Nucleus accumbens (NAc) medium spiny neurons cycle between two states, a functionally inactive downstate and a functionally active upstate. Here, we show that activation of the transcription factor cAMP-response element binding protein (CREB), a common molecular response to several drugs of abuse, increases both duration of the upstate and action-potential firing during the upstate. This effect of CREB is mediated by enhanced N-methyl-D-aspartate glutamate receptor (NMDAR) function: increased CREB activity increases both NMDAR-mediated synaptic currents and surface level of NMDARs, while inhibition of NMDARs abolishes the effect of CREB on upstate duration. Furthermore, mimicking the effect of CREB by pharmacological enhancement of NMDAR function in the NAc in vivo suppressed novelty- and cocaine-elicited locomotor activity. These findings suggest that by enhancing NMDAR-mediated synaptic transmission, CREB activation promotes the proportion of time NAc neurons spend in the upstate. This effect, along with CREB’s enhancement of NAc membrane excitability (1), may counteract drug-induced maladaptations in the NAc, and thus ameliorate the addictive state.