Expression of the cAMP response element (CRE)-binding protein (CREB) has been thought to be constitutive and not subject to regulation. In the course of investigating effects of chronic morphine on the cAMP pathway in the locus coeruleus, a brain region important for opiate addiction, we found that levels of CREB immunoreactivity and CRE binding were increased by chronic morphine administration. To further investigate possible mechanisms underlying this unexpected finding, we studied the regulation of CREB expression in a cell line (CATH.a) that exhibits many properties of locus coeruleus neurons. Agents that activate the cAMP pathway led to a > 60% decrease in CREB mRNA in this cell line. Moreover, these alterations in CREB mRNA levels were associated with changes in levels of CREB immunoreactivity and CRE-binding activity. In contrast, the same treatments fail to alter CREB expression in PC12 pheochromocytoma cells.