Researchers Find Alterations In Brain's Circuitry Caused By Cocaine

Such findings suggest possible new directions for treatments for addiction to the drug, they said.

In a study available online and in the Oct. 20 issue of Neuron, UT Southwestern researchers used rodents to pinpoint an important molecular mechanism that switches genes "on" in the part of the brain involved in drug-induced rewards. They also determined that cocaine, through a process called "chromatin remodeling," alters the normal biochemical processes that allow these specific genes to be turned on and off.

"Our study provides a fundamentally new level of analysis by which we can better understand the actions of cocaine in brain-reward regions at the molecular level," said senior author Dr. Eric Nestler, chairman of UT Southwestern's Department of Psychiatry. "It also points to new potential treatments for addiction."

In order for genes to be activated, or "expressed," proteins called transcription factors have to be able to access the gene and copy its instructions for making other proteins. Typically, a group of proteins called histones tightly binds genes, keeping them from being accessed by transcription factors. Normally, histones undergo chemical changes to convert them from tightly binding a gene to a state where they are less bound and no longer inhibit gene expression.

However, through chromatin remodeling - or modifying the genetic material located in the cell's nucleus - cocaine chemically alters histones, causing them to loosen their "grip" on certain genes and allowing transcription factors to turn the genes on, the researchers found.

"Our study was the first to examine histone changes on particular genes in brain-reward regions known to be important for cocaine addiction," said Dr. Nestler, who holds the Lou and Ellen McGinley Distinguished Chair in Psychiatric Research. "We have shown that several genes known to be activated by acute or chronic cocaine use indeed show changes in histone chemical modifications that lead to the genes' activation."

Another discovery was that chronic cocaine use causes chemical changes to a different type of histone than acute cocaine use does, which may help explain why the behavioral effects of acute versus chronic cocaine use in people are so different, Dr. Nestler said.

Researchers learned, through administering single doses and repeated doses of cocaine to groups of rats and mice, that some of the changes in histones caused by the drug are quite stable, lasting for more than a week after the last cocaine dosage. From that, they concluded that chronic cocaine use may cause long-lasting changes in the brain's circuitry, whereas short-term use affects genes differently.

"One of the cardinal features of addiction is how long-lived it is," Dr. Nestler said. "A key question in the field has been: By what mechanisms do drugs of abuse cause changes in the brain that last this long?"

Researchers have hypothesized that one such mechanism could be regulation of gene expression and have shown that several transcription factors are regulated by drugs of abuse. This study, however, ventures a step further, providing evidence that histone changes on particular genes are a paramount part of the addiction process.

The researchers also showed that they could reduce or enhance cocaine's behavioral effects in animals by directly and artificially influencing histone changes with different types of chemicals. One chemical modified histones in a way that increased the animals' reward response from cocaine, while rats given a different type of chemical, which modified histones in another way, showed decreased rewarding effects.

"We are seeing for the first time how certain genes in the reward center of the brain are regulated by chromatin modifications," said Dr. Arvind Kumar, the study's lead author and an instructor of psychiatry. "Now that we understand the mechanism of how these stable, cocaine-induced changes in the brain are regulated, this may help us find targets that can be manipulated for future treatment of cocaine addiction."

Other researchers from UT Southwestern's Department of Psychiatry contributing to the study included Dr. Kwang-Ho Choi, instructor; William Renthal and Nadia Tsankova, Medical Scientist Training Program students; David Theobald and Kimberly Whisler, research associates; Teresa Sasaki and Hoang-Trang Truong, research assistants; Dr. Scott Russo, postdoctoral research fellow; Quincey LaPlant, graduate student fellow/medical student; and Dr. David Self, associate professor. A researcher from Harvard Medical School also contributed.

The study was supported by grants from the National Institute on Drug Abuse and the National Institute of Mental Health.