Response fluctuations and dyskinesias are often associated with chronic dopamine-replacement therapy for Parkinson's disease (PD). It is these 'side-effects' that severely limit the long-term usefulness of this therapy. Drug-induced changes in motor behavior are also observed in an animal model of PD, rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway. These animals show response sensitization upon repeated treatment with dopamine agonists, a phenomenon called 'priming'. Priming of 6- OHDA rats can be established following injection of D1, D2 or D2/D1 dopamine agonists and once established can persist for many months suggesting that both the induction and maintenance of priming require changes in gene expression. While D1- or D2-priming enhance D2-mediated rotational behavior to a similar extent, the adaptive changes underlying this behavioral sensitization appear to involve different molecular adaptations occurring in separate striatal output neurons. For example, D1-priming permits a challenge with a D2 agonist to induce Fos expression in D1 receptor-expressing striatoentopeduncular 'direct pathway' neurons, suggesting that D1-priming influences the expression of genes in the 'direct pathway'. In contrast, D2-priming permits a challenge with a D2 agonist to enhance motor behavior, but without the induction of Fos in 'direct pathway' neurons, suggesting that the molecular basis of D2-priming is different from that of D1-priming. Consequently, D2-priming should produce different alterations in gene expression compared with D1-priming--changes that would likely occur in D2 receptor-expressing striatopallidal 'indirect pathway' neurons. Experiments in this proposal will use in situ hybridization to examine the expression genes encoding striatal neuropeptides and dopamine receptors following D1- and D2-priming in order to correlate changes in specific mRNA molecules with the priming of D2-mediated rotational behavior. Characterization of the molecular changes in striatal output pathways following D1- and D2-priming in 6-OHDA rats may lead to a better understanding of the molecular basis of dyskinesias associated with dopamine replacement therapy for PD. Elucidation of this mechanism could lead to treatment strategies aimed to prevent these dyskinesias, which would, in turn, lengthen the time that dopamine replacement therapy is effective to treat patients with PD.
