The transcription factor cAMP response element-binding protein (CREB) within the nucleus accumbens (NAc) plays an important role in regulating mood. In rodents, increased CREB activity within the NAc produces depression-like signs including anhedonia, whereas disruption of CREB activity by expression of a dominant-negative CREB (mCREB, which acts as a CREB antagonist) has antidepressant-like effects. We examined how disruption of CREB activity affects brain reward processes using intracranial self-stimulation (ICSS) and inducible bitransgenic mice with enriched expression of mCREB in forebrain regions including the NAc. Mutant mice or littermate controls were prepared with lateral hypothalamic stimulating electrodes, and trained in the ICSS procedure to determine the frequency at which the stimulation becomes rewarding (threshold). Inducible expression of mCREB did not affect baseline sensitivity to brain stimulation itself. However, mCREB-expressing mice were more sensitive to the rewarding (threshold-lowering) effects of cocaine. Interestingly, mCREB mice were insensitive to the depressive-like (threshold-elevating) effects of the kappa-opioid receptor agonist U50,488. These behavioral differences were accompanied by decreased mRNA expression of G-protein receptor kinase-3 (GRK3), a protein involved in opioid receptor desensitization, within the NAc of mCREB mice. Disruption of CREB or GRK3 activity within the NAc specifically by viral-mediated gene transfer enhanced the rewarding impact of brain stimulation in rats, establishing the contribution of functional changes within this region. Together with previous findings, these studies raise the possibility that disruption of CREB in the NAc influences motivation by simultaneously facilitating reward and reducing depressive-like states such as anhedonia and dysphoria.