Frequent Cocaine Use Linked to Alterations in DNA

Findings May Provide Insight Into Underlying Mechanisms of Addictive Behavior

Jacquelyn K. Beals, PhD

February 08, 2011

February 8, 2011 — Regular cocaine use can affect DNA transcription networks and chromatin remodeling across the genome, according to a new study published online February 7 in Proceedings of the National Academy of Sciences of the United States of America.

The study suggests that derepressing parts of the genome by cocaine use can alter patterns of gene transcription in specific neuron types, affecting their drug sensitivity.

Focusing on the nucleus accumbens (NAc), a brain region studied for its role in addiction and associated with reward pathways, this study is among the first to look at the effect of cocaine not on genes but on heterochromatin — DNA regions that are condensed and inactive (although inactive regions vary with cell type).

"The spools of DNA are wrapped around histone complexes called nucleosomes," senior study author Eric J. Nestler, MD, PhD, professor and chair of neuroscience and director of the Mount Sinai Friedman Brain Institute, Mount Sinai School of Medicine, New York City, told Medscape Medical News.

"In euchromatin, the nucleosomes are broadly spaced, allowing for gene expression. In heterochromatin, they are tightly packed, preventing gene expression."

Histones not only contribute to chromosome structure but are recognized as having regulatory effects on DNA. For example, histone H3 trimethylated at lysine residue 9 (H3K9me3) is associated with heterochromatin and is found in repetitive or telomeric genomic regions.

"Many studies have shown that H3K9me3...promotes the formation of heterochromatin," explained Dr. Nestler. "This modification [of histone H3] occurs almost solely in the large spans of DNA that exist in between genes."

More Rapid Effect

The present study investigated whether H3K9me3 levels in the NAc of mice were affected by short-term and/or repeated administration of cocaine. Cocaine was given in a single dose (short-term group) or doses repeated on 7 consecutive days; control animals received saline (5 to 8 animals per treatment group).

The researchers analyzed variation in H3K9me3 levels in NAc samples obtained 0.5, 1, 24, or 168 hours after cocaine administration.

Mice in the short-term administration group had significantly increased (P < .01) H3K9me3 levels within 0.5 hours. At 1 hour after treatment, levels were still significantly greater than controls (P < .05); by 24 and 168 hours, levels returned to control values.

Mice that received repeated cocaine (7 days) showed significantly low (P < .05) levels of H3K9me3 at time 0, which increased to near-control values by 0.5 hours. At 1 hour after treatment, these mice had significantly increased levels (P < .01), which decreased again to subcontrol values (P < .05) by 24 and 168 hours.

In summary, the mice in the short-term administration group demonstrated a more rapid effect of cocaine on H3K9me3 levels, with a return to control levels by 24 hours. The mice repeatedly receiving cocaine had lower baseline levels of H3K9me3, required 1 hour to reach increased levels (similar to those animal in the short-term administration group), then returned to the significantly lower baseline level by 24 hours.

A decrease in the levels of H3K9me3, whose presence is associated with genomic silencing and transcriptional repression, would logically lead to "unsilencing" or derepression of previously repressed regions.

"Consistent with H3K9me3 levels," the study authors report. "We observed a significant increase in heterochromatin domains in NAc 1 h[our] after repeated cocaine and a significant decrease at 24 hours."

Cocaine 'Wakes Up' Heterochromatin

"I think that the real essence of this paper is that they looked for...the chromatin that had not been studied at all," commented Schahram Akbarian, MD, PhD, director of the Brudnick Neuropsychiatric Research Institute and associate professor, Department of Psychiatry, University of Massachusetts Medical School, Worcester, by telephone to Medscape Medical News.

"The heterochromatin is packed in bundles, it's packed together — it's almost like you put something in a storage bin and pack it all together and put it in a storage room," Dr. Akbarian said. "So what [the study authors] say is that heterochromatin gets unpacked, and that is very meaningful for the nerve cells to have heterochromatin suddenly waked up and then become more active.

"The heterochromatin is typically silent, it is quiet, not supposed to express RNA," said Dr. Akbarian. "What they have shown that the cocaine is doing is the unsilencing of the heterochromatin, meaning that it's activated and it starts to transcribe RNA."

Histone modification, especially by methylation, is known to create binding sites for various repressive protein complexes and control the accessibility of DNA-binding proteins that "ultimately control the maintenance of gene expression and genomic stability," said first study author Ian Maze, PhD, postdoctoral associate, Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York City, in an email to Medscape Medical News.

"In terms of how cocaine-induced unsilencing...at these specific genomic regions could affect gene expression, we still do not know," Dr. Maze acknowledged.

"However, when these genomic [regions] are unsilenced, they are sometimes able to insert themselves into other regions of the genome...thereby disrupting or enhancing the expression of genes involved in regulating addictive-like behaviors."

The study authors suggest additional studies are needed to better understand the underlying mechanisms. However, they raise the possibility that learning "how these mechanisms contribute to drug-induced behaviors will further aid in our understanding of the molecular mechanisms controlling cocaine addiction and may open doors for the future development of novel therapeutics aimed at alleviating this devastating condition."

Dr. Nestler, Dr. Maze, and Dr. Akbarian have disclosed no relevant financial relationships.

Proc Natl Acad Sci U S A. Published online February 7, 2011.

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