Addiction to psychostimulants (PS) is a chronic condition of compulsive drug seeking. This condition is thought to arise from cellular and molecular adaptations in the brain reward systems. In particular, the mesolimbic dopaminergic system, which plays a role in rewarding properties of most drugs of abuse, is severely affected by PS. The chronic PS use enhances the D1 dopamine receptor-mediated signaling in the nucleus accumbens (Acb), and overactive D1 receptor-cAMP-PKA signaling cascade seems to be critical for PS addiction. The signaling of G protein-coupled receptors, including dopamine receptors, is regulated by G protein-coupled receptor kinases (GRKs) and arrestins via the homologous desensitization mechanism. We hypothesize that GRKs and arrestins play the key role in signaling alterations responsible for addiction to PS. We have recently established that overexpression of GRK6 in the striatum of parkinsonian rodents and monkeys significantly alleviated L-DOPA-induced dyskinesia. Since both chronic PS consumption and L-DOPA treatment produce intermittent hyperdopaminergic states, many molecular adaptations are common for both conditions. Thus, this evidence suggests that overexpression of select GRK isoforms and/or simultaneous overexpression of a GRK and an arrestin would suppress PS-induced behaviors. To test this hypothesis, we will express GRKs and GRK/arrestin combinations in Acb using lentiviruses and examine locomotor sensitization to PS. We expect increased availability of arrestins/GRKs to suppress sensitization and GRK/arrestin knockdown via lentivirally- delivered microRNAs to facilitate it. Aim 2 is designed to elucidate the effect of arrestin/GRK overexpression and knockdown on rewarding properties of PS measured in the conditioned place preference paradigm. The critical point in addiction treatment is prevention of relapse. We will determine whether arrestins/GRK expressed in Acb affects extinction and drug-induced reinstatement of cocaine-induced conditioned place preference. These studies will define the role of arrestins and GRKs in addiction to PS drugs and suggest novel therapeutic targets to treat addiction. PUBLIC HEALTH RELEVANCE: Individuals addicted to psychostimulant drugs, such as cocaine, have strong craving for drugs and have to straggle every day to remain drug-free. At present, we still understand poorly how the drug addiction is formed, and there are no methods to treat addiction to psychostimulants. This project is designed to explore whether the proteins called G protein-coupled receptor kinases and arrestin are important in drug addiction, and whether we could target them to help people combat addiction and prevent reinstatement of drug-seeking behavior.