Long-term dopamine (DA) replacement therapy in Parkinson's disease (PD) leads to the development of abnormal involuntary movements known as l-Dopa-induced dyskinesia (LID). The transcription factor ÄFosB that is highly up-regulated in the striatum following chronic l-Dopa exposure may participate in the mechanisms of altered neuronal responses to DA generating LID. To identify intrinsic effects of elevated ÄFosB on l-Dopa responses, we induced transgenic ÄFosB overexpression in the striatum of parkinsonian nonhuman primates kept na?ve of l-Dopa treatment. Elevated ÄFosB levels led to consistent appearance of LID since the initial acute l-Dopa tests. In line with this motor response, striatal projection neurons (SPNs) responded to DA with changes in firing frequency that reversed at the peak of the motor response, and these unstable SPN activity changes in response to DA are typically associated with the emergence of LID. Transgenic ÄFosB overexpression also induced up-regulation of other molecular markers of LID. These results support an autonomous role of striatal ÄFosB in the adaptive mechanisms altering motor responses to chronic DA replacement in PD.
Animals Animals, Genetically Modified