Opioid addiction caused by prolonged exposure to strong opioid receptor agonists follows from a series of incompletely understood molecular and cellular changes in the brain. Following the cloning of the delta opioid receptor by groups headed by Evans and Kieffer, many mechanistic details responsible for mu, delta and kappa opioid receptor desensitization in transfected cell lines have been defined. These insights complement the large literature describing behavioral measures of opioid tolerance and dependence. This project would build upon the molecular understanding of the desensitization process to explore the relationship between mu receptor desensitization and behavioral tolerance. Opioid-dependent learning mechanisms and the underlying synaptic plasticity mechanisms are thought to form a distinct, second component of opioid tolerance. The role of synaptic plasticity in cellular tolerance to opioids will also be explored. Advances in mouse genetics have provided powerful new tools that have been useful in defining the molecular components underlying complex behaviors. In this project, we propose to use mice having specifically engineered genetic mutations to study the role of those genes in controlling the cellular and behavioral responses to opiate drugs. Sustained exposure to opiate drugs produces adaptive changes in the nervous system that result in tolerance, dependence, and in some cases addiction. Our hypothesis is that opiate-induced synaptic plasticity forms the cellular basis of drug addiction. Ultimately, a better understanding of the consequences of prolonged opioid exposure at the cellular and molecular levels is likely to help define the changes in brain physiology responsible for opioid addiction.