Rates of drug abuse in the United States vary considerably over and from place to place. However, the past 30 years or so have seen consistent patterns of drug abuse involving substances known to be (at least in part) inhibitors of dopamine neuronal uptake. In this proposal, we plan to determine how dopamine release and uptake rates are affected by drugs of abuse on the time scale of neuronal function (milliseconds). This information is needed in order to better understand how the spatial and temporal characteristics of dopaminergic neuronal chemical signaling are altered by drugs of abuse. The work proposed will: (1) refine newly developed techniques for the measurement of endogenous release and reuptake rates and rate constants on the millisecond time scale in vitro (using a rotating disk electroanalytical technique) and in vivo (using in vivo voltammetry), (2) determine how dopamine receptors, biosynthesis, biodegradation, and intracellular localization of dopamine influences the measured rates and rate constants, (3) determine how acute and chronic administration drugs of abuse (amphetamine and cocaine) will affect the rates measured, and (4) compare the results obtained with amphetamine and cocaine to results obtained with other dopamine blockers (bupropion, nomifensine, benztropine, and GBR-12909. The animal model in these studies is the rat because much of the experimental behavioral and biochemical work related to drug abuse has been conducted with this animal.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DA000184-05
Application #
2517842
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Program Officer
Pilotte, Nancy S
Project Start
1993-09-20
Project End
1999-01-31
Budget Start
1997-09-01
Budget End
1999-01-31
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Washington State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Volz, Trent J; Schenk, James O (2005) A comprehensive atlas of the topography of functional groups of the dopamine transporter. Synapse 58:72-94
Volz, Trent J; Bjorklund, Nicole L; Schenk, James O (2005) Methylphenidate analogs with behavioral differences interact differently with arginine residues on the dopamine transporter in rat striatum. Synapse 57:175-8
Robinson, Donita L; Volz, Trent J; Schenk, James O et al. (2005) Acute ethanol decreases dopamine transporter velocity in rat striatum: in vivo and in vitro electrochemical measurements. Alcohol Clin Exp Res 29:746-55
Schenk, James O; Wright, Cortney; Bjorklund, Nicole (2005) Unraveling neuronal dopamine transporter mechanisms with rotating disk electrode voltammetry. J Neurosci Methods 143:41-7
Volz, Trent J; Schenk, James O (2004) L-arginine increases dopamine transporter activity in rat striatum via a nitric oxide synthase-dependent mechanism. Synapse 54:173-82
Volz, Trent J; Kim, M; Schenk, James O (2004) Covalent and noncovalent chemical modifications of arginine residues decrease dopamine transporter activity. Synapse 52:272-82
Schenk, James O; George, Shannon E; Schumacher, Paul Dietrich (2003) What can be learned from studies of multisubstrate mechanisms of neuronal dopamine transport? Eur J Pharmacol 479:223-8
Wayment, H K; Schenk, J O; Sorg, B A (2001) Characterization of extracellular dopamine clearance in the medial prefrontal cortex: role of monoamine uptake and monoamine oxidase inhibition. J Neurosci 21:35-44
Earles, C; Schenk, J O (1999) Multisubtrate mechanism for the inward transport of dopamine by the human dopamine transporter expressed in HEK cells and its inhibition by cocaine. Synapse 33:230-8
Wayment, H K; Deutsch, H; Schweri, M M et al. (1999) Effects of methylphenidate analogues on phenethylamine substrates for the striatal dopamine transporter: potential as amphetamine antagonists? J Neurochem 72:1266-74

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