The aim of the present project is to further characterize the role of endogenous opioids in the neurobiological substrate of affective disorders and drug dependence by using two new tools: the complete inhibitors of enkephalin catabolism, able to cross the blood brain barrier, that have been syntesized in this laboratory, and the recently generated mutant mice deficient in CREB. By using these mutant mice, we have shown that CREB-dependent transcription is required for the expression of physical opiate withdrawal. We will now investigate the role of CREB-on the psychological component of dependence induced by endogenous and exogenous opiods, and in the Genesis of affective disorders. In a second step, we will investigate the role played by the kinases in the specific brain structures implicated in opiate dependence. The results obtained from these studies will also provide important information about the possible therapeutic application of the new inhibitors of the enke phalin catabolism.