High affinity cocaine recognition sites on the dopamine transporter are elevated in fatal cocaine overdose victims

J. K. Staley, W. L. Hearn, A. J. Ruttenber, C. V. Wetli, Deborah C Mash

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Cocaine mediates its powerful reinforcement by binding to recognition sites on the dopamine (DA) transporter. The pharmacological identity of cocaine recognition sites and their relevance to dopamine transport function has remained unclear. Ligand binding studies with transport inhibitors and cocaine congeners have provided evidence for multiple sites or 'states' of the DA transporter. The potent cocaine congener [3H]WIN 35,428 {(CFT), 2B- carbomethoxy-3β-(4-fluorophenyl)-tropane} has been shown to recognize high and low affinity binding sites on the DA transporter. We have used [3H]WIN 35,428 to map and quantify the high affinity cocaine recognition site on the DA transporter in victims of fatal cocaine overdose. Region-of-interest densitometric analysis of the autoradiograms demonstrated a 2- to 3-fold elevation in the apparent density of [3H]WIN 35,428 binding in particular sectors of the striatum from victims of cocaine overdose as compared to age- matched and drug-free control subjects. The most marked increase in [3H]WIN 35,428 binding was seen in the nucleus accumbens. The apparent increase in the density of high affinity sites was confirmed by saturation binding analysis of [3H]WIN 35,428 to putamen membranes. Saturation analysis revealed high and low affinity binding components with affinities (K(D) values) of 4.3 ± 1.2 and 84.7 ± 19.7 nM (mean ± S.E.) and densities of 9.9 ± 4.0 and 193.0 ± 28.6 pmol/g of tissue, respectively. Rosenthal plots of the saturation binding curves demonstrated a significant increase in the apparent density of high affinity sites on the DA transporter for the cocaine overdose cases as compared with the control subjects (P < .01), with no change in the affinity or density of the low affinity binding component. The increase in high affinity recognition sites on DA transporter suggests that these pharmacological sites may upregulate as a compensatory response to elevated intrasynaptic levels of DA.

Original languageEnglish
Pages (from-to)1678-1685
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - Jan 1 1994


ASJC Scopus subject areas

  • Pharmacology

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