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Quantitative autoradiographic characterization of the binding of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine ([3H]MK-801) in rat brain: regional effects of polyamines.
J Pharmacol Exp Ther. 1991 Feb; 256(2):811-9.JP

Abstract

The distribution and properties of N-methyl-D-aspartate (NMDA) receptors, labeled with [3H](+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5 5,10-imine (MK-801), were examined in rat brain. In sections of brain mash, the kinetics of association and dissociation of [3H]MK-801 were monophasic in the presence of 100 microM glutamate and glycine, and Scatchard transformations of saturation isotherms resulted in linear plots. Inhibition of the binding of [3H]MK-801 by other noncompetitive antagonists produced competition curves with Hill coefficients close to 1.0, consistent with a simple bimolecular interaction between the radioligand and the receptor. Scatchard plots based upon densitometric measurements of [3H]MK-801 binding in serial sections of rat brain were also linear, with dissociation constant values ranging from 5.0 to 8.4 nM in different regions at the level of the hippocampus. The distribution of [3H]MK-801 binding sites paralleled the distribution of NMDA displaceable L-[3H]glutamate binding sites. One exception was the cerebellar granule cell layer, where the density of binding sites for [3H]MK-801 was extremely low. The relative density of [3H]MK-801 to NMDA displaceable L-[3H]glutamate binding sites was approximately 1 to 2, consistent with the existence of two transmitter recognition sites per NMDA receptor. The modulatory effects of polyamines on [3H]MK-801 binding were studied in washed brain sections. The polyamine agonists spermine and spermidine enhanced [3H]MK-801 binding in all regions studied, with increases ranging from 18% in the thalamus to 106% in the ventromedial striatum. The effects of spermine and spermidine in these regions were highly correlated. Diethylenetriamine, which blocks the effects of spermidine, by itself produced decreases in the binding of [3H]MK-801 in most regions ranging from 5 to 21% but increased binding in parts of the striatum by 3 to 22%. The decrease in binding produced by diethylenetriamine in different brain regions was negatively correlated with the increase in binding produced by the agonists, suggesting that variability in the residual concentration of endogenous polyamines contributes to the regional variability of agonist effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors+Show Affiliations

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

1671602

Citation

Subramaniam, S, and P McGonigle. "Quantitative Autoradiographic Characterization of the Binding of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine ([3H]MK-801) in Rat Brain: Regional Effects of Polyamines." The Journal of Pharmacology and Experimental Therapeutics, vol. 256, no. 2, 1991, pp. 811-9.
Subramaniam S, McGonigle P. Quantitative autoradiographic characterization of the binding of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine ([3H]MK-801) in rat brain: regional effects of polyamines. J Pharmacol Exp Ther. 1991;256(2):811-9.
Subramaniam, S., & McGonigle, P. (1991). Quantitative autoradiographic characterization of the binding of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine ([3H]MK-801) in rat brain: regional effects of polyamines. The Journal of Pharmacology and Experimental Therapeutics, 256(2), 811-9.
Subramaniam S, McGonigle P. Quantitative Autoradiographic Characterization of the Binding of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine ([3H]MK-801) in Rat Brain: Regional Effects of Polyamines. J Pharmacol Exp Ther. 1991;256(2):811-9. PubMed PMID: 1671602.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Quantitative autoradiographic characterization of the binding of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine ([3H]MK-801) in rat brain: regional effects of polyamines. AU - Subramaniam,S, AU - McGonigle,P, PY - 1991/2/1/pubmed PY - 1991/2/1/medline PY - 1991/2/1/entrez SP - 811 EP - 9 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 256 IS - 2 N2 - The distribution and properties of N-methyl-D-aspartate (NMDA) receptors, labeled with [3H](+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5 5,10-imine (MK-801), were examined in rat brain. In sections of brain mash, the kinetics of association and dissociation of [3H]MK-801 were monophasic in the presence of 100 microM glutamate and glycine, and Scatchard transformations of saturation isotherms resulted in linear plots. Inhibition of the binding of [3H]MK-801 by other noncompetitive antagonists produced competition curves with Hill coefficients close to 1.0, consistent with a simple bimolecular interaction between the radioligand and the receptor. Scatchard plots based upon densitometric measurements of [3H]MK-801 binding in serial sections of rat brain were also linear, with dissociation constant values ranging from 5.0 to 8.4 nM in different regions at the level of the hippocampus. The distribution of [3H]MK-801 binding sites paralleled the distribution of NMDA displaceable L-[3H]glutamate binding sites. One exception was the cerebellar granule cell layer, where the density of binding sites for [3H]MK-801 was extremely low. The relative density of [3H]MK-801 to NMDA displaceable L-[3H]glutamate binding sites was approximately 1 to 2, consistent with the existence of two transmitter recognition sites per NMDA receptor. The modulatory effects of polyamines on [3H]MK-801 binding were studied in washed brain sections. The polyamine agonists spermine and spermidine enhanced [3H]MK-801 binding in all regions studied, with increases ranging from 18% in the thalamus to 106% in the ventromedial striatum. The effects of spermine and spermidine in these regions were highly correlated. Diethylenetriamine, which blocks the effects of spermidine, by itself produced decreases in the binding of [3H]MK-801 in most regions ranging from 5 to 21% but increased binding in parts of the striatum by 3 to 22%. The decrease in binding produced by diethylenetriamine in different brain regions was negatively correlated with the increase in binding produced by the agonists, suggesting that variability in the residual concentration of endogenous polyamines contributes to the regional variability of agonist effects.(ABSTRACT TRUNCATED AT 250 WORDS) SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/1671602/Quantitative_autoradiographic_characterization_of_the_binding_of__+__5_methyl_1011_dihydro_5H_dibenzo[ad]cyclohepten_5_10_imine__[3H]MK_801__in_rat_brain:_regional_effects_of_polyamines_ DB - PRIME DP - Unbound Medicine ER -