GABA storage and release in the medial globus pallidus in L-DOPA-induced dyskinesia priming

Abstract

Levo-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease; however, most patients develop uncontrollable abnormal involuntary movements known as L-DOPA-induced dyskinesia. L-DOPA-induced dyskinesia can be reduced by pallidotomy of the medial globus pallidus or pallidal deep brain stimulation, suggesting that the medial globus pallidus plays a significant role in the development of L-DOPA-induced dyskinesia. In the present study, the pathological changes of the medial globus pallidus in L-DOPA-induced dyskinesia were studied in rat models of Parkinson's disease (unilateral 6-hydroxydopamine lesioning) and L-DOPA-induced dyskinesia (L-DOPA injection in Parkinson's disease-model rats twice daily for 2 weeks, confirmed by display of dyskinesia-like abnormal involuntary movements). L-DOPA-induced dyskinesia-model rats displayed medial globus pallidus hypertrophy, enlarged axon terminals surrounding the dendrites of medial globus pallidus neurons, and increased density of synaptic vesicles in enlarged axon terminals on the lesioned side. Synaptic terminal enlargement reversed after discontinuation of L-DOPA. Histological studies revealed the enlarged synaptic terminals were those of GABAergic striatal (direct pathway) neurons. A single injection of L-DOPA enhanced GABA release in the medial globus pallidus on the lesioned side in L-DOPA-induced dyskinesia-model rats compared to Parkinson's disease-model rats. In addition, microinjection of muscimol, a GABAA receptor agonist, into the medial globus pallidus on the lesioned side of Parkinson's disease-model rats induced dyskinesia-like abnormal involuntary movements. Microinjection of bicuculline, a GABAA receptor antagonist, into the medial globus pallidus on the lesioned side alleviated L-DOPA-induced dyskinesia in Parkinson's disease-model rats that had received L-DOPA prior to the microinjection. These results indicate that priming for L-DOPA-induced dyskinesia comprises excessive GABA storage in axon terminals of the direct pathway and that expression of L-DOPA-induced dyskinesia is associated with enhanced GABA release into the medial globus pallidus after L-DOPA dosing and the resultant excessive stimulation of GABAA receptors.