Effects of bilateral ibotenate-induced lesions of the nucleus basalis magnocellularis upon selective cholinergic biochemical markers in the rat anterior cerebral cortex

Mark Watson, Thomas W. Vickroy, Hans C. Fibiger, William R Roeske, Henry I. Yamamura

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

The relationship of choline acetyltransferase (ChAT) activity and high affinity binding of the potent and selective sodium-dependent choline uptake inhibitor [3H]hemicholinium-3 ([3H]HC-3) to high-affinity binding of the muscarinic agonist [3H](+)-cis-methyl-dioxolane ([3H](+)CD), the putative M1 selective antagonist [3H]pirenzepine ([3H]PZ) and the classical antagonist [3H](-)-quinuclidinyl benzilate ([3H](-)QNB) in homogenates of the rat neocortex was studied. ChAT activity was 42% lower in rats with ibotenate-induced lesions of the nucleus basalis magnocellularis (nbm) when compared to controls, and [3H]HC-3 binding was similarly reduced by 44%. However, equilibrium dissociation constants (Kd values) for [3H]HC-3 (0.8-1.0 nM), [3H](-)QNB (11-24 pM), [3H]PZ (4.0-4.3 nM) and [3H](+)CD (2.1-2.9 nM) were each unchanged. Mean Bmax values (total binding site densities) for [3H](+)CD were significantly altered in both hemispheres of the anterior cerebral cortex, showing a 25% reduction in the number of sites which display the highest affinity conformation for this potent muscarinic agonist. The decreased ChAT activity and [3H]HC-3 binding after nbm lesions were associated with only slight reductions in putative M1 muscarinic site density (14%) and [3H](-)QNB binding site density (13%). Thus, it appears that while [3H]PZ and [3H](-)QNB label predominantly postsynaptic muscarinic binding sites, a significant number of sites labeled by [3H](+)CD may be associated with presynaptic cholinergic nerve terminals. These data suggest that cholinergic input differentially regulates the drug binding sites of anterior cerebral cortical muscarinic receptors, exerting a substantial effect upon the highest affinity conformational state for agonists.

Original languageEnglish (US)
Pages (from-to)387-391
Number of pages5
JournalBrain Research
Volume346
Issue number2
DOIs
StatePublished - Nov 4 1985

Fingerprint

Basal Nucleus of Meynert
Cerebral Cortex
Cholinergic Agents
Choline O-Acetyltransferase
Biomarkers
Binding Sites
Muscarinic Agonists
Hemicholinium 3
Quinuclidinyl Benzilate
Pirenzepine
Neocortex
Muscarinic Receptors
Choline
Sodium
Pharmaceutical Preparations

Keywords

  • choline acetyltransferase
  • cholinergic
  • hemicholinium-3
  • high-affinity choline uptake
  • muscarinic receptor
  • nucleus basalis magnocellularis

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology
  • Clinical Neurology
  • Neuroscience(all)

Cite this

Effects of bilateral ibotenate-induced lesions of the nucleus basalis magnocellularis upon selective cholinergic biochemical markers in the rat anterior cerebral cortex. / Watson, Mark; Vickroy, Thomas W.; Fibiger, Hans C.; Roeske, William R; Yamamura, Henry I.

In: Brain Research, Vol. 346, No. 2, 04.11.1985, p. 387-391.

Research output: Contribution to journalArticle

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abstract = "The relationship of choline acetyltransferase (ChAT) activity and high affinity binding of the potent and selective sodium-dependent choline uptake inhibitor [3H]hemicholinium-3 ([3H]HC-3) to high-affinity binding of the muscarinic agonist [3H](+)-cis-methyl-dioxolane ([3H](+)CD), the putative M1 selective antagonist [3H]pirenzepine ([3H]PZ) and the classical antagonist [3H](-)-quinuclidinyl benzilate ([3H](-)QNB) in homogenates of the rat neocortex was studied. ChAT activity was 42{\%} lower in rats with ibotenate-induced lesions of the nucleus basalis magnocellularis (nbm) when compared to controls, and [3H]HC-3 binding was similarly reduced by 44{\%}. However, equilibrium dissociation constants (Kd values) for [3H]HC-3 (0.8-1.0 nM), [3H](-)QNB (11-24 pM), [3H]PZ (4.0-4.3 nM) and [3H](+)CD (2.1-2.9 nM) were each unchanged. Mean Bmax values (total binding site densities) for [3H](+)CD were significantly altered in both hemispheres of the anterior cerebral cortex, showing a 25{\%} reduction in the number of sites which display the highest affinity conformation for this potent muscarinic agonist. The decreased ChAT activity and [3H]HC-3 binding after nbm lesions were associated with only slight reductions in putative M1 muscarinic site density (14{\%}) and [3H](-)QNB binding site density (13{\%}). Thus, it appears that while [3H]PZ and [3H](-)QNB label predominantly postsynaptic muscarinic binding sites, a significant number of sites labeled by [3H](+)CD may be associated with presynaptic cholinergic nerve terminals. These data suggest that cholinergic input differentially regulates the drug binding sites of anterior cerebral cortical muscarinic receptors, exerting a substantial effect upon the highest affinity conformational state for agonists.",
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AU - Yamamura, Henry I.

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N2 - The relationship of choline acetyltransferase (ChAT) activity and high affinity binding of the potent and selective sodium-dependent choline uptake inhibitor [3H]hemicholinium-3 ([3H]HC-3) to high-affinity binding of the muscarinic agonist [3H](+)-cis-methyl-dioxolane ([3H](+)CD), the putative M1 selective antagonist [3H]pirenzepine ([3H]PZ) and the classical antagonist [3H](-)-quinuclidinyl benzilate ([3H](-)QNB) in homogenates of the rat neocortex was studied. ChAT activity was 42% lower in rats with ibotenate-induced lesions of the nucleus basalis magnocellularis (nbm) when compared to controls, and [3H]HC-3 binding was similarly reduced by 44%. However, equilibrium dissociation constants (Kd values) for [3H]HC-3 (0.8-1.0 nM), [3H](-)QNB (11-24 pM), [3H]PZ (4.0-4.3 nM) and [3H](+)CD (2.1-2.9 nM) were each unchanged. Mean Bmax values (total binding site densities) for [3H](+)CD were significantly altered in both hemispheres of the anterior cerebral cortex, showing a 25% reduction in the number of sites which display the highest affinity conformation for this potent muscarinic agonist. The decreased ChAT activity and [3H]HC-3 binding after nbm lesions were associated with only slight reductions in putative M1 muscarinic site density (14%) and [3H](-)QNB binding site density (13%). Thus, it appears that while [3H]PZ and [3H](-)QNB label predominantly postsynaptic muscarinic binding sites, a significant number of sites labeled by [3H](+)CD may be associated with presynaptic cholinergic nerve terminals. These data suggest that cholinergic input differentially regulates the drug binding sites of anterior cerebral cortical muscarinic receptors, exerting a substantial effect upon the highest affinity conformational state for agonists.

AB - The relationship of choline acetyltransferase (ChAT) activity and high affinity binding of the potent and selective sodium-dependent choline uptake inhibitor [3H]hemicholinium-3 ([3H]HC-3) to high-affinity binding of the muscarinic agonist [3H](+)-cis-methyl-dioxolane ([3H](+)CD), the putative M1 selective antagonist [3H]pirenzepine ([3H]PZ) and the classical antagonist [3H](-)-quinuclidinyl benzilate ([3H](-)QNB) in homogenates of the rat neocortex was studied. ChAT activity was 42% lower in rats with ibotenate-induced lesions of the nucleus basalis magnocellularis (nbm) when compared to controls, and [3H]HC-3 binding was similarly reduced by 44%. However, equilibrium dissociation constants (Kd values) for [3H]HC-3 (0.8-1.0 nM), [3H](-)QNB (11-24 pM), [3H]PZ (4.0-4.3 nM) and [3H](+)CD (2.1-2.9 nM) were each unchanged. Mean Bmax values (total binding site densities) for [3H](+)CD were significantly altered in both hemispheres of the anterior cerebral cortex, showing a 25% reduction in the number of sites which display the highest affinity conformation for this potent muscarinic agonist. The decreased ChAT activity and [3H]HC-3 binding after nbm lesions were associated with only slight reductions in putative M1 muscarinic site density (14%) and [3H](-)QNB binding site density (13%). Thus, it appears that while [3H]PZ and [3H](-)QNB label predominantly postsynaptic muscarinic binding sites, a significant number of sites labeled by [3H](+)CD may be associated with presynaptic cholinergic nerve terminals. These data suggest that cholinergic input differentially regulates the drug binding sites of anterior cerebral cortical muscarinic receptors, exerting a substantial effect upon the highest affinity conformational state for agonists.

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