RTI-336, a compound that mimics the effects of cocaine by inhibiting dopamine transporters, holds promise for effectively treating cocaine addiction according to a new study published in the early online edition of The Journal of Pharmacology and Experimental Therapeutics. Using a unique combination of behavioral and brain imaging studies for medications development at the Yerkes National Primate Research Center, Yerkes researcher Leonard Howell, PhD, and his research team showed RTI-336 eliminates self-administration of cocaine in rhesus macaque monkeys by mimicking the effects of cocaine. This finding will be tested in humans beginning at two sites in 2007 as part of the National Institute on Drug Abuse's large-scale effort to move cocaine addiction treatments to human clinical trials as quickly as possible.
In the study, the researchers trained rhesus macaques on a complex behavioral task that, when completed successfully, resulted in the monkeys receiving an intravenous dose of cocaine. When the monkeys received a daily dose of RTI-336 30 minutes before they performed the behavioral task, the researchers found the monkeys stopped working on the behavioral task and no longer self-administered the cocaine. Further research found RTI-336 did not appear to have abuse liability similar to cocaine.
"Our results support the use of RTI-336 as a medication to treat cocaine addiction in humans," explained Howell. "This type of agonist therapy is used for treatment of heroin addiction, but RTI-336 does not cause the same physical withdrawal symptoms upon discontinuation that are seen in some other agonist therapies such as methadone," he continued.
In addition to the behavioral task, the researchers used positron emission tomography (PET) to image RTI-336 binding to the dopamine transporter. "Imaging was vital to the clinical portion of this study because it helped us determine the optimal dose for humans," said Howell. "Yerkes is unique in its capabilities to offer both behavioral testing and brain imaging for the study of pharmacological therapies in nonhuman primates."
Also as part of the study, researchers examined the combination of RTI-336 with serotonin transporter inhibitors as a means to further reduce the abuse liability of RTI-336. This co-administration produced even more robust reductions of cocaine self-administration compared to RTI-336 used alone. "If RTI-336 mimics cocaine too much in human studies, co-administration of serotonin inhibitors will provide the next avenue of study," said Howell. "Abuse liability is a concern in agonist therapies, but co-administration, already proven effective in nonhuman primate studies, offers a means of reducing the probability of abuse and increasing the effectiveness of the therapy," he continued.
The research was supported by grants from the U.S. Public Health Service, Division of Research Resources, National Institutes of Health, and the Yerkes Research Center Base Grant.
For more than seven decades, the Yerkes National Primate Research Center, Emory University, has been dedicated to advancing scientific understanding of primate biology, behavior, veterinary care and conservation, and to improving human health and well-being. Today, the center, as one of only eight National Institutes of Health–funded national primate research centers, provides specialized scientific resources, expertise and training opportunities. Recognized as a multidisciplinary research institute, the Yerkes Research Center is making landmark discoveries in the fields of microbiology and immunology, neuroscience, psychobiology and sensory-motor systems. Research programs are seeking ways to: develop vaccines for infectious and noninfectious diseases, such as AIDS, malaria and Alzheimer's disease; treat cocaine addiction; interpret brain activity through imaging; increase understanding of progressive illnesses such as Parkinson's and Alzheimer's; unlock the secrets of memory; determine behavioral effects of hormone replacement therapy; address vision disorders; and advance knowledge about the evolutionary links between biology and behavior.