? To date, there is no effective medication for treating cocaine addiction. A better understanding of the manner by which cocaine exerts its effects on the brain will focus medication development efforts. Although cocaine blocks the reuptake of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine, the reinforcing effects of cocaine have been primarily attributed to its effects at the dopamine transporter (DAT). However, not all DAT inhibitors are equally reinforcing. Examining the pharmacokinetics, more specifically, the onset and duration of action, of cocaine and related compounds is important in determining which of these properties are involved in the reinforcing effects of these compounds. In the present research proposal, the reinforcing effectiveness of several monoamine transporter inhibitors (DAT-selective and mixed-action) will be assessed in nonhuman primates. The stimulant effects of these compounds will be assessed by administering them systemically to squirrel monkeys trained on a stimulus termination task. The reinforcing effects will be assessed in separate groups of squirrel monkeys and rhesus monkeys that have been trained to self-administer cocaine. These data will allow us to determine the relative stimulant and reinforcing efficacy and potency of each combination. To determine drug effects on brain dopamine function, squirrel monkeys will undergo in vivo microdialysis procedures following drug administration, allowing us to determine how dopamine levels are altered by the administration of these drug combinations. PET imaging of DAT occupancy will be conducted in rhesus monkeys, allowing us to correlate DAT occupancy with the observed behavior and neurochemistry. Ex vivo binding assays will be conducted in rodents to determine the rate that these compounds bind to DAT. These data will further characterize the role of pharmacokinetics in the addictive properties of cocaine and provide critical information for the development of effective pharmacotherapies that are not, themselves, addictive. This research proposal will extend the candidate's research training in rodent behavioral pharmacology and neurochemistry to nonhuman primate behavioral pharmacology and neurochemistry. In addition, this research plan represents a new research direction for the applicant. The training experiences described will provide for the candidate's transition from a mentored scientist to an independent investigator. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DA015092-03
Application #
6896768
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Pilotte, Nancy S
Project Start
2003-06-01
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$136,161
Indirect Cost
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Kimmel, Heather L; Negus, S Stevens; Wilcox, Kristin M et al. (2008) Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys. Pharmacol Biochem Behav 90:453-62
Kimmel, Heather L; O'Connor, Joann A; Carroll, F Ivy et al. (2007) Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys. Pharmacol Biochem Behav 86:45-54
Howell, Leonard L; Carroll, F Ivy; Votaw, John R et al. (2007) Effects of combined dopamine and serotonin transporter inhibitors on cocaine self-administration in rhesus monkeys. J Pharmacol Exp Ther 320:757-65
Wilcox, Kristin M; Kimmel, Heather L; Lindsey, Kimberly P et al. (2005) In vivo comparison of the reinforcing and dopamine transporter effects of local anesthetics in rhesus monkeys. Synapse 58:220-8
Kimmel, Heather L; Ginsburg, Brett C; Howell, Leonard L (2005) Changes in extracellular dopamine during cocaine self-administration in squirrel monkeys. Synapse 56:129-34
Ginsburg, Brett C; Kimmel, Heather L; Carroll, F Ivy et al. (2005) Interaction of cocaine and dopamine transporter inhibitors on behavior and neurochemistry in monkeys. Pharmacol Biochem Behav 80:481-91