Cocaine causes specific alterations in the brain's circuitry at a genetic level, including short-term changes that result in a high from the cocaine, as well as long-term changes seen in addiction, researchers from UT Southwestern Medical Center have found.
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."