Levodopa-Induced Dyskinesia Is Associated with Increased Thyrotropin Releasing Hormone in the Dorsal Striatum of Hemi-Parkinsonian Rats

Ippolita Cantuti-Castelvetri,Zane R Hollingsworth,Alex Landy,Esen Saka,Eduardo A Nillni,Ann M Graybiel,Ledia F Hernandez,Anne B Young,Lauren R Kett,David G Standaert,Jill R Crittenden,Christine E Keller-Mcgandy,Mark R Cookson

doi:10.1371/journal.pone.0013861

Abstract

BackgroundDyskinesias associated with involuntary movements and painful muscle contractions are a common and severe complication of standard levodopa (L-DOPA, L-3,4-dihydroxyphenylalanine) therapy for Parkinson's disease. Pathologic neuroplasticity leading to hyper-responsive dopamine receptor signaling in the sensorimotor striatum is thought to underlie this currently untreatable condition.Methodology/Principal FindingsQuantitative real-time polymerase chain reaction (PCR) was employed to evaluate the molecular changes associated with L-DOPA-induced dyskinesias in Parkinson's disease. With this technique, we determined that thyrotropin releasing hormone (TRH) was greatly increased in the dopamine-depleted striatum of hemi-parkinsonian rats that developed abnormal movements in response to L-DOPA therapy, relative to the levels measured in the contralateral non-dopamine-depleted striatum, and in the striatum of non-dyskinetic control rats. ProTRH immunostaining suggested that TRH peptide levels were almost absent in the dopamine-depleted striatum of control rats that did not develop dyskinesias, but in the dyskinetic rats, proTRH immunostaining was dramatically up-regulated in the striatum, particularly in the sensorimotor striatum. This up-regulation of TRH peptide affected striatal medium spiny neurons of both the direct and indirect pathways, as well as neurons in striosomes.Conclusions/SignificanceTRH is not known to be a key striatal neuromodulator, but intrastriatal injection of TRH in experimental animals can induce abnormal movements, apparently through increasing dopamine release. Our finding of a dramatic and selective up-regulation of TRH expression in the sensorimotor striatum of dyskinetic rat models suggests a TRH-mediated regulatory mechanism that may underlie the pathologic neuroplasticity driving dopamine hyper-responsivity in Parkinson's disease.

Highlights

The loss of striatal dopamine that results from degeneration of midbrain dopamine-containing neurons is responsible for much of the motor dysfunction characteristic of Parkinson’s disease (PD)
To determine the neural basis for these effects of the mRNA for preprothyrotropin releasing hormone (TRH) and thyroid hormones, we examined the effects of dopamine depletion and subsequent L-DOPA treatment on the striatal expression of preproTRH mRNA by quantitative polymerase chain reaction (PCR) and proTRH peptide by immunohistochemistry and by radioimmunoassay (RIA) [10,20,21]
To induce behavioral changes similar to the dyskinesias observed in PD patients [22,23,24,25,26], we employed the wellestablished neurotoxic rat model of PD, in which unilateral infusion of 6-OHDA into the medial forebrain bundle, inducing loss of dopamine-containing neurons in the nigrostriatal system, was followed by chronic L-DOPA treatment

Summary

Introduction

The loss of striatal dopamine that results from degeneration of midbrain dopamine-containing neurons is responsible for much of the motor dysfunction characteristic of Parkinson’s disease (PD). Of the several animal models that reproduce the features of LID, among the most extensively studied is the classic hemi-parkinsonian rat model, in which one side of the striatum is depleted of dopamine by 6-hydroxydopamine (6-OHDA) before the dyskinesia-inducing treatment with L-DOPA. We used this model here to identify genes related to pathologic neuroplasticity associated with PD and LID. Pathologic neuroplasticity leading to hyper-responsive dopamine receptor signaling in the sensorimotor striatum is thought to underlie this currently untreatable condition

Methods

Results

Conclusion