To investigate the role of cAMP response element-binding protein (CREB) in the adaptive responses to psychotropic drugs, we have developed inducible, brain region-specific CREB transgenic mice using the tetracycline-regulated gene expression system. The tetracycline transactivator (tTA) was placed under the control of 1.8-kilobase neuron-specific enolase (NSE) promoter for this purpose. Different patterns of CREB overexpression were found in striatum, nucleus accumbens, and cingulate cortex in different lines of bitransgenic mice, and CREB expression was blocked by addition of doxycycline, an analog of tetracycline. Overexpression of CREB influenced the expression of other members of the CREB/ATF family of transcription factors, consistent with previous reports. In addition, psychostimulant induction of dynorphin, a neuropeptide regulated by drugs of abuse, was up-regulated in striatum. Finally, there was a significant reduction in cocaine-induced locomotor activity in the CREB bitransgenic mice. These results are consistent with a role for CREB in mediating adaptive changes that occur in response to drugs of abuse.