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Functional Alterations in the Dopamine Transporter of Rodents following Self-Administration of Cocaine, Heroin and Speedball

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abstract
Cocaine/heroin combinations (speedball) induce a synergistic elevation in extracellular dopamine (DA) concentrations ([DA]e) in the nucleus accumbens (NAc) that can explain the continued patterns of abuse even after seeking treatment for heroin addiction. To further delineate the mechanism of this neurochemical synergism, in vivo fast-scan cyclic voltammetry (FSCV) was used to compare evoked DA release and DA transporter (DAT)-mediated reuptake kinetic parameters following acute administration of cocaine, heroin and speedball in drug-naïve rats, as well in rats with chronic self-administration (SA) history of cocaine, heroin and speedball. Together, the results have shown that speedball combinations likely induced DA autoreceptor feedback in attempt to regulate increased [DA]e, and that there is also a significant increase in baseline reuptake rate by DAT following chronic speedball SA. In order to deduce the potential mechanism by which DAT is altered to increase reuptake rate, cocaine-like ligands were used in membrane binding assays and quantitative autoradiography for DAT in the NAc of rats to assess the long-term effects of chronic SA of cocaine, heroin and speedball on DAT high- and low-affinity binding sites. The results show a significant increase in affinity of the DAT low-affinity binding site and a shift in DAT binding site composition toward a greater percent of high-affinity binding sites following chronic speedball. These binding data suggest that long-term speedball SA induces a flexibility in the DAT substrate binding sites toward an outward facing conformation in order to increase maximal reuptake rate in compensation for chronically elevated [DA]e. Knowledge of these chronic alterations in DAT function may be able to provide insight into the development of novel pharmacotherapies for the treatment of polysubstance abuse, as well as for cocaine and heroin addictions alone.
subject
cocaine
dopamine
dopamine transporter
heroin
nucleus accumbens
reuptake
contributor
Pattison, Lindsey Patricia (author)
Hemby, Scott E (committee chair)
Hegde, Ashok N (committee member)
Jones, Sara R (committee member)
McCool, Brian A (committee member)
Nader, Michael A (committee member)
Parsons, Loren H (committee member)
date
2013-06-06T21:19:23Z (accessioned)
2013-12-06T09:30:11Z (available)
2013 (issued)
degree
Neuroscience (discipline)
embargo
2013-12-06 (terms)
identifier
http://hdl.handle.net/10339/38519 (uri)
language
en (iso)
publisher
Wake Forest University
title
Functional Alterations in the Dopamine Transporter of Rodents following Self-Administration of Cocaine, Heroin and Speedball
type
Dissertation

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