Drug addiction is a disease, characterized by long-term alterations in behavior and neurochemistry. This project seeks to identify abnormalities in brain function and behavior, which occur following the repeated administration of psychostimulants and opiates, and to develop pharmacological treatments, which can prevent the development and/or expression of these phenomenon. In rodents, prior exposure to cocaine, amphetamine or morphine results in an enhancement of the rewarding and stimulant effects of these drugs. Such sensitization has been linked to D2 autoreceptor subsensitivity within the mesolimbic dopamine system and a subsequent increase in dopaminergic neurotransmission. Our studies have shown that synthetic kappa-opioid receptor agonists prevent behavioral and neurochemical sensitization to cocaine and similar effects can be observed following the administration of the endogenous kappa -opioid receptor ligand (e.g., dynorphin). In-vivo and in-vitro studies have shown that the administration of kappa-opioid agonists alters dopamine release as well as uptake. Evidence that these agents can modify the dopamine transporter and D2 dopamine receptor number has also been collected. Ongoing studies seek to determine the site and mechanism by which kappa-opioid agonists function as cocaine-antagonists and if kappa-opioid agonists can also prevent the effects of other psychoactive drugs (e.g. amphetamine and methamphetamine). An involvement of delta- opioid receptors in mediating sensitization to cocaine and morphine has also been demonstrated. It is also apparent that drug-induced alterations in delta-opioid receptor function within the nucleus accumbens and/or amygdala may be of particular importance in mediating the affective component of opioid withdrawal. Our work to date indicates a specific role of the delta 2- opioid receptor subtype in mediating withdrawal from opioids as well as psychostimulants. In vivo methods to assess the function of dopamine and opioid peptide systems in animals models of drug addiction are currently being developed. In the mouse we are evaluating the use of microdialysis to detect changes in neurochemistry which occur in response to the voluntary self-administration of cocaine and in the primate, we are developing a model which will enable measurement of transient changes in dopamine neurochemistry via positron emission tomography.