In a mouse model, chronic nicotine exposure before cocaine use exacerbated the epigenetic, gene-expression, electrophysiological, and behavioral effects that occur during the transition from acute to chronic responses to cocaine that have been linked with the addictive process. Nicotine enhancement of the effects can be mimicked with an inhibitor of chromatin-modifying enzymes (class I and II histone deacetylases). These findings may spur the discovery of therapeutics for the treatment of addiction.