This is a request for a Research Scientist Award for J. B. Justice, Jr., Professor of Chemistry, Emory University. The long term objective of this research is the understanding of the biological significance of the neurotransmitter dopamine (DA) in several structures in the central nervous system with respect to its role in drug abuse. Four areas of investigation are planned: 1) fundamental questions of in vivo measurement of neurotransmitters; 2) the neurochemistry of reward; 3) neurochemical effects of chronic cocaine; 4) individual differences in response to cocaine. Experiments are proposed which will test a new interpretation of in vivo microdialysis results and exploit these new findings to study the neurochemistry of drug abuse. It is essential to have a clear understanding of the data generated in microdialysis experiments to avoid misinterpretations as microdialysis is increasingly used in studies of drug abuse. The proposed fundamental studies apply to all transmitter systems, not just the dopaminergic system currently under investigation. In the second group of experiments, the relative importance of different DA pathways in cocaine abuse will be assessed using the self-administration paradigm.
The aim of the present study is to reassess the relative contribution of several DA terminal fields and cell body regions in the reinforcing effects of cocaine. The particular methods used, that is local intracranial injection of cocaine during intravenous self-administration, will help to clarify the extent that structures other than the nucleus accumbens contribute to the reinforcing effects of cocaine. In the third group of experiments, the neurochemical perturbations caused by chronic cocaine administration will be assessed in vivo in DA systems using microdialysis and voltammetry. Alterations in synthesis, metabolism, release, uptake, and basal extracellular level will be determined in vivo as a function of time after chronic treatment. Individual differences in these processes with respect to response to cocaine will be assessed in the fourth group of experiments. The results of these experiments will help to guide future in vivo monitoring of neurochemical processes associated with abuse of drugs. A better understanding of the neurochemistry and neuroanatomy of drug induced reinforcement will help in developing approaches to treatment of drug abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DA000179-03
Application #
2116059
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1992-04-01
Project End
1997-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Emory University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Vaughan, Roxanne A; Parnas, M Laura; Gaffaney, Jon D et al. (2005) Affinity labeling the dopamine transporter ligand binding site. J Neurosci Methods 143:33-40
Reed, Brian; Chen, Nianhang; Justice Jr, Joseph B (2003) Dual-electrode voltammetry of catecholamine transport: simultaneous monitoring of uptake and efflux. J Neurosci Methods 126:127-35
Schad, Christina A; Justice Jr, Joseph B; Holtzman, Stephen G (2002) Endogenous opioids in dopaminergic cell body regions modulate amphetamine-induced increases in extracellular dopamine levels in the terminal regions. J Pharmacol Exp Ther 300:932-8
Chen, N; Justice, J B (2000) Differential effect of structural modification of human dopamine transporter on the inward and outward transport of dopamine. Brain Res Mol Brain Res 75:208-15
Gong, W; Neill, D B; Lynn, M et al. (1999) Dopamine D1/D2 agonists injected into nucleus accumbens and ventral pallidum differentially affect locomotor activity depending on site. Neuroscience 93:1349-58
Chen, N; Trowbridge, C G; Justice Jr, J B (1999) Cationic modulation of human dopamine transporter: dopamine uptake and inhibition of uptake. J Pharmacol Exp Ther 290:940-9
Danek Burgess, K S; Justice Jr, J B (1999) Effects of serine mutations in transmembrane domain 7 of the human norepinephrine transporter on substrate binding and transport. J Neurochem 73:656-64
Danek, K; Justice Jr, J B (1998) Voltammetric studies on kinetics of uptake and efflux at catecholamine transporters. Methods Enzymol 296:649-60
Chen, N; Trowbridge, C G; Justice Jr, J B (1998) Voltammetric studies on mechanisms of dopamine efflux in the presence of substrates and cocaine from cells expressing human norepinephrine transporter. J Neurochem 71:653-65
Chen, N; Justice Jr, J B (1998) Cocaine acts as an apparent competitive inhibitor at the outward-facing conformation of the human norepinephrine transporter: kinetic analysis of inward and outward transport. J Neurosci 18:10257-68

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