GALVESTON, Texas -- The National Institute on Drug Abuse has awarded University of Texas Medical Branch at Galveston researchers a four-year, $3.4 million grant to develop what may become the first effective drugs to help people conquer cocaine addiction.
The researchers believe this ambitious program may ultimately benefit compulsive overeaters as well.
Led by the director of UTMB's Center for Addiction Research, Kathryn A. Cunningham, the effort centers on components of the brain's electrochemical signaling system that laboratory research suggests are crucially linked to success or failure in recovering from cocaine addiction. The scientists will focus on two types of molecules on the surfaces of nerve cells in the brain that respond to serotonin, a chemical that carries messages across the tiny gaps between the cells. Stimulation of these "receptor" molecules prompts a nerve cell to generate an electrical pulse that travels from one end of the nerve to the other, where the signal launches still more chemical messengers to be picked up by receptors on other nerve cells.
UTMB scientists have discovered that chemicals that increase the activity of one of the two kinds of serotonin receptors under study -- designated the 5-HT2C receptor -- dramatically reduce cocaine-induced behavior in rats, including the animals' tendency to press a lever to dose themselves intravenously with the drug.
Chemicals that block the activity of the other serotonin receptor, called the 5-HT2A receptor, suppress a characteristic seen in humans with a history of addiction: the sudden craving for a drug long associated with certain stimuli, like the desire for a cigarette some smokers get when having a drink in a bar.
In the laboratory, scientists have found that when rats were trained to associate lights and sound with pressing a lever to self-administer cocaine and then denied the drug for a time, they "relapsed" by pressing the lever for the drug when again exposed to the same sounds and lights. When the scientists activated the 5-HT2C receptor or blocked the 5-HT2A receptor, the rats were significantly less likely to initiate such "relapses."
Changes in serotonin signaling have also been implicated in such disorders as depression, anxiety and anorexia, Cunningham said. Recent experiments have led the UTMB investigators to believe that drugs affecting the 5-HT2A and 5-HT2C receptors may also curb compulsive overeating and obesity.
"Our ongoing research strongly suggests that drug therapies aimed at the 5-HT2A and 5-HT2C receptors could be potent weapons against both cocaine addiction and obesity, two of the most significant public health problems facing the U.S.," Cunningham said. "We hope this research will bring us closer to developing treatments for substance abuse and addiction that are as effective as those used for such other conditions as high blood pressure, asthma and diabetes."
The new program is divided into three parts.
A clinical research component, directed by Professor F. Gerard Moeller of the University of Texas Health Science Center at Houston, will investigate the responses of cocaine addicts to two antidepressants that increase the concentration of serotonin in nerve cell synapses.
A neurobiology project, headed by Cunningham, will use laboratory rat experiments to study the effects of new compounds specifically targeted at the 5-HT2A and 5-HT2C receptors (two of 14 known serotonin receptor subtypes).
Finally, a drug-design project led by UTMB chemical biologist Scott Gilbertson will seek to produce new molecules that could become powerful anti-addiction drugs themselves.
The entire effort will be supported by a cellular and molecular biology core lab directed by UTMB biochemistry and molecular biology professor Cheryl Watson, enabling the researchers to perform genetic analyses of serotonin function in individuals, along with cell-culture studies of new compounds aimed at the 5-HT2A and 5-HT2C receptors.
"We believe that recovery in the brain's serotonin signaling systems can lead to recovery from cocaine addiction," Cunningham said. "Our new research may jump-start a new generation of discovery for anti-addiction, and, potentially, anti-obesity therapies."
|Contact: Jim Kelly|
University of Texas Medical Branch at Galveston