Drug abuse is a major social problem in the United States, with an estimated 15 million individuals addicted and millions more incarcerated, in addition to many billions of dollars of direct and indirect costs. Abused drugs share two common properties: they provide an initial rewarding "high," and their use sets in motion a chain of neurochemical changes that ultimately lead to continued drug-seeking behavior, often despite diminished satisfaction by the user. Many abused drugs affect the neuromodulator dopamine, which acts through binding and activation of a family of five G protein-coupled receptors. Dopamine receptors are targets for regulation by G protein-coupled receptor kinases (GRKs), which phosphorylate dopamine-bound, activated receptors and reduce the ability of these receptors to activate downstream signaling pathways. We have created mice bearing targeted deletion of the GRK6 gene, and here show that these knockout animals exhibit a profound supersensitivity to the locomotor effects of cocaine. Cocaine acts by inhibiting the presynaptic transporters, which remove released dopamine from synapses, allowing endogenous dopamine to accumulate to high levels and to activate dopamine receptors to a high degree. These GRK6 knockout animals appear to have normal levels of dopamine receptors, but exhibit a markedly increased coupling of these receptors to G proteins. These results suggest the hypothesis that dopamine receptor regulation by GRK6 is an important component of the mechanisms that control dopamine receptor responsiveness to drugs of abuse and that altered GRK6 function may be a predisposing factor favoring drug addiction. We will use studies in genetically-modified mice and in model cells systems to define the importance of GRK6 regulation of dopamine receptors for drug abuse. We will determine whether loss of GRK6 affects responses to other drugs of abuse, and investigate the role of GRK6 in additional behavioral and neurochemical correlates of drug addiction. We will identify the dopamine receptor subtype(s) that GRK6 acts on in mouse striatum, and investigate whether other GRKs have similar effects. Finally, we will use transgenic and conditional knockout approaches in mice to explore whether dopamine receptor regulation by GRK6 is important postsynaptically, presynaptically, or both. The results of these studies will define the role of GRK6 in setting the basal tone of dopamine signaling in the striatum. [unreadable] [unreadable] [unreadable]