Heather L. Kimmel - US grants

Cocaine is a potent inhibitor of monoamine uptake in the central nervous system, thereby potentiating the neurochemical actions of dopamine, serotonin, and norepinephrine. Many proposed medications for cocaine abuse have focused on substitute therapies, but it is also important to understand the physiological changes that occur to the dopamine transporter during acquisition and repeated use of cocaine. It is possible that these changes may be involved in the maintenance of cocaine use and cocaine withdrawal after termination of its use. The purpose of this study is to examine changes in the dopamine transporter after repeated cocaine treatment and withdrawal in the rat using both biochemical and behavioral methods. In these studies, turnover of dopamine transporter binding and dopamine uptake in the rat will be measured after acute and repeated cocaine administration as well as after withdrawal. In order to characterize changes in dopamine transporter function in squirrel monkeys, we will use in vivo microdialysis to measure dopamine levels before, during acquisition and maintenance of cocaine self-administration, and during cocaine abstinence. Our hypothesis is that changes in dopamine transporters are correlated with acquisition and repeated use of cocaine and cocaine withdrawal. If changes in the dopamine transporter function are indeed involved in the acquisition of cocaine use and cocaine withdrawal, then development of medications that could offset or revert these changes would be useful in maintaining cocaine abstinence.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] 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. [unreadable] [unreadable] [unreadable] [unreadable]

neuroregulation; dopamine transporter; Primates; animal colony; laboratory rat;

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Currently, there is no effective medication for treating cocaine addiction. A better understanding of how 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 attributed primarily to its effects at the dopamine transporter (DAT). However, not all DAT inhibitors are equally reinforcing. It is important to examine the properties involved in the effects of these compounds. During the reporting period, research has been conducted reinforcing effectiveness of several monoamine transporter inhibitors (DAT-selective and mixed-action) is assessed in nonhuman primates. The stimulant effects of these compounds are assessed by administering them systemically to squirrel monkeys trained on a stimulus-termination task. The reinforcing effects are assessed in separate groups of squirrel monkeys trained to self-administer cocaine. These data will enable us to determine the relative stimulant and reinforcing efficacy and potency of each combination. To determine drug effects on brain dopamine function, squirrel monkeys undergo in vivo microdialysis procedures following drug administration. PET imaging of the uptake of radiolabeled monoamine transporter inhibitors is conducted in rhesus monkeys to correlate drug levels in brain with observed behavior and neurochemistry. The present data showed that the time to peak drug levels in brain were very highly correlated with the time to peak increases in brain dopamine. In addition, the data showed a trend for compounds with a shorter duration of action or DAT selectivity to produce significant behavioral-stimulant and reinforcing effects. These data 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.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] 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. [unreadable] [unreadable] [unreadable] [unreadable]