Repeated cocaine use downregulates active Rac1 and leads to remodelling of neurons in brain reward center.

Scientists report new insights into the mechanism by which repeated exposure to cocaine induces addiction. The studies in mice demonstrate that cocaine downregulates the active form of Rac1, a small GTPase known to control actin remodelling, and that this leads to enhanced actin turnover, and increases the density of immature dendritic spines on nucleus accumbens (NAc) neurons in the brain’s key reward center.  

The researchers, led by a team at Mount Sinai School of Medicine’s Fishberg Department of Neuroscience and Friedman Brain Institute, showed in mice that overexpression of a dominant negative mutant of Rac1 or local knockout of the native gene was enough to increase the density of immature dendritic spines on the NAc neurons, without cocaine administration. Encouragingly, transiently increasing levels of Rac1 blocked the addiction-causing effects of repeated cocaine use and the accompanying neural changes.

Reporting their findings in Nature Neuroscience, Eric J. Nestler and colleagues suggest their results could help in the design of new treatments for cocaine addiction. Their paper is titled “Rac1 is essential in cocaine-induced structural plasticity of nucleus accumbens neurons.”

“The research gives us new information on how cocaine affects the brain’s reward center and how it could potentially be repaired,” Dr. Nestler says. “This is the first case in the brain in vivo where it’s been possible to control the activity of a protein, inside nerve cells in real time. Our findings reveal new pathways and targets.” 

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