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Molecular Pharmacology

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Research ArticleArticle

In Vivo Evidence for Dopamine-Mediated Internalization of D2-Receptors after Amphetamine: Differential Findings with [3H]Raclopride versus [3H]Spiperone

W. Sun, N. Ginovart, F. Ko, P. Seeman and S. Kapur
Molecular Pharmacology February 2003, 63 (2) 456-462; DOI: https://doi.org/10.1124/mol.63.2.456
W. Sun
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N. Ginovart
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F. Ko
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P. Seeman
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S. Kapur
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Abstract

Competition with endogenous dopamine (DA) is usually invoked to explain changes in [11C]raclopride binding observed after amphetamine administration in animals and humans. This account has recently been questioned because a number of inconsistencies have been reported that contradict it. In the present study, we investigated whether the decrease in [3H]raclopride binding observed in the rat striatum after an amphetamine challenge reflects true competition with endogenous DA or agonist-mediated internalization of D2-receptors. We found that the amphetamine-induced decrease in [3H]raclopride binding is caused by a decrease in D2-receptor density (Bmax) with no change in affinity (Kd). In contrast, in the same tissue, neither the Bmax nor theKd were affected when measured with [3H]spiperone. Challenge with amphetamine not only decreased the number of D2-receptors but also eliminated the proportion (22%) of receptors usually in the high-affinity state. The addition of Gpp(NH)p had no effect onBmax, suggesting that these receptors were not just noncompetitively bound with dopamine at the cell-surface. Subcellular fractionation studies showed that amphetamine treatment led to a decrease in radioligand binding in the cell-surface fraction for both [3H]raclopride and [3H]spiperone; however, in the case of [3H]spiperone, this was accompanied by a compensatory increase in binding in the intracellular compartment, whereas no increase was seen with [3H]raclopride. These data suggest that amphetamine releases dopamine, which binds to the high-affinity state of the D2-receptor, leading to its sequestration in some intracellular compartment; in this compartment, sequestered receptors are inaccessible to [3H]raclopride binding but can still be bound by [3H]spiperone.

Footnotes

  • This study was supported by a grant from the Canadian Institutes of Health Research.

  • Abbreviations:
    PET
    positron emission tomography
    SPECT
    single photon emission computed tomography
    DA
    dopamine
    IBZM
    iodobenzamide
    NMSP
    N-methyl-spiperone
    GPP(NH)p
    5′-guanylylimidodiphosphate
    • Received July 11, 2002.
    • Accepted November 6, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (2)
Molecular Pharmacology
Vol. 63, Issue 2
1 Feb 2003
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Research ArticleArticle

In Vivo Evidence for Dopamine-Mediated Internalization of D2-Receptors after Amphetamine: Differential Findings with [3H]Raclopride versus [3H]Spiperone

W. Sun, N. Ginovart, F. Ko, P. Seeman and S. Kapur
Molecular Pharmacology February 1, 2003, 63 (2) 456-462; DOI: https://doi.org/10.1124/mol.63.2.456

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Research ArticleArticle

In Vivo Evidence for Dopamine-Mediated Internalization of D2-Receptors after Amphetamine: Differential Findings with [3H]Raclopride versus [3H]Spiperone

W. Sun, N. Ginovart, F. Ko, P. Seeman and S. Kapur
Molecular Pharmacology February 1, 2003, 63 (2) 456-462; DOI: https://doi.org/10.1124/mol.63.2.456
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