This protein drives cocaine cravings after withdrawal

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Neuroscientists know that cocaine addiction and withdrawal rewire the brain. Figuring out how to disrupt those changes to treat addiction requires an extremely detailed understanding of how those changes occur.

Now, they say they’ve identified an important piece of the puzzle.

As reported in the journal Biological Psychiatry, the team has discovered that a protein in the brain’s reward center, the nucleus accumbens, regulates genes that help drive the craving for cocaine after a period of withdrawal.

“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 David Dietz, associate professor in the department of pharmacology and toxicology at the University at Buffalo.

Why these rats got hooked and stayed hooked on cocaine

In 2015, Dietz and colleagues identified a transcription factor called SMAD3 as playing an essential role in the brain plasticity that cocaine induces, and leading 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, 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,” Dietz says. “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.”

Antidote for cocaine may hinge on dopamine

Cocaine not only changes the expression of BRG1, but 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,” Dietz says.

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. 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,” Dietz says. “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.”

Other researchers from the University at Buffalo and from Massachusetts Institute of Technology are coauthors of the study that was funded by the National Institute on Drug Abuse.

Source: University at Buffalo