Extrastriatal dopamine D2 receptors: Distribution, pharmacological characterization and region-specific regulation by clozapine

Aaron Janowsky, Kim Neve, John (Mark) Kinzie, B. Taylor, T. De Paulis, John Belknap

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Abstract

The distribution of dopamine D2 receptors in the rat brain was determined by quantitative autoradiography of the binding of [125I]epidepride and the effects of chronic drug administration on regulation of receptors in striatal and extrastriatal brain regions were characterized. [125I]Epidepride (2200 Ci/mmol) bound with high affinity to coronal tissue sections from the rat brain (K(d) = 78 pM), and specific binding was detected in a number of discrete layers, nuclei or regions of the hippocampus, thalamus, cerebellum and other extrastriatal sites. Pharmacological analysis of radioligand binding to hippocampal and cerebellar membranes indicated binding to dopamine D2 receptors, and approximately 10% of the binding appeared to represent low affinity idazoxan-displaceable binding to alpha-2 adrenoceptors. The binding to extrastriatal regions resembled previously reported radioligand binding to dopamine D2 receptors in striatal and cortical membranes. Chronic (14 day) administration of two dopamine D2 receptor antagonists, either the typical neuroleptic haloperidol (1.5 mg/kg i.p.) or the atypical neuroleptic clozapine (30 mg/kg i.p.), caused a significant increase in the density of [125I]epidepride binding sites in the medial prefrontal cortex and parietal cortex. Only haloperidol caused a significant increase in the density of [3H]spiperone and [125I]epidepride binding sites in the striatum and a slight increase in [125I]epidepride binding sites in the hippocampus. Similar administration of amphetamine (5 mg/kg i.p.) had no significant effect on the density of dopamine D2 receptors in any brain region examined. In addition, no drug-induced changes in the characteristics of dopamine D2 receptors in discrete areas of the cerebellum were observed. The data indicate that clozapine exerts a regionally specific effect on dopamine D2 receptors, and these changes may play a role in its therapeutic profile. In addition, [125I]epidepride appears to be relatively selective, and one of the most potent radioactive ligands available for characterizing changes in the regulation of dopamine D2 receptors in brain regions that contain a very low density of binding sites.

Original languageEnglish (US)
Pages (from-to)1282-1290
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume261
Issue number3
StatePublished - 1992
Externally publishedYes

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Dopamine D2 Receptors
Clozapine
Pharmacology
Binding Sites
Brain
Corpus Striatum
Haloperidol
Cerebellum
Antipsychotic Agents
Hippocampus
Idazoxan
Spiperone
Parietal Lobe
Membranes
Amphetamine
Prefrontal Cortex
Autoradiography
Thalamus
Pharmaceutical Preparations
Adrenergic Receptors

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{2097f179216042c2b631a41bbb12bd64,
title = "Extrastriatal dopamine D2 receptors: Distribution, pharmacological characterization and region-specific regulation by clozapine",
abstract = "The distribution of dopamine D2 receptors in the rat brain was determined by quantitative autoradiography of the binding of [125I]epidepride and the effects of chronic drug administration on regulation of receptors in striatal and extrastriatal brain regions were characterized. [125I]Epidepride (2200 Ci/mmol) bound with high affinity to coronal tissue sections from the rat brain (K(d) = 78 pM), and specific binding was detected in a number of discrete layers, nuclei or regions of the hippocampus, thalamus, cerebellum and other extrastriatal sites. Pharmacological analysis of radioligand binding to hippocampal and cerebellar membranes indicated binding to dopamine D2 receptors, and approximately 10{\%} of the binding appeared to represent low affinity idazoxan-displaceable binding to alpha-2 adrenoceptors. The binding to extrastriatal regions resembled previously reported radioligand binding to dopamine D2 receptors in striatal and cortical membranes. Chronic (14 day) administration of two dopamine D2 receptor antagonists, either the typical neuroleptic haloperidol (1.5 mg/kg i.p.) or the atypical neuroleptic clozapine (30 mg/kg i.p.), caused a significant increase in the density of [125I]epidepride binding sites in the medial prefrontal cortex and parietal cortex. Only haloperidol caused a significant increase in the density of [3H]spiperone and [125I]epidepride binding sites in the striatum and a slight increase in [125I]epidepride binding sites in the hippocampus. Similar administration of amphetamine (5 mg/kg i.p.) had no significant effect on the density of dopamine D2 receptors in any brain region examined. In addition, no drug-induced changes in the characteristics of dopamine D2 receptors in discrete areas of the cerebellum were observed. The data indicate that clozapine exerts a regionally specific effect on dopamine D2 receptors, and these changes may play a role in its therapeutic profile. In addition, [125I]epidepride appears to be relatively selective, and one of the most potent radioactive ligands available for characterizing changes in the regulation of dopamine D2 receptors in brain regions that contain a very low density of binding sites.",
author = "Aaron Janowsky and Kim Neve and Kinzie, {John (Mark)} and B. Taylor and {De Paulis}, T. and John Belknap",
year = "1992",
language = "English (US)",
volume = "261",
pages = "1282--1290",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
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TY - JOUR

T1 - Extrastriatal dopamine D2 receptors

T2 - Distribution, pharmacological characterization and region-specific regulation by clozapine

AU - Janowsky, Aaron

AU - Neve, Kim

AU - Kinzie, John (Mark)

AU - Taylor, B.

AU - De Paulis, T.

AU - Belknap, John

PY - 1992

Y1 - 1992

N2 - The distribution of dopamine D2 receptors in the rat brain was determined by quantitative autoradiography of the binding of [125I]epidepride and the effects of chronic drug administration on regulation of receptors in striatal and extrastriatal brain regions were characterized. [125I]Epidepride (2200 Ci/mmol) bound with high affinity to coronal tissue sections from the rat brain (K(d) = 78 pM), and specific binding was detected in a number of discrete layers, nuclei or regions of the hippocampus, thalamus, cerebellum and other extrastriatal sites. Pharmacological analysis of radioligand binding to hippocampal and cerebellar membranes indicated binding to dopamine D2 receptors, and approximately 10% of the binding appeared to represent low affinity idazoxan-displaceable binding to alpha-2 adrenoceptors. The binding to extrastriatal regions resembled previously reported radioligand binding to dopamine D2 receptors in striatal and cortical membranes. Chronic (14 day) administration of two dopamine D2 receptor antagonists, either the typical neuroleptic haloperidol (1.5 mg/kg i.p.) or the atypical neuroleptic clozapine (30 mg/kg i.p.), caused a significant increase in the density of [125I]epidepride binding sites in the medial prefrontal cortex and parietal cortex. Only haloperidol caused a significant increase in the density of [3H]spiperone and [125I]epidepride binding sites in the striatum and a slight increase in [125I]epidepride binding sites in the hippocampus. Similar administration of amphetamine (5 mg/kg i.p.) had no significant effect on the density of dopamine D2 receptors in any brain region examined. In addition, no drug-induced changes in the characteristics of dopamine D2 receptors in discrete areas of the cerebellum were observed. The data indicate that clozapine exerts a regionally specific effect on dopamine D2 receptors, and these changes may play a role in its therapeutic profile. In addition, [125I]epidepride appears to be relatively selective, and one of the most potent radioactive ligands available for characterizing changes in the regulation of dopamine D2 receptors in brain regions that contain a very low density of binding sites.

AB - The distribution of dopamine D2 receptors in the rat brain was determined by quantitative autoradiography of the binding of [125I]epidepride and the effects of chronic drug administration on regulation of receptors in striatal and extrastriatal brain regions were characterized. [125I]Epidepride (2200 Ci/mmol) bound with high affinity to coronal tissue sections from the rat brain (K(d) = 78 pM), and specific binding was detected in a number of discrete layers, nuclei or regions of the hippocampus, thalamus, cerebellum and other extrastriatal sites. Pharmacological analysis of radioligand binding to hippocampal and cerebellar membranes indicated binding to dopamine D2 receptors, and approximately 10% of the binding appeared to represent low affinity idazoxan-displaceable binding to alpha-2 adrenoceptors. The binding to extrastriatal regions resembled previously reported radioligand binding to dopamine D2 receptors in striatal and cortical membranes. Chronic (14 day) administration of two dopamine D2 receptor antagonists, either the typical neuroleptic haloperidol (1.5 mg/kg i.p.) or the atypical neuroleptic clozapine (30 mg/kg i.p.), caused a significant increase in the density of [125I]epidepride binding sites in the medial prefrontal cortex and parietal cortex. Only haloperidol caused a significant increase in the density of [3H]spiperone and [125I]epidepride binding sites in the striatum and a slight increase in [125I]epidepride binding sites in the hippocampus. Similar administration of amphetamine (5 mg/kg i.p.) had no significant effect on the density of dopamine D2 receptors in any brain region examined. In addition, no drug-induced changes in the characteristics of dopamine D2 receptors in discrete areas of the cerebellum were observed. The data indicate that clozapine exerts a regionally specific effect on dopamine D2 receptors, and these changes may play a role in its therapeutic profile. In addition, [125I]epidepride appears to be relatively selective, and one of the most potent radioactive ligands available for characterizing changes in the regulation of dopamine D2 receptors in brain regions that contain a very low density of binding sites.

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