Deletion of CREB1 from the dorsal telencephalon reduces motivational properties of cocaine.

Transcriptional changes in neurons underpin the long-lived cellular response to environmental stimuli, and cAMP-responsive element-binding protein (CREB1) has been implicated in this process. Exposure to psychostimulants such as cocaine results in persistent neuronal plasticity in cortical circuitry that likely modulates the motivation to use the drug again. To examine whether CREB1 in cortical glutamatergic neurons was implicated in cocaine use, we developed conditional CREB1 mutants that exhibit ablation of functional CREB1 in the cortex and hippocampus. Here we report that CREB1 mutants show normal locomotor responses to acute and chronic cocaine and develop a place preference for cocaine. However, CREB1 mutants demonstrate a diminished drive to self-administer cocaine under operant conditions. We conclude that there is a specific role for CREB1 in telencephalic glutamatergic neurons regulating the motivational properties of cocaine.