The Dopamine Transporter Is Absent in Parkinsonian Putamen and Reduced in the Caudate Nucleus

Hyman B. Niznik, Evan F. Fogel, Frank F. Fassos, Philip Seeman

Research output: Contribution to journalArticle

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Abstract

Abstract: The neuronal dopamine transporter/uptake site can be covalently labeled with the photoaffinity probe 1‐(2‐[bis‐(4‐fluorophenyl)methoxy]ethyl)‐4‐[2‐(4‐azido‐3‐[125I]iodophenyl)ethyl]piperazine ([125I]FAPP) and visualized following sodium dodecyl sulfate polyacrylamide gel electrophoresis and autoradiography. Upon photolysis, [125I]FAPP specifically incorporated into a polypeptide of apparent Mr= 62,000 in membranes from both the putamen and the caudate nucleus of control, Alzheimer's, schizophrenia, and Huntington's diseased brain, and, following complete deglycosylation, migrated as an Mr∼48,000 polypeptide. In parkinsonian postmortem putamen, however, there was no detectable photoincorpqration of [125I]FAPP into the ligand binding subunit of the dopamine transporter. [125I]FAPP did specifically label the Mr 62,000 polypeptide of parkinsonian caudate, although with efficiencies of 20–50% of control. The asymmetrical loss of the dopamine transporter in Parkinson's diseased striatum was confirmed in reversible receptor binding experiments using [3H]GBR‐12935 {3H‐labeled 1‐[2‐(diphenylmethoxy)ethyl]‐4‐(3‐phenylpropyl)piperazine}. In parkinsonian putamen, mazindol competitively inhibited the binding of [3H]GBR‐12935 with an estimated affinity (Ki∼ 2,000 nM) 10 times lower than in controls (Ki∼ 30 nM), while the affinity of mazindol for [3H]GBR‐12935 binding in the caudate was equal to that seen with controls (Ki∼ 50 nM). The proportion of [3H]GBR‐12935 binding sites recognized by mazindol with high affinity in Parkinson's diseased caudate was, however, reduced by 50–80%. Taken together, these data clearly suggest that (a) the dopamine transporter is not detectable in Parkinson's diseased putamen, (b) [3H]GBR‐12935 binding in the putamen of Parkinson's diseased brain is probably not to the dopamine uptake carrier, and (c) there is an interregional variation in the loss of dopamine uptake sites (lost in putamen and somewhat spared in caudate), which appears to parallel markedly the reported loss of dopamine content in idiopathic Parkinson's diseased striatum.

Original languageEnglish (US)
Pages (from-to)192-198
Number of pages7
JournalJournal of Neurochemistry
Volume56
Issue number1
DOIs
StatePublished - Jan 1991

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Keywords

  • Dopamine uptake
  • Parkinson's disease
  • Photoaffinity labeling
  • [H]GBR‐12935

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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