title: Reinforcing Doses of Intravenous Cocaine Produce Only Modest Dopamine Uptake Inhibition.
abstract: 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.
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine , Philadelphia, Pennsylvania 19129, United States.
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Brodnik
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine , Winston-Salem, North Carolina 27501, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ferris
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine , Winston-Salem, North Carolina 27501, United States.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Jones
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine , Philadelphia, Pennsylvania 19129, United States.
authors.forename: Rodrigo A
authors.identifier: 0000-0003-2403-6342
authors.initials: RA
authors.lastname: España
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008839:Microelectrodes; D012054:Reinforcement, Psychology; D012646:Self Administration; D014326:Tropanes / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
chemical_list: C112780:2-propanoyl-3-(2-naphthyl)-tropane; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D014326:Tropanes; C114627:WF 11; D003042:Cocaine; D004298:Dopamine
keywords: Dopamine transporter; PTT; WF23; fast scan cyclic voltammetry; occupancy