Dopamine transport function is elevated in cocaine users

Deborah C Mash, John Pablo, Qinjie Ouyang, W. Lee Hearn, Sari E Izenwasser

Research output: Contribution to journalArticle

111 Scopus citations

Abstract

Dopaminergic transmission has been suggested to be a primary mechanism mediating reinforcement, withdrawal and craving associated with psychostimulant addiction. Pyscho-stimulants attenuate dopamine transporter (DAT) clearance efficiency, resulting in a net increase in synaptic dopamine levels. Re-uptake rate is determined by the number of functional DAT molecules at the membrane surface. Previous in vivo imaging studies in humans and in vitro studies in postmortem human brain have demonstrated that chronic cocaine abuse results in a neuroadaptive increase in DAT-binding site density in the limbic striatum. Whether this increase in DAT availability represents an increase in the functional activity of the transporter is unknown. Here, we present evidence that DAT function is elevated by chronic cocaine abuse. The effect of increasing post-mortem interval on the functional viability of synaptosomes was modeled in the baboon brain. Baboon brains sampled under conditions similar to human brain autopsies yielded synaptosomal preparations that were viable up to 24 h post-mortem. Dopamine (DA) uptake was elevated twofold in the ventral striatum from cocaine users as compared to age-matched drug-free control subjects. The levels of [3H]DA uptake were not elevated in victims of excited cocaine delirium, who experienced paranoia and marked agitation prior to death. In keeping with the increase in DAT function, [3H]WIN 35,428 binding was increased in the cocaine users, but not in the victims of excited delirium. These results demonstrate that DA uptake function assayed in cryopreserved human brain synaptosomes is a suitable approach for testing hypotheses of the mechanisms underlying human brain disorders and for studying the actions of addictive drugs in man.

Original languageEnglish
Pages (from-to)292-300
Number of pages9
JournalJournal of Neurochemistry
Volume81
Issue number2
DOIs
StatePublished - Aug 5 2002

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Keywords

  • Binding
  • Cocaine
  • Delirium
  • Dopamine transporter (DAT)
  • Post-mortem
  • Uptake

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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