Preclinical Finding Sheds Light on How Cocaine Rewires Brain

“The finding highlights how highly addictive drugs, such as cocaine, alter the brain and why relapse after abstinence is so common and so difficult to reverse,” says Dietz, an associate professor in the Department of Pharmacology and Toxicology.

The paper, “BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior,” has been published in Biological Psychiatry.

Research conducted by Dietz and his colleagues in 2015 saw that a transcription factor called SMAD3 plays an essential role in the brain plasticity that cocaine induces and leads to relapse behaviors after a period of withdrawal. Transcription factors help control which genes are expressed and which are not.

In the current experiments, laboratory animals self-administered cocaine and then experienced abstinence for seven days. After the abstinence period, the researchers saw increased expression of a protein called BRG1 and increased interaction between it and the transcription factor SMAD3.

“We noticed that this transcription factor, which was critical in mediating relapse-like behaviors, was also known to interact with a molecule like BRG1 in other cells in the body,” explains Dietz. 

“We wanted to know if BRG1 and this transcription factor also interact following cocaine addiction and if those interactions helped regulate genes in these individuals.”

The researchers learned that cocaine changes the expression of BRG1 and also changes how BRG1 interacts with transcription factors known to be essential in mediating gene expression following cocaine use. 

“In this way, BRG1 facilitates how transcription factors regulate genes after cocaine use and withdrawal,” says Dietz.

BRG1 is a chromatin remodeler, meaning that it is involved in the dynamic structural changes that impact chromatin, the mass of genetic material in the cell nucleus that condenses into chromosomes.

Dietz explains that BRG1 therefore controls the access that transcription factors have to DNA, in part by possibly changing the chromatin structure itself so that it is more or less accessible to DNA.

“We need a more defined and clear picture of how drugs of abuse change the brain so that we can really begin to understand what may be a true target for treatment,” says Dietz.

“This research more strongly points to the possibility that the interaction of SMAD3 with BRG1 may be a key possibility for such a treatment target.”

Zi-Jun Wang, PhD, a postdoctoral fellow, is first author.

Co-authors in the Department of Pharmacology and Toxicology are:

• graduate students Jennifer A. Martin, Lauren E. Mueller and Aaron Caccamise
• Craig T. Werner, PhD, postdoctoral associate
• Jun-Xu Liu, MD, PhD, associate professor

Co-author Amy M. Gancarz, PhD, formerly a postdoctoral scholar in Dietz’s lab, is now an assistant professor at California State University, Bakersfield. Rachael L. Neve, PhD, of Massachusetts Institute of Technology, is another co-author.

The work is funded by a grant awarded in 2014 to Dietz from the National Institute on Drug Abuse to study the short- and long-term neurobiological changes — known as neuroplasticity — induced by cocaine addiction.