Evaluation of Levodopa Dose and Magnitude of Dopamine Depletion as Risk Factors for Levodopa-Induced Dyskinesia in a Rat Model of Parkinson's Disease

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 (Grandas et al., 1999). Risk factors for LID include young age of PD onset, duration and dose of levodopa treatment, severity and duration of PD symptoms, and female gender (Nutt, 1992;Schrag and Quinn, 2000;Zappia et al., 2005). However, it is also clear that not all PD patients develop LID despite the presence of multiple risk factors. Because LID can severely limit the usefulness of levodopa treatment (Hurtig, 1997), this has prompted much research aimed at discovering mechanisms that underlie the development of LID in PD.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 ne...

Enhanced striatal cholinergic neuronal activity mediatesl-DOPA–induced dyskinesia in parkinsonian mice

“…S5C), consistent with the literature using this model (2,(30)(31)(32)(33)(34). Acute treatment with L-DOPA-induced pERK in predominantly medium-sized neurons and repeated L-DOPA administration reduced the number of medium-sized pERK-labeled cells by 72% and increased the number of large-diameter pERK-labeled neurons by 3.4-fold in lesioned striatum (Fig.…”

“…Unilateral 6-OHDA lesions used in this study produced massive striatal DA depletions of 94%, covering the entire striatum, whereas striatal DA depletion is limited to the most dorsal aspect of dorsal striatum in Pitx3 ak/ak mice. LID has been reported with the first exposure to L-DOPA in unilateral 6-OHDA-lesioned rats (2,(30)(31)(32)(33)(34) and the level of dyskinetic behavior is influenced by the amount of DA loss (34). Therefore, we believe the Pitx3 ak/ak mice show the time course more consistent with mild to moderate PD, whereas 6-OHDAlesioned mice model a more severe stage of PD.…”

Dyskinesia and the antiparkinsonian response always temporally coincide

“…The fact that dyskinesia can emerge very quickly in severely affected or young people with PD is consistent with this argument, 10,11 as is the observation that dyskinesia can be seen with the first dose of levodopa in rodents and monkeys with toxin-induced parkinsonism. 12,13 The second important observation of this study is that the antiparkinsonian responses and the dyskinesia response evolved in a similar manner during the first 4 years of levodopa therapy. With time, both the increase in tapping speed and dyskinesia began with a shorter latency during the 2-hour levodopa infusions.…”

Sigma ligands, but not N-methyl-D-aspartate antagonists, reduce levodopa-induced dyskinesias

“…Significant modifications from Cenci et al [9] include the use of males, altered lesion coordinates, desipramine to protect noradrenergic neurons, and a higher 6-OHDA dose. Our collaborators recently demonstrated that severe dopamine depletion is necessary but not sufficient to evoke dyskinesias and reviewed factors that may affect dyskinesia emergence [10].…”