Effects of oligonucleotide antisense to dopamine D 1A receptor messenger RNA in a rodent model of levodopa-induced dyskinesia

Abstract

Dyskinesias are abnormal involuntary movements which develop as a side-effect of long-term treatment with levodopa in patients with Parkinson’s disease. The pathophysiology underlying these dyskinesias remains unclear, although, it has been suggested that heightened activity of dopamine D 1 receptor-bearing striatonigral neurons may play a key role. Chronic pulsatile levodopa administration to hemiparkinsonian rats results in sensitization of rotational responses to apomorphine. This sensitization is thought to be analogous to levodopa-induced dyskinesias in humans. In these studies, we further clarify the role of the dopamine D 1A receptor in this rodent model of levodopa-induced dyskinesias using an in vivo oligonucleotide antisense approach. Hemiparkinsonian rats received twice daily injections of levodopa for three weeks followed by intrastriatal infusion of dopamine D 1A receptor antisense (7 nmol/day, three days), a scrambled missense control sequence, or saline. Those animals treated with antisense displayed significantly fewer apomorphine-induced rotations than saline- or missense-treated controls. By reducing dopamine D 1A receptor expression, we were able to attenuate sensitization of the response to apomorphine resulting from chronic pulsatile levodopa treatment. Thus, the dopamine D 1A receptor appears to play a significant role in levodopa-induced dyskinesias and warrants further examination. These findings may have important implications for the development of selective treatment strategies designed to alleviate parkinsonian symptoms, while minimizing motor complications.