Feb. 19, 2004 DURHAM, N.C. -- Howard Hughes Medical Institute investigators at Duke University Medical Center have linked a gene previously shown to play a role in learning and memory to the early manifestations of drug addiction in the brain. Although scientists had previously speculated that similar brain processes underlie aspects of learning and addiction, the current study in mice is the first to identify a direct molecular link between the two.
The findings suggest new genetic approaches for assessing an individual's susceptibility to drug addiction. They also illuminate the complex series of molecular events that underlie addiction, the researchers said, and ultimately may lead to new therapeutic methods to interfere with that process, thereby curbing the cravings common to addiction.
The Duke-based study, which examined genes involved in the brain's response to cocaine, appears in the Feb. 19, 2004, issue of Neuron. The work was supported by the National Institutes of Health, the Zaffaroni Foundation and the Wellcome Trust.
"There has been the idea that brain changes in response to psychostimulants may be similar to those critical for learning and memory," said Marc G. Caron, Ph.D., an HHMI investigator at Duke. "Now, for the first time, we have found a molecule that links drug-induced plasticity in one part of the brain to a mechanism that underlies learning and memory in another brain region." Caron is also interim director of the Center for Models of Human Disease, part of Duke's Institute for Genome Sciences and Policy, and James B. Duke professor of cell biology.
Previous work by other researchers revealed that exposure to cocaine triggers changes in a brain region called the striatum -- a reward center that also plays a fundamental role in movement and emotional responses. Cocaine leads to a sharp increase in communication among nerve cells in the striatum that use dopamine as their chemical messenger. This brain chemical surge is responsible for the feeling of pleasure, or high, that leads drug users to crave more.
"Drugs essentially hijack the brain's natural reward system," thereby leading to addiction, explained Wei-Dong Yao, Ph.D., an HHMI fellow at Duke and first author of the new study.
The study sought to identify genes involved in the brain's heightened response after drug use. The researchers compared the activity of more than 36,000 genes in the striatum of mice that had "super-sensitivity" to cocaine due to a genetic defect or prior cocaine exposure, with the gene activity in the same brain region of normal mice. The genetic screen revealed six genes with consistently increased or decreased activity in super-sensitive versus normal mice, the team reported.
The protein encoded by one of the genes -- known as postsynaptic density-95 or PSD-95 -- dropped by half in the brains of super-sensitive mice, the researchers found. The protein had never before been linked to addiction, Caron said, but had been shown by Seth Grant, a member of the research team at the Wellcome Trust Sanger Institute, to play a role in learning. Mice lacking PSD-95 take longer than normal mice to learn their way around a maze. In other words, mice with normal amounts of PSD-95 appear less likely to become addicted and more likely to learn.
Two of the other five genes had earlier been suggested to play a role in addiction. The function of the remaining three genes is not known, Caron said, and will be the focus of further investigation.
Among the mice more responsive to the effects of cocaine, the decline in PSD-95 occurred only in the striatum, while levels of the protein in other brain regions remained unaffected. In normal mice, the protein shift occurred after three injections of cocaine and lasted for more than two months.
The researchers also measured the activity of nerve cells in brain slices from the different groups of mice. Neurons in the brains of super-sensitive mice exhibited a greater response to electrical stimulation than did the nerve cells of control mice. Neurons from mice lacking a functional copy of PSD-95 showed a similar increase in activity, the team reported.
Mice deficient in PSD-95 also became more hyperactive than normal mice following cocaine injection, further linking the protein to the drug's brain effects. However, the deficient mice failed to gain further sensitivity upon repeated cocaine exposure, as mice typically do.
"Drug abuse is a complex disorder and will therefore be influenced by multiple genes," Caron noted. "PSD-95 represents one cog in the wheel."
The brain protein likely plays a role in addiction to other drugs -- including nicotine, alcohol, morphine and heroine -- because they all exert effects through dopamine, Caron added. Natural variation in brain levels of PSD-95 might lead to differences in individual susceptibility to drugs of abuse, he suggested. The gene might therefore represent a useful marker for measuring such differences.
The researchers will next examine the effects of PSD-95 on the addictive behavior of mice, Caron said. For example, they will test whether PSD-95-deficient mice self-administer greater amounts of cocaine than do normal mice.
Other study investigators at Duke include Raul Gainetdinov, M.D., Tatyana Sotnikova, Ph.D., Michel Cyr, Ph.D., Jean-Martin Beaulieu, Ph.D. and Gonzalo Torres, Ph.D. Margaret Arbuckle, Ph.D., of the University of Edinburgh also contributed to the research.
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