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Pathway Linked to Cocaine-Related Brain Changes in Mice

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A research team has uncovered a pathway governing the histone modifications that occur following repeated cocaine use in mice — findings that provide clues about cocaine-related changes observed in a brain region implicated in drug use.

The team knew from past studies that cocaine use leads to widespread gene activation, with epigenetic processes contributing to these changes, says lead author Ian Maze, a graduate student in Eric Nestler's Mount Sinai School of Medicine lab.

Last year, the team reported using chromatin immunoprecipitation paired with promoter microarrays to examine cocaine-related chromatin regulation patterns in the mouse nucleus accumbens. Among the changes they detected following repeated cocaine exposure were alterations in histone H3 lysine 9 and histone H3 lysine 27 methylation patterns that affected promoters in the nucleus accumbens.

"This fundamental discovery advances our understanding of how cocaine addiction works," National Institute of Drug Abuse Director Nora Volkow said in a statement. "Although more research will be required, these findings have identified a key new player in the molecular cascade triggered by repeated cocaine exposure, and thus a potential novel target for the development of addiction medications."

For the current study, researchers continued exploring the regulation and consequences of such histone modifications. Using quantitative PCR experiments, Maze says, they looked for enzymes governing histone methylation changes related to repeated cocaine exposure. In the process, they found two enzymes that consistently showed transcriptional changes following repeated exposure to cocaine in mice: G9a and G9a-like protein, also known as GLP.

The enzymes, which dimethylate H3K9, were both down-regulated after cocaine use in the nucleus accumbens of mice — consistent with the decrease in H3K9 dimethylation observed after repeated exposure to the drug. On the other hand, the team did not see changes in H3K27 methylation changes after repeated cocaine use.

In their subsequent experiments, the researchers found that curbing G9a activity ramps up the expression of a subset of genes following chronic cocaine use in mice. And, they report, the changes in G9a activity seem to be caused by a transcription factor called delta-FosB, a splice variant of FosB that can't be degraded. Past work implicated delta-FosB in increased sensitivity to — and preference for — cocaine and other drugs of abuse, Maze notes.

By exploiting their observation that delta-FosB over-expression can decrease G9a levels in the mouse nucleus accumbens, the researchers looked more carefully at the consequences of increasing or decreasing G9a activity.

And because G9a regulates a slew of genes in the nucleus accumbens, including those involved in neuronal plasticity, the researchers propose a mechanism in which delta-FosB-mediated decreases in G9a levels alter neurons in the mouse nucleus accumbens during chronic cocaine use.

If so, the findings could provide clues about brain changes that occur in chronic human cocaine users, though human drug users are more difficult to study — not only because of the problems associated with sampling human brain tissue but also because cocaine addiction tends to co-occur with addictions to alcohol and/or other drugs, Maze says.

Even so, Maze and his co-workers are involved in studies of a collection of post-mortem brain tissue from deceased drug users. They are also investigating how G9a activity affects signaling cascades in heterogeneous cell populations in the mouse nucleus accumbens.

Although more research is needed, the findings provide a window into brain processes and pathways that respond to repeated cocaine use — insights that could ultimately yield targets for new drug addiction treatments.

"The more complete picture that we have today of the genetic and epigenetic processes triggered by chronic cocaine give us a better understanding of the broader principles governing biochemical regulation in the brain," senior author Eric Nestler said in a statement, "which will help us identify not only additional pathways involved but potentially new therapeutic approaches."

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