Drug addiction is considered as a disease perturbing the brain's natural reward system. It is well established thatdrugs of abuse exert their effects by interfering with dopaminergic neurotransmission. It has been shown forexample that the dopaminergic system plays an important role in reward-related behaviours. The major goal ofthis Project is to determine by which mechanisms DARPP-32, a crucial phosphoprotein integrating upstreamdopaminergic signals and regulated by casein kinase 1 (CK1) and casein kinase 2 (CK2), mediates the effectsof drugs of abuse and psychostimulants. Using phospho-specific DARPP-32 antibodies and DARPP-32phospho-site mutant mice, we have demonstrated that changes in the phosphorylation state of DARPP-32 occurin response to the in vivo administration of drugs of abuse. We have identified four regulatory phosphorylationsites converting DARPP-32 either into a potent inhibitor of a major protein phosphatase (PP-1), or into a potentinhibitor of a crucial kinase (PKA) depending of the combination of sites phosphorylated. Two of these sites aretargeted by CK1 and CK2. The striatum, the major brain region for the dopaminergic functions, is composed oftwo important heterogeneous neuronal cell populations. The importance of these two neuronal cell populationsfor the above mentioned observations is unknown. We will thus extend our previous in vivo studies to includecell-type specific studies of DARPP-32 phosphorylation. In addition, chronic exposure to drugs of abuse hasbeen shown to induce changes in gene expression that are involved in the rewarding effects of cocaine. We willperform studies in a cell-type specific manner to determine the relative contribution of each cell-type to theseeffects.
Aim I will be the characterization of cell-type specific effects of acute and chronic administrationof drugs of abuse on DARPP-32 phosphorylation and on mRNA translation. We will further investigatethe mechanism by which CK1 and CK2 modulate the effects of drugs of abuse through DARPP-32 usinggenetically modified mice. In addition we will characterize novel CK1 and CK2 interacting proteins in a searchto find putative upstream regulators.
Aim II and Aim III will be the characterization of the role of CK1 andCK2 in the actions of drugs of abuse. Taken together, these studies will provide detailed information onDARPP-32 phosphorylation and DARPP-32-mediated transcriptional events in a cell type specific manner, andalso on the importance and the regulation of CK1 and CK2 in the actions of drugs of abuse.
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