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Some long-term users of cocaine develop severe, often treatment-refractory, addiction. In animal studies, researchers identified a molecular mechanism that may underlie the failure to adapt neurally to chronic cocaine exposure. This epigenetic mechanism involves histone deacetylases (HDACs), enzymes that repress gene activation by stopping acetylation of histone proteins on the chromatin surrounding DNA. Acetylation relaxes chromatin, thus easing access to genes by transcriptional activators.
Overexpression of HDAC5 in the nucleus accumbens weakened the rewarding effects of cocaine, and chronic (but not acute) cocaine exposure transiently inactivated HDAC5. Mice with knocked-out HDAC5 were hypersensitized to the effects of chronic, but not a…