The alpha(2)-adrenergic receptor antagonist idazoxan reduces dyskinesia and enhances anti-parkinsonian actions of L-dopa in the MPTP-lesioned primatemodel of parkinson's disease

Dopamine replacement therapy in patients with Parkinson's disease is plague d by the emergence of abnormal involuntary movements known as L-dopa-induce d dyskinesias. It has been demonstrated that yohimbine can reduce L-dopa-in duced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease. Yohimbine is, among other things, an alpha-adrenergic receptor antagonist. In this study, we demonstrate that the selective and potent alpha(2)-adren egic receptor antagonist idazoxan reduces L-dopa-induced dyskinesia in the MPTP-lesioned marmoset model of Parkinson's disease. The alpha(2)-adrenergi c receptor antagonists rauwolscine and yohimbine also reduce L-dopa-induced dyskinesia. Furthermore, we demonstrate that coadministration of idazoxan with L-dopa can pro-vide an anti-parkinsonian action mote than twice the le ngth of that seen with L-dopa alone. However, idazoxan as a monotherapy dis played no anti-parkinsonian actions, We propose that idazoxan in combinatio n with L-dopa may provide a novel approach to the treatment of Parkinson's disease that will not only reduce the dyskinetic side effects, but extend t he antiparkinsonian actions of L-dopa. Idazoxan, as an adjunct to dopamine replacement, may prove useful in the treatment of parkinsonian patients at all stages of disease progression.