Evaluation of levodopa dose and magnitude of dopamine depletion as risk factors for levodopainduced dyskinesia in a rat model of Parkinson's disease

Abstract

ABSTRACT Levodopa dose and severity of Parkinson's disease (PD) are recognized risk factors for levodopa-induced dyskinesia (LID) in humans. The purpose of the present study was to evaluate the ability of these variables to predict severity of LID in a rat model of PD. Varied concentrations of 6-hydroxydopamine were injected into the midbrain to produce wide ranges of dopamine depletion in striatum. Three weeks later, rats were given daily injections of levodopa (2-10 mg/kg i.p.) plus benserazide (12.5 mg/kg i.p.) for 15 days. Abnormal involuntary movements (AIMs) were measured for limb, axial, orolingual, and rotatory movements. Dose-response analysis for total AIM scores yielded a levodopa ED 50 value of 3.2 mg/kg on treatment day 15. There were strong interrelated correlations between individual AIM categories ( Ͼ 0.7) and for each AIM category in regard to total AIM score ( Ͼ 0.7). In rats that received levodopa doses that were greater than the ED 50 , rates of amphetamine-induced rotation were significantly correlated with total AIM scores ( ϭ 0.413). However, of those rotating Ͼ5 times/min, 34% had relatively low AIM scores (Ͻ8). Likewise, there was a significant correlation between percentages of tyrosine hydroxylase (TH) loss and total AIM scores ( ϭ 0.388). However, in those rats that had Ͼ85% TH loss, 30% had AIM scores Ͻ8. Our results show that given an adequate dose and magnitude of striatal dopamine depletion, levodopa produces dyskinesia with a continuous spectrum of severity. Although levodopa dose and level of dopamine depletion are significant risk factors for LID, we conclude that other factors must contribute to LID susceptibility. The tremor, rigidity, and akinesia of Parkinson's disease (PD) are caused by progressive loss of dopamine innervation in the basal ganglia. Symptoms of PD can be largely alleviated by treatment with the dopamine precursor levodopa. However, chronic treatment is often complicated by the emergence of levodopa-induced dyskinesia (LID), which is characterized by involuntary choreiform or dystonic movements of the face, trunk, or limbs. After 1 year of levodopa treatment, more than 60% of PD patients reportedly show signs of LID, and new cases occur at an incidence of 10% per year In the last few decades, there has been steady advancement in using the hemi-parkinsonian rat to investigate LID. In this model of PD, rats receive a unilateral intracerebral injection of 6-hydroxydopamine (6-OHDA) that causes ipsilateral destruction of dopamine-containing neuron