Abstract
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.
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|