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Reinforcing Doses of Intravenous Cocaine Produce Only Modest Dopamine Uptake Inhibition
Journal article   Open access   Peer reviewed

Reinforcing Doses of Intravenous Cocaine Produce Only Modest Dopamine Uptake Inhibition

Zachary D Brodnik, Mark J Ferris, Sara R Jones and Rodrigo A España
ACS chemical neuroscience, v 8(2), pp 281-289
15 Feb 2017
DOI: https://doi.org/10.1021/acschemneuro.6b00304
PMID: 27936579
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc5553220View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Administration, Intravenous Animals Cocaine - administration & dosage Cocaine - analogs & derivatives Cocaine - pharmacology Dopamine - metabolism Dopamine Plasma Membrane Transport Proteins - deficiency Dopamine Plasma Membrane Transport Proteins - genetics Dopamine Uptake Inhibitors - administration & dosage Dopamine Uptake Inhibitors - pharmacology Dose-Response Relationship, Drug Electric Stimulation Mice Mice, Inbred C57BL Mice, Knockout Microelectrodes Reinforcement (Psychology) Self Administration Tropanes - pharmacology Ventral Tegmental Area - drug effects Ventral Tegmental Area - metabolism
The reinforcing efficacy of cocaine is thought to stem from inhibition of the dopamine transporter (DAT) and subsequent increases in extracellular dopamine concentrations in the brain. In humans, this hypothesis has generally been supported by positron emission tomography imaging studies where the percent of DATs occupied by cocaine is used as a measure of cocaine activity in the brain. Interpretation of these studies, however, often relies on the assumption that measures of DAT occupancy directly correspond with functional DAT blockade. In the current studies, we used in vivo and in vitro fast scan cyclic voltammetry in mice to measure dopamine uptake inhibition following varying doses of cocaine as well as two high affinity DAT inhibitors. We then compared dopamine clearance rates following these drug treatments to dopamine clearance obtained from DAT knockout mice as a proxy for complete DAT blockade. We found that administration of abused doses of cocaine resulted in approximately 2% of maximal DAT blockade. Overall, our data indicate that abused doses of cocaine produce a relatively modest degree of DA uptake inhibition, and suggest that the relationship between DAT occupancy and functional blockade of the DAT is more complex than originally posited.

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Collaboration types
Domestic collaboration
Web of Science research areas
Biochemistry & Molecular Biology
Chemistry, Medicinal
Neurosciences
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