The NK1 receptor antagonist N-acetyl-L-tryptophan reduces dyskinesia in a hemi-parkinsonian rodent model

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-t-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. Conclusion: Daily administration of a SP NK1 receptor antagonist may represent a novel treatment regime that reduces the onset of LID whilst conserving motor function. (C) 2014 Elsevier Ltd. All rights reserved.