Journal Article

Rac1 is essential in cocaine-induced structural plasticity of nucleus accumbens neurons

Scobie, Kimberly N, Dietz, David M, Zheng, Yi, Ferguson, Deveroux, Ohnishi, Yoko, Koo, Ja Wook, Sun, Haosheng, Hahn, Klaus M, Christoffel, Daniel, Neve, Rachael L, Nestler, Eric J, Chadwick, Benjamin, Hodes, Georgia E, Maze, Ian, Russo, Scott J, Dietz, Karen C, Dias, Caroline, Lobo, Mary Kay, Damez-Werno, Diane, Cahill, Michael E, Gao, Virginia, Mazei-Robison, Michelle S

2012

Overview

Repeated exposure to cocaine increases dendritic spine density on nucleus accumbens (NAc) neurons. Here the authors show that the small GTPase Rac1 is necessary and sufficient for cocaine-induced behavior and spine changes in NAc neurons, adding support for a causal role for structural plasticity in cocaine-induced behavior. Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here we show that repeated exposure to cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. Further, we show, using viral-mediated gene transfer, that overexpression of a dominant negative mutant of Rac1 or local knockout of Rac1 is sufficient to increase the density of immature dendritic spines on nucleus accumbens neurons, whereas overexpression of a constitutively active Rac1 or light activation of a photoactivatable form of Rac1 blocks the ability of repeated cocaine exposure to produce this effect. Downregulation of Rac1 activity likewise promotes behavioral responses to cocaine exposure, with activation of Rac1 producing the opposite effect. These findings establish that Rac1 signaling mediates structural and behavioral plasticity in response to cocaine exposure.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/200 / 631/378/1689/5 / 631/378/2597/2599 / 631/80/86 / Animal Genetics and Genomics / Animals / Behavioral Sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Blotting, Western / Brain / Cocaine / Cocaine - pharmacology / Cocaine-Related Disorders / Dendritic Spines - drug effects / Dendritic Spines - metabolism / Dopamine Uptake Inhibitors - pharmacology / Gene Knockdown Techniques / Guanosine triphosphatase / Health aspects / Male / Mice / Mice, Inbred C57BL / Neurobiology / Neuronal Plasticity - drug effects / Neuronal Plasticity - physiology / Neurons - drug effects / Neurons - metabolism / Neuropeptides - genetics / Neuropeptides - metabolism / Neuroplasticity / Neurosciences / Nucleus Accumbens - drug effects / Nucleus Accumbens - metabolism / Physiological aspects / Proteins / rac GTP-Binding Proteins - genetics / rac GTP-Binding Proteins - metabolism / rac1 GTP-Binding Protein / Reverse Transcriptase Polymerase Chain Reaction / Signal Transduction - drug effects / Signal Transduction - physiology