Parkinson's disease (PD) is a neurodegenerative disorder currently afflicting nearly over one million Americans. Initially, treatment with levodopa (L-DOPA) or a direct dopamine agonist ordinarily confers substantial clinical benefit. Within a few years, however, repetitive administration of these drugs to PD patients ultimately leads to development of disabling motor response complications. Current evidence suggests that these response alterations involve activation of striatal signal transduction cascades causing upregulation of corticostriatal glutamatergic synaptic transmission which in turn modifies striatal output in ways that compromise motor behavior. FosB-mediated activation of cycline-dependent kinase 5 (Cdk5) has been increasingly implicated in the neuroadaptive mechanisms related to repeated psychostimulant administration in drug addiction. To elucidate molecular mechanisms that underlie the pathogenesis of motor response occurring with chronic L-DOPA treatment of parkinsonian animals, the time course of response shortening and the appearance of Abnormal Involuntary Movements (AIMs) is evaluated in relation to change in striatal Cdk5 and glutamatergic signaling in 6-hydroxydopamine lesioned rats. The striatal tissue from these animals is also evaluated for these biochemical changes by using Western blot, Immunoprecipitation and immunohistochemical analyses. The functional significance of striatal Cdk5 activation is then determined by assessing the ability of Cdk5 antisense and inhibitors to affect both the biochemical and motor response changes associated with chronic dopaminomimetic treatment and its subsequent withdrawal. Findings from the proposed studies can provide more accurate understanding of molecular mechanisms underlying striatal neuroadaptive plasticity contributing to the pathogenesis of LDOPA- induced genesis of maladaptive motor complications in advanced PD, and suggest novel approaches to safer and more effective therapy of extrapyramidal motor dysfunction and other dopamine disease states.
