title: The NK1 receptor antagonist N-acetyl-L-tryptophan reduces dyskinesia in a hemi-parkinsonian rodent model.
abstract: BACKGROUND
  Dyskinesia or abnormal involuntary movements (AIMs) are a disabling effect of chronic L-DOPA administration and consequent pulsatile stimulation of dopamine receptors. This abnormal activation causes maladaptive changes including upregulation of FosB expression in dynorphin containing striatal cells. Substance P (SP) is co-localized within dynorphin positive cells and is increased within the substantia nigra by L-DOPA (L-3,4-dihydroxyphenylalanine) treatment. Accordingly, we determined if treatment with a SP NK1 receptor antagonist reduced the onset of L-DOPA induced dyskinesia (LID) in the hemi-parkinsonian rodent model.
  
  
  METHODS
  Adult male Sprague-Dawley rats underwent unilateral 6-OHDA (6-hydroxydopamine-hydrobromide) lesions of the medial forebrain bundle. At day 21, daily administration commenced of either L-DOPA (6 mg/kg plus 15 mg/kg of benseraside), L-DOPA with the NK1 antagonist N-acetyl-L-tryptophan (NAT) or equal volume of saline. Animals were tested with the rodent AIM scale assessing axial, contralateral forelimb and orolingual AIMs. Assessment of L-DOPA induced turning was undertaken, and motor function determined using the accelerating rotarod and adjusting step test. Dopaminergic neuronal counts and immunoreactivity for SP and FosB were undertaken.
  
  
  RESULTS
  All animals treated with L-DOPA alone developed dyskinesia, whereas combined administration of NAT with L-DOPA significantly reduced onset of AIMs and prevented mild to moderate dyskinesia. In non-dyskinetic NAT treated animals, similar numbers of FosB+ striatal cells were recorded as in saline treated animals. Importantly NAT treatment did not interfere with the anti-parkinsonian effect of L-DOPA.
  
  
  CONCLUSIONS
  Daily administration of a SP NK1 receptor antagonist may represent a novel treatment regime that reduces the onset of LID whilst conserving motor function.
authors.affiliation: The Adelaide Centre for Neuroscience Research, School of Medical Sciences, The University of Adelaide, South Australia, Australia. Electronic address: Emma.Thornton@adelaide.edu.au.
authors.forename: Emma
authors.initials: E
authors.lastname: Thornton
authors.affiliation: The Adelaide Centre for Neuroscience Research, School of Medical Sciences, The University of Adelaide, South Australia, Australia.
authors.forename: Mark Macquarie
authors.initials: MM
authors.lastname: Hassall
authors.affiliation: The Adelaide Centre for Neuroscience Research, School of Medical Sciences, The University of Adelaide, South Australia, Australia.
authors.forename: Frances
authors.initials: F
authors.lastname: Corrigan
authors.affiliation: The Adelaide Centre for Neuroscience Research, School of Medical Sciences, The University of Adelaide, South Australia, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: Vink
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D007839:Functional Laterality / Q000187:drug effects / Q000502:physiology*; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D008474:Medial Forebrain Bundle / Q000293:injuries; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D000978:Antiparkinson Agents; C483820:Fosb protein, rat; D016760:Proto-Oncogene Proteins c-fos; C086089:3,5-bis(trifluoromethyl)benzyl N-acetyltryptophan; C006392:N-acetyltryptophan; D007980:Levodopa; D014364:Tryptophan; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase
keywords: Dyskinesia; FosB; Motor function; Substance P; Tachykinin NK1 receptor; l-DOPA