MOLECULAR BASIS OF STRIATAL D1 SUPERSENSITIVITY

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Dopamine receptor supersensitivity may underlie the dyskinesias that limit levodopa treatment for Parkinson's disease (PD). Its mechanism is unknown. Following destruction of the substantia nigra in human and rat, D1 receptor supersensitivity develops despite unchanged receptor number and affinity. our preliminary data indicate that nigral lesions alter D1- mediated regulation of cAMP- or Ca++-regulated signal transduction pathways, or both, suggesting the hypothesis that altered Intracellular signal transduction underlies D1 receptor supersensitivity. This application proposes to test this hypothesis. Aim 1 will determine whether D1 supersensitivity following nigral destruction is associated with altered expression of molecules in the cAMP signal transduction pathway, using Northern analyses and in situ hybridization. Aim 2 will determine if Ca++-regulated signal transduction pathways could be important for D1 supersensitivity by examining the effects of blocking different steps in Ca++-regulated pathways on D1- mediated CREB phosphorylation and Fos expression in primary striatal cell culture. Aim 3 will determine whether antisense phosphorothioate oligonucleotides can specifically inactivate signal transduction molecules important for D1 function in primary striatal cell culture. Aim 4 will test the hypothesis that upregulation of factors identified in earlier experiments plays a causal role in D1 supersensitivity by attempting to block rotational behavior in 6-OHDA-lesioned rats with intracerebral infusions of antisense phosphorothioate oligonucleotides. Successful completion of the proposed experiments will provide insight into the mechanisms of striatal adaptation to dopaminergic denervation and, in particular, D1 supersensitivity. The results may suggest new avenues for prevention or treatment of levodopa-induced dyskinesias in PD.