Regional distribution and characterization of [3H]dextrorphan binding sites in rat brain determined by quantitative autoradiography

Jane E. Roth, Thomas F. Murray, Paul H. Franklin

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14 Citations (Scopus)

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-imine (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 σ binding sites.

Original languageEnglish
Pages (from-to)1823-1836
Number of pages14
JournalJournal of Pharmacology and Experimental Therapeutics
Volume277
Issue number3
StatePublished - Jun 1996
Externally publishedYes

Fingerprint

Dextrorphan
Autoradiography
Binding Sites
Brain
Glycine
Glutamic Acid
tenocyclidine
N-Methylaspartate
N-Methyl-D-Aspartate Receptors
Cerebral Cortex
Cerebellum
Dextromethorphan
2-Amino-5-phosphonovalerate
Hippocampal CA1 Region
Thalamic Nuclei
Imines
Dizocilpine Maleate
Prosencephalon
Population
Hippocampus

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

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title = "Regional distribution and characterization of [3H]dextrorphan binding sites in rat brain determined by quantitative autoradiography",
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-imine (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 σ binding sites.",
author = "Roth, {Jane E.} and Murray, {Thomas F.} and Franklin, {Paul H.}",
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TY - JOUR

T1 - Regional distribution and characterization of [3H]dextrorphan binding sites in rat brain determined by quantitative autoradiography

AU - Roth, Jane E.

AU - Murray, Thomas F.

AU - Franklin, Paul H.

PY - 1996/6

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N2 - 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-imine (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 σ binding sites.

AB - 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-imine (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 σ binding sites.

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