Possible relationship between glial cells, dopamine and the effects of antipsychotic drugs

Henn, F. A., Anderson, D. J., Sellstrom, A. (April 1977) Possible relationship between glial cells, dopamine and the effects of antipsychotic drugs. Nature, 266 (5603). pp. 637-8. ISSN 0028-0836 (Print)0028-0836

URL: http://www.ncbi.nlm.nih.gov/pubmed/859629
DOI: 10.1038/266637a0

Abstract

THE hypothesis that a functional excess of dopamine underlies many of the abnormalities seen in schizophrenia is receiving much attention. The supporting evidence is principally pharmacological. There is a correlation between antipsychotic drug action and the ability of a neuroleptic drug to block dopaminergic transmission1–3. The exact site of antipsychotic drug activity is not known and evidence for the presynaptic inhibition of dopamine release4, as well as the blockade of postsynaptic receptors5,6 has been presented to explain neuroleptic drug action. Studies of binding properties of the dopamine receptor, however, provide a coherent explanation of neuroleptic drug action. Butyrophenones, phenothiazines, thioxanines and diphenyl-butylpiperadines inhibit 3H-haloperidol binding to a central nervous system (CNS) membrane fraction in exactly the order of their clinical potency7–10: the inhibition occurs at drug concentrations similar to those expected in the CNS of patients taking these drugs. These results with 3H-haloperidol, a dopamine antagonist, are used to argue that neuroleptics bind to postsynaptic dopamine receptors, and are effective by decreasing the activity of pathways using dopamine as their neurotransmitter. On the other hand, dopamine-sensitive adenylate cyclase is associated with the postsynaptic receptors5,11, yet the inhibition of this enzyme by neuroleptic butyrophenones does not correlate with in vivo or clinical potency. The difference between butyrophenone inhibition of 3H-haloperidol binding and inhibition of adenylate cyclase has been attributed to “variable degrees of coupling of dopamine receptor sites with the adenylate cyclase”9. Alternatively, there could be several dopamine sensitive adenylate cyclases with differing binding affinities and localisations : this is suggested by the presence of this enzyme in several tissue culture lines of glia12. Lesion studies show that the enzyme is not localised presynaptically in the caudate nucleus13 or in the substantia nigra14. The only defined dopaminergic receptors in the substantia nigra are localised on dopaminergic neurones15, and the elimination of these cells as the site of the enzyme was established by unilateral injections of 6-hydroxydopamine which removed these cells14. It therefore seems necessary to define more exactly the site of the dopamine binding receptor and the dopamine-stimulated adenylate cyclase. We report here that a large proportion of CNS dopamine haloperidol binding sites seem to be present on glial membranes and may be associated with an adenylate cyclase localised on these membranes.

Item Type: Paper
Uncontrolled Keywords: Adenylate Cyclase/metabolism Animals Astrocytes/metabolism Cattle Caudate Nucleus/metabolism Cerebral Cortex/metabolism Dopamine/*metabolism Enzyme Activation Glutamate Decarboxylase/metabolism Haloperidol/*metabolism Neuroglia/enzymology/*metabolism Rabbits Receptors, Dopamine/*metabolism Synaptosomes/metabolism Tranquilizing Agents/*pharmacology
Subjects: diseases & disorders > mental disorders > schizophrenia
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > dopaminergic neuron
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > dopaminergic neuron
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > dopaminergic neuron
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons > dopaminergic neuron
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons > dopaminergic neuron
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons > dopaminergic neuron

organs, tissues, organelles, cell types and functions > cell types and functions > cell types > glia cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > glia cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > glia cells
CSHL Authors:
Communities: CSHL labs > Henn lab
Depositing User: Matt Covey
Date: 14 April 1977
Date Deposited: 09 Jul 2014 14:55
Last Modified: 09 Jul 2014 14:55
Related URLs:
URI: http://repository.cshl.edu/id/eprint/30209

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