The National Institute on Drug Abuse has awarded a five-year, $6.6 million grant to the University of Texas Medical Branch at Galveston to establish the Translational Addiction Sciences Center. The center will investigate the mechanisms underlying addiction with the goal of discovering and validating novel treatment options.
Substance addiction can have disastrous personal, economic and social consequences and continues to be one of the world's most serious public health problems. While addiction and associated medical problems are treatable, there is a great opportunity to optimize new therapeutics, particularly for cocaine addiction. As such, the advances in treatment options made by this team of scientists, led by principal investigator Kathryn Cunningham, are poised to impact clinical care of patients.
"Our goals are to identify targets within the brain serotonin system involved in relapse to cocaine use, to design new molecules that selectively affect these targets and to validate these new molecules as potential medications to extend abstinence from cocaine use," said Cunningham, who also directs the UTMB Center for Addiction Research.
To achieve this goal, the Translational Addiction Sciences Center brings together a team of experts from a range of disciplines, including Scott Gilbertson, professor of chemistry at the University of Houston who designs and synthesizes new chemical compounds; Cheryl Watson, professor of biochemistry and molecular biology from UTMB who guides signaling analyses in cellular models; Dr. F. Gerard Moeller, professor of psychiatry at Virginia Commonwealth University School of Medicine who leads analyses in human subjects; and Cunningham, professor of pharmacology and toxicology who directs pharmacological and neurochemical analyses in phenotypic models of addiction.
The team is pioneering studies to establish receptor proteins that respond to the neurotransmitter serotonin as important regulators of the mechanisms underlying addiction. "Targeting the serotonin system is a novel approach for treatment of drug addiction and relapse," said Gilbertson. "Scientists have examined other aspects of the central nervous system, like the dopamine neurotransmitter system, for a long time with little success."
Cunningham noted that it is well known that an imbalance in the serotonin system in the brain is related to depression and anxiety; however, "our scientific advances are now bringing to light the importance of serotonin in cocaine addiction and implicate serotonin imbalance as a mechanism underlying certain behavioral traits that enhance susceptibility to relapse."
Individuals who tend to act on impulse and show elevated responses to cues associated with cocaine use have a higher incidence of relapse. Targeting individuals who express these behavioral traits is an additional unique and innovative aspect of these investigations.
"These factors are interconnected and appear to be related to an underlying imbalance in serotonin receptor function, providing an opportunity to individualize treatment strategies," said Moeller. "We believe that addicted patients who exhibit these particular traits will respond better to medications that selectively target certain serotonin receptors."
The serotonin receptor system, however, is complex, consisting of at least 14 different receptor proteins, and current medications that act on this system do not distinguish the receptor subtypes very well. Thus, there is a need to develop new compounds that selectively target the desired receptors.
That is where the chemists and cell biologists come in. "When new compounds are synthesized by Dr. Gilbertson's group, the effects of these compounds are first measured at the cellular level because it is much more efficient, less costly, and reduces the number of animal and human evaluations necessary," said Watson. These technologies will give the team new insights into previously unappreciated signaling mechanisms that could reveal new therapies.
"We can easily sprinkle these chemicals on cells and observe the receptors to which they bind and the signals they generate; the value of testing these new compounds at the cellular level is that we can narrow down what would be safe and effective to try in animals and humans, " noted Watson.
Gilbertson added that it is an iterative process that requires input at the cellular, animal and human levels. "The more we understand how the systems function and adapt during addiction and in response to the medications, the better can we pinpoint where we need to target the new molecules," he said.
Cunningham believes their research will be successful in jumpstarting a new generation of discovery for treatments to help prevent relapse in individuals suffering from cocaine addiction.
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