February 19, 2004
Cocaine Depresses Expression Of Protein Involved In Learning

Cocaine interferes with the expression of a gene for a protein involved in learning.

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.


"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.

Humans have a problem with addictive drugs because humans did not get much exposure to these drugs as humans evolved. The limited previous exposure means there was little selective pressure to select for genetic variations that would make humans less susceptible to drug addiction. Addictive drugs in the quantity and quality now available are, evolutionarily speaking, new to human experience and humans are not adapted to deal with them.

Note the sheer number of genes which were compared for activity under different conditions and in different strains of mice. Most likely the researchers used gene array chips that allow the expression levels of thousands of genes to be compared at the time. As gene array chip technology improves the ability to do this kind of work becomes cheaper and easier.

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.

There is a difference between easily addicted mice and regular mice in the change of their PSD-95 gene expression when exposed to cocaine.

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.

If the human equivalent of the PSD-95 gene reacts to cocaine in the same manner then a fairly small amount of cocaine use may hobble learning for weeks and perhaps even for months.

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.

It would be interesting to know how PSD-95 expression responds to various drugs which are used to treat a variety of mental illnesses. For instance, how do SSRI (Selective Serotonin Reuptake Inhibitor) antidepressants such as Prozac and Zoloft change PSD-95 expression? Or how does Ritalin, which is used to treat youthful ADHD (Attention Deficit Hyperactivity Disorder), change PSD-95 expression?

Share |      Randall Parker, 2004 February 19 03:16 PM  Brain Addiction

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