Heroin or cocaine addictions are major public health problems, with massive biomedical and societal costs. The onset of these addictive states is characterized by cycles of repeated exposure to the drug of abuse, followed by withdrawal/abstinence and re-exposure. Therefore these cycles may be cardinal features of addictions as chronic relapsing disorders. Persisting adaptations in endogenous opioid neuropeptide and opioid receptor systems (e.g., prodynorphin [Pdyn], MOP-r and KOP-r) in dopaminergic nigrostriatal and meso-limbic pathways occur as a result of exposure to heroin or cocaine, as well as withdrawal therefrom. It is hypothesized that these neurobiological changes underlie the increased propensity to self-administer drugs, or increased propensity to escalate such self-administration upon re-exposure. The neurobiological effects of a standardized cycle of chronic exposure, withdrawal and re-exposure cannot be directly studied in humans, and have not been systematically studied in experimental animals. Thus, the main objective of this project is to determine dynamic neurobiological changes (at the mRNA and protein level in the aforementioned and related target systems) in rats at specific stages in a cycle of chronic (14-day) escalating exposure to heroin or cocaine, followed by long term (14-day) withdrawal and chronic (14-day) re-exposure to the drug of abuse, modeling the neurobiological consequences of an addiction-like cycle (Aim 1). Parallel studies would define changes to reward-related functions of heroin or cocaine (in self-administration and conditioned place preference assays) that occur at defined stages of exposure, withdrawal and re-exposure (Aims 2 and 3). Further studies in mice would determine analogous changes in this addiction-like cycle, also with respect to critical neurochemical effects of heroin, cocaine and opioid neuropeptides on dopamine levels in terminal fields of these dopaminergic pathways (Aim 4). Targeted gene "knockdown" with RNA interference using siRNAs specific for MOP-r or Pdyn will be directed toward areas containing cell bodies of the above pathways, either prior to chronic exposure, or at the onset of withdrawal (Aim 5). These siRNA studies will determine whether "knockdown" interventions can block neurobiological, neurochemical or reward-related behavioral changes occurring at specific stages of the addiction-like cycle to heroin or cocaine. Locally administered pharmacological probes (e.g., opioid receptor antagonists) will be used to confirm potential pharmacotherapeutic approaches mechanistically identified with siRNA knockdown. This proposal would determine neurobiological changes underlying an addiction-like cycle of exposure, withdrawal and re-exposure to heroin or cocaine, and will identify targets for pharmacotherapeutic intervention in such stages. For synergy, studies in this Project (Aim 1) will use parallel methodology with Project 2 (Aim 2) of this Center (and will focus on the influence of stress-responsive systems in this setting).