title: Levodopa-induced dyskinesia is associated with increased thyrotropin releasing hormone in the dorsal striatum of hemi-parkinsonian rats.
abstract: BACKGROUND
  Dyskinesias 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.
  
  
  RESULTS
  Quantitative 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
  TRH 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.
authors.affiliation: Neurology Department, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Ippolita
authors.initials: I
authors.lastname: Cantuti-Castelvetri
authors.forename: Ledia F
authors.initials: LF
authors.lastname: Hernandez
authors.forename: Christine E
authors.initials: CE
authors.lastname: Keller-McGandy
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Kett
authors.forename: Alex
authors.initials: A
authors.lastname: Landy
authors.forename: Zane R
authors.initials: ZR
authors.lastname: Hollingsworth
authors.forename: Esen
authors.initials: E
authors.lastname: Saka
authors.forename: Jill R
authors.initials: JR
authors.lastname: Crittenden
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Nillni
authors.forename: Anne B
authors.initials: AB
authors.lastname: Young
authors.forename: David G
authors.initials: DG
authors.lastname: Standaert
authors.forename: Ann M
authors.initials: AM
authors.lastname: Graybiel
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D010302:Parkinson Disease, Secondary / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D007980:Levodopa; D013973:Thyrotropin-Releasing Hormone; D004298:Dopamine