A M, Hyde T M, Knable M B, Herman M M, Bigelow L B, Carter J M, Weinberger D R, Kleinman J E
National Institute of Mental Health, Clinical Brain Disorders Branch, St. Elizabeths Hospital, Washington, D.C. 20032.
J Neurosci. 1995 Mar;15(3 Pt 2):2186-91. doi: 10.1523/JNEUROSCI.15-03-02186.1995.
The identification of five dopamine receptor subtypes has given the dopamine hypothesis of schizophrenia new life. The D4 receptor is particularly intriguing because it binds clozapine with high affinity. Putative D4 receptors were labeled in postmortem human brain by subtracting the binding of a saturating concentration of 3H-raclopride (6 nM, which labels D2 and D3 receptors) from that labeled by a saturating concentration of [3H]YM 09151-2 (1-1.3 nM, which labels D2, D3, and D4 receptors). In the control brain, putative D4 receptors show a homogenous distribution in striatum and nucleus accumbens. This is also true in schizophrenic brains, although the levels are significantly higher (twofold). These data are inconsistent with mRNA studies that have shown negligible amounts in striatum and accumbens, with modest amounts reported in most of cerebral cortex. These findings suggest that the putative D4 receptors are not synthesized in this region, but are presynaptically localized on striatal afferent terminals. Our findings confirm and extend the report of Seeman et al. (1993). Extension of these findings into the nucleus accumbens is important because of its extensive connections to the limbic system while the putamen is exclusively "motor" striatum.
五种多巴胺受体亚型的鉴定为精神分裂症的多巴胺假说注入了新的活力。D4受体尤其引人关注，因为它与氯氮平具有高亲和力。通过从饱和浓度的[3H]YM 09151-2（1-1.3 nM，标记D2、D3和D4受体）标记的结合量中减去饱和浓度的3H-雷氯必利（6 nM，标记D2和D3受体）的结合量，在死后人类大脑中标记出假定的D4受体。在对照大脑中，假定的D4受体在纹状体和伏隔核中呈均匀分布。在精神分裂症患者的大脑中也是如此，尽管其水平显著更高（两倍）。这些数据与mRNA研究结果不一致，mRNA研究表明纹状体和伏隔核中的含量可忽略不计，而大多数大脑皮层中的含量适中。这些发现表明，假定的D4受体并非在该区域合成，而是突触前定位在纹状体传入终末上。我们的发现证实并扩展了Seeman等人（1993年）的报告。将这些发现扩展到伏隔核很重要，因为它与边缘系统有广泛的联系，而壳核则完全是“运动”纹状体。
