Positron emission tomography of radioligand binding in porcine striatum in vivo

Haloperidol inhibition linked to endogenous ligand release

Koichi Ishizu, Donald F. Smith, Dirk Bender, Erik Danielsen, SØren B. Hansen, Dean Foster Wong, Paul Cumming, Albert Gjedde

Research output: Contribution to journalArticle

Abstract

The ligands N-methylspiperone and haloperidol both bind to D 2-1ike dopamine receptors. The competitive nature of the binding over a wide range of haloperidol concentrations and the effect on dopamine release have never been tested in vivo. We determined the competitive interaction between 3-N-[ 11C]methylspiperone ([ 11C]NMSP) and haloperidol binding to striatal dopamine D 2-1ike receptors with positron emission tomography (PET) of pig brain. [ 11C]NMSP tomography was performed with haloperidol at five different plasma concentrations maintained constant by programmed infusion. Kinetic parameters of ligand competition for binding in the striatum were determined by deconvolving time - activity curves of the striatum and cerebellum from metabolite-corrected arterial plasma [ 11C]NMSP and haloperidol concentrations. Two types of [ 11C]NMSP-binding sites were evident in the striatum, both saturable by haloperidol administration. The preponderant or primary sites bound [ 11C]NMSP irreversibly, as dopamine D2-1ike receptors, while the secondary sites bound [ 11C]NMSP reversibly, as do serotonin S2 receptors. Woolf-Hanes plots revealed the predicted approximately linear relationships between the binding indices and the haloperidol plasma concentration. For the irreversible binding sites, this relationship indicated a 50% inhibitory concentration of haloperidol of 2 nM in plasma and a maximum binding capacity of 64 pmol cm -3 in striatum. For the reversible binding sites, the relationship indicated a 50% inhibitory plasma concentration of haloperidol of 1 nM and a maximum binding capacity of 4.5 pmol cm -3. Second-order polynomial Eadie-Hofstee-Scatchard plots were consistent with increased competition from an endogenous ligand of the irreversibly binding sites only with increasing doses of haloperidol. At the highest haloperidol dose, this hypothetical endogenous ligand had risen 6-7-fold. We contend that this reveals the release of dopamine by high concentrations of haloperidol. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish (US)
Pages (from-to)87-101
Number of pages15
JournalSynapse
Volume38
Issue number1
DOIs
StatePublished - 2000

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Haloperidol
Positron-Emission Tomography
Swine
Ligands
Binding Sites
Dopamine
Inhibitory Concentration 50
Serotonin 5-HT2 Receptors
Corpus Striatum
Competitive Binding
Dopamine D2 Receptors
Dopamine Receptors
Cerebellum
Tomography

Keywords

  • 3-N-[ C]methylspiperone
  • Dopamine
  • Haloperidol
  • PET
  • Pig brain
  • Receptor binding

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology
  • Pharmacology

Cite this

Positron emission tomography of radioligand binding in porcine striatum in vivo : Haloperidol inhibition linked to endogenous ligand release. / Ishizu, Koichi; Smith, Donald F.; Bender, Dirk; Danielsen, Erik; Hansen, SØren B.; Wong, Dean Foster; Cumming, Paul; Gjedde, Albert.

In: Synapse, Vol. 38, No. 1, 2000, p. 87-101.

Research output: Contribution to journalArticle

Ishizu, Koichi ; Smith, Donald F. ; Bender, Dirk ; Danielsen, Erik ; Hansen, SØren B. ; Wong, Dean Foster ; Cumming, Paul ; Gjedde, Albert. / Positron emission tomography of radioligand binding in porcine striatum in vivo : Haloperidol inhibition linked to endogenous ligand release. In: Synapse. 2000 ; Vol. 38, No. 1. pp. 87-101.
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N2 - The ligands N-methylspiperone and haloperidol both bind to D 2-1ike dopamine receptors. The competitive nature of the binding over a wide range of haloperidol concentrations and the effect on dopamine release have never been tested in vivo. We determined the competitive interaction between 3-N-[ 11C]methylspiperone ([ 11C]NMSP) and haloperidol binding to striatal dopamine D 2-1ike receptors with positron emission tomography (PET) of pig brain. [ 11C]NMSP tomography was performed with haloperidol at five different plasma concentrations maintained constant by programmed infusion. Kinetic parameters of ligand competition for binding in the striatum were determined by deconvolving time - activity curves of the striatum and cerebellum from metabolite-corrected arterial plasma [ 11C]NMSP and haloperidol concentrations. Two types of [ 11C]NMSP-binding sites were evident in the striatum, both saturable by haloperidol administration. The preponderant or primary sites bound [ 11C]NMSP irreversibly, as dopamine D2-1ike receptors, while the secondary sites bound [ 11C]NMSP reversibly, as do serotonin S2 receptors. Woolf-Hanes plots revealed the predicted approximately linear relationships between the binding indices and the haloperidol plasma concentration. For the irreversible binding sites, this relationship indicated a 50% inhibitory concentration of haloperidol of 2 nM in plasma and a maximum binding capacity of 64 pmol cm -3 in striatum. For the reversible binding sites, the relationship indicated a 50% inhibitory plasma concentration of haloperidol of 1 nM and a maximum binding capacity of 4.5 pmol cm -3. Second-order polynomial Eadie-Hofstee-Scatchard plots were consistent with increased competition from an endogenous ligand of the irreversibly binding sites only with increasing doses of haloperidol. At the highest haloperidol dose, this hypothetical endogenous ligand had risen 6-7-fold. We contend that this reveals the release of dopamine by high concentrations of haloperidol. (C) 2000 Wiley-Liss, Inc.

AB - The ligands N-methylspiperone and haloperidol both bind to D 2-1ike dopamine receptors. The competitive nature of the binding over a wide range of haloperidol concentrations and the effect on dopamine release have never been tested in vivo. We determined the competitive interaction between 3-N-[ 11C]methylspiperone ([ 11C]NMSP) and haloperidol binding to striatal dopamine D 2-1ike receptors with positron emission tomography (PET) of pig brain. [ 11C]NMSP tomography was performed with haloperidol at five different plasma concentrations maintained constant by programmed infusion. Kinetic parameters of ligand competition for binding in the striatum were determined by deconvolving time - activity curves of the striatum and cerebellum from metabolite-corrected arterial plasma [ 11C]NMSP and haloperidol concentrations. Two types of [ 11C]NMSP-binding sites were evident in the striatum, both saturable by haloperidol administration. The preponderant or primary sites bound [ 11C]NMSP irreversibly, as dopamine D2-1ike receptors, while the secondary sites bound [ 11C]NMSP reversibly, as do serotonin S2 receptors. Woolf-Hanes plots revealed the predicted approximately linear relationships between the binding indices and the haloperidol plasma concentration. For the irreversible binding sites, this relationship indicated a 50% inhibitory concentration of haloperidol of 2 nM in plasma and a maximum binding capacity of 64 pmol cm -3 in striatum. For the reversible binding sites, the relationship indicated a 50% inhibitory plasma concentration of haloperidol of 1 nM and a maximum binding capacity of 4.5 pmol cm -3. Second-order polynomial Eadie-Hofstee-Scatchard plots were consistent with increased competition from an endogenous ligand of the irreversibly binding sites only with increasing doses of haloperidol. At the highest haloperidol dose, this hypothetical endogenous ligand had risen 6-7-fold. We contend that this reveals the release of dopamine by high concentrations of haloperidol. (C) 2000 Wiley-Liss, Inc.

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