Roth J E, Murray T F, Franklin P H
College of Pharmacy, Oregon State University, Corvallis, USA.
J Pharmacol Exp Ther. 1996 Jun;277(3):1823-36.
The pharmacologic specificity and anatomic distribution of [3H]dextrorphan recognition sites in the rat brain was characterized by quantitative autoradiography. Equilibrium saturation analysis indicated that [3H]dextrorphan labeled a single population of high affinity binding sites. These sites are heterogeneously distributed throughout rat forebrain with the following order of binding densities: hippocampal formation > cerebral cortex > thalamic nuclei > striatum. The association rate of [3H]dextrorphan with its binding site in area stratum radiatum of CA1 is accelerated by the addition of glycine and glutamate. [3H]Dextrorphan binding is, however, relatively insensitive to glycine and glutamate under equilibrium conditions, despite extensive prewashing procedures to deplete endogenous levels of these substances. The competitive N-methyl-D-aspartate (NMDA) antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) and the glycine site antagonist 7-chlorokynurenic acid completely inhibit specific [3H]dextrorphan binding. D-AP5 suppresses [3H]dextrorphan binding in a regionally distinctive manner; a population of binding sites is weakly inhibited by D-AP5 in the lateral thalamic regions, whereas D-AP5 potently inhibits [3H]dextrorphan binding in the cerebral cortex. The rank order of potencies of an array of noncompetitive antagonists to inhibit [3H]dextrorphan binding unambiguously displays the pharmacologic profile of the noncompetitive antagonist domain of the NMDA receptor-channel complex. Furthermore, the distribution of [3H]dextrorphan binding sites in slide-mounted tissue appears qualitatively similar to the distribution of NMDA receptors previously reported using NMDA-displacement of [3H]glutamate, 3H-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne (MK-801) and [3H]1-[1-(2-thienyl)cyclohexyl]-piperidine (TCP) in most brain areas examined except the cerebellum. The molecular layer of the cerebellum displays a particularly high density of [3H]dextrorphan binding sites. The regional distribution of [3H]dextrorphan binding sites in rat brain does not correspond to the reported distributions of [3H]dextromethorphan or sigma binding sites.
通过定量放射自显影法对大鼠脑中[3H]右啡烷识别位点的药理特异性和解剖分布进行了表征。平衡饱和分析表明，[3H]右啡烷标记了单一群体的高亲和力结合位点。这些位点在大鼠前脑各处呈异质性分布，结合密度顺序如下：海马结构＞大脑皮层＞丘脑核＞纹状体。在CA1区辐射层中，加入甘氨酸和谷氨酸可加速[3H]右啡烷与其结合位点的结合速率。然而，尽管进行了广泛的预洗涤程序以耗尽这些物质的内源性水平，但在平衡条件下，[3H]右啡烷结合对甘氨酸和谷氨酸相对不敏感。竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂D-（-）-2-氨基-5-膦酰基戊酸（D-AP5）和甘氨酸位点拮抗剂7-氯犬尿氨酸完全抑制特异性[3H]右啡烷结合。D-AP5以区域特异性方式抑制[3H]右啡烷结合；在外侧丘脑区域，一群结合位点被D-AP5弱抑制，而D-AP5在大脑皮层中有效抑制[3H]右啡烷结合。一系列非竞争性拮抗剂抑制[3H]右啡烷结合的效价顺序明确显示了NMDA受体-通道复合物非竞争性拮抗剂结构域的药理特征。此外，在玻片固定组织中[3H]右啡烷结合位点的分布在质量上似乎与先前使用[3H]谷氨酸、[3H]（+）-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺（MK-801）和[3H]1-[1-（2-噻吩基）环己基]-哌啶（TCP）的NMDA置换法报道的NMDA受体分布相似，但在除小脑外的大多数脑区中有所不同。小脑分子层显示出特别高的[3H]右啡烷结合位点密度。大鼠脑中[3H]右啡烷结合位点的区域分布与报道的[3H]右美沙芬或σ结合位点分布不一致。
