Inhibition of [3H]-(+)-MK 801 binding to rat brain sections by CPP and 7-chlorokynurenic acid: an autoradiographic analysis

Br J Pharmacol. 1993 Mar;108(3):577-82. doi: 10.1111/j.1476-5381.1993.tb12845.x.

Abstract

1. The regional binding of [3H]-(+)-5-methyl-10,11-dihydro-5H-dibenzo (a,d)cyclohepten-5,10-imine maleate ([3H]-(+)-MK 801) to sections of rat brain was measured by an in vitro quantitative autoradiographic technique. A heterogeneous distribution of binding sites was observed. 2. High values of binding were detected in the hippocampal formation and cerebral cortex, while very low binding was found in cerebellum. [3H]-(+)-MK 801 binding was not detectable in white matter tracts or in the brain stem. 3. [3H]-(+)-MK 801 binding was inhibited by increasing concentrations of both 7-chlorokynurenate (1-1000 microM) and ((+)-2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP) (0.1-100 microM). High concentrations of both drugs were able to inhibit completely specific [3H]-(+)-MK 801 binding. 4. IC50 values calculated for both 7-chlorokynurenate and CPP-induced [3H]-(+)-MK 801 binding inhibition were similar in all brain regions analyzed. 5. The inhibitory action of 7-chlorokynurenate and that of CPP on [3H]-(+)-MK 801 binding were reversed by addition of glycine and glutamate respectively. 6. It is concluded that activation of glycine and N-methyl-D-aspartate (NMDA) receptors is obligatory for the binding of [3H]-(+)-MK 801 to occur in all of the brain regions examined in the present study. Furthermore, on the basis of the similar regional sensitivities of [3H]-(+)-MK 801 binding to the inhibitory action of 7-chlorokynurenate and CPP, a single pharmacological classification of the NMDA receptor complex in brain is suggested. The cerebellum was not included in the study due to the very low level of [3H]-(+)-MK 801 binding detected under the experimental conditions used.

MeSH terms

  • Animals
  • Autoradiography
  • Brain / anatomy & histology
  • Brain / drug effects
  • Brain / metabolism*
  • Cerebellum / drug effects
  • Cerebellum / metabolism
  • Dizocilpine Maleate / metabolism*
  • Glutamates / pharmacology
  • Glutamic Acid
  • Glycine / pharmacology
  • Image Processing, Computer-Assisted
  • In Vitro Techniques
  • Kynurenic Acid / analogs & derivatives*
  • Kynurenic Acid / pharmacology
  • Male
  • Piperazines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism

Substances

  • Glutamates
  • Piperazines
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • Dizocilpine Maleate
  • 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid
  • Kynurenic Acid
  • 7-chlorokynurenic acid
  • Glycine