Differential roles of two isoforms of dopamine D2 receptors in l-dopa-induced abnormal involuntary movements in mice

l-dopa and dopamine D2 receptor (D2R) agonists are commonly used to relieve the motor deficits of Parkinson's disease. However, long-term treatment with l-dopa or D2R agonists can induce adverse effects such as abnormal involuntary movements (AIMs), which are major limiting factors in achieving long-term control of parkinsonian syndromes. The pathophysiological mechanisms involved in the development of dopaminergic agonist-induced adverse effects are not well understood. Here, we examined the role of two D2R isoforms, D2S and D2L, in l-dopa-induced AIMs using dopamine D2L knockout (D2L KO) mice (expressing purely D2S) and wild-type mice (expressing predominantly D2L). We found that D2L KO mice displayed markedly enhanced AIMs in response to chronic treatment of l-dopa compared to wild-type mice. The l-dopa-induced enhancement of AIMs in D2L KO mice was significantly reduced by the D2R antagonist eticlopride. D2L KO mice also displayed markedly enhanced AIMs in response to chronic treatment with quinpirole, a preferential D2R agonist. These results suggest that D2S contributes more than D2L to dopaminergic agonist-induced AIMs. Our findings may uncover a new factor that contributes to the pathophysiology of dopaminergic drug-induced AIMs, a characteristic manifestation of dyskinesia and also present in psychosis. There is a possibility that the increased ratio of D2S to D2L in the brain plays a significant role in the development of AIM side effects induced by l-dopa or D2R agonists. Copyright (c) 2021 Wolters Kluwer Health, Inc. All rights reserved.