Abstract
Bradykinesia (slowness of movement) and other characteristic motor manifestations of Parkinson’s disease (PD) are alleviated by treatment with L-dihydroxyphenylalanine (L-DOPA). Long-term L-DOPA treatment, however, is associated with complications such as motor fluctuations and dyskinesia that severely impair the quality of life. It is unclear whether the effect of L-DOPA on spontaneous motor activity and its dyskinesia-inducing effect share a common mechanism. To investigate the possible connection between these two effects, we analyzed the spontaneous locomotor activity of parkinsonian rats before surgery (unilateral injection of 6-OHDA in the right medial forebrain bundle), before treatment with L-DOPA, during L-DOPA treatment (the “ON” phase), and after the end of L-DOPA treatment (the “OFF” phase). We correlated the severity of dyskinesia (AIM scores) with locomotor responses in the ON/OFF phases of chronic L-DOPA treatment at two different doses. We treated three groups of parkinsonian animals with chronic injections of 8 mg/kg L-DOPA, 6 mg/kg L-DOPA, and saline solution and one group of non-lesioned animals with 8 mg/kg L-DOPA. At the end of the experiment, tyrosine hydroxylase (TH) immunoreactivity was analyzed in the striatum of all parkinsonian rats. We found no correlation between the severity of dyskinesia and spontaneous locomotor activity in the ON or OFF phase of L-DOPA treatment. The only observed correlation was between the pathological rotation induced by L-DOPA at the highest dose and locomotor activity in the ON phase of L-DOPA treatment. In addition, a L-DOPA withdrawal effect was observed, with worse motor performance in the OFF phase than before the start of L-DOPA treatment. These findings suggest that different neural mechanisms underlie the effect of L-DOPA on spontaneous motor activity and its dyskinesia-inducing effect, with a different dose-response relationship for each of these two effects.
Highlights
In Parkinson’s disease (PD), loss of dopaminergic neurons in the pars compacta of the substantia nigra (SN) results in a functional impairment of basal ganglia motor circuits, which leads, in turn, to a characteristic parkinsonian syndrome (Crossman, 1989; Jenner, 2008) including bradykinesia, resting tremor, rigidity, and impairment of posture and gait (Jankovic, 2008; Massano and Bhatia, 2012)
We found no correlation between the severity of dyskinesia and spontaneous locomotor activity in the ON or OFF phase of L-DOPA treatment
All animals lesioned with the 6-OHDA toxin had reduced locomotor activity for total distance traveled (PD + L-DOPA 8 mg: 68.2% ± 4.3%; PD + L-DOPA 6 mg: 72.4% ± 8.7%; PD + saline: 66.2% ± 9.0%) and mean velocity (PD + L-DOPA 8 mg: 67.94% ± 4.3%; PD + L-DOPA 6 mg: 72.3% ± 8.7%; PD + saline: 66.1% ± 9.0%) in the “before treatment” phase compared to the “before surgery” phase
Summary
In Parkinson’s disease (PD), loss of dopaminergic neurons in the pars compacta of the substantia nigra (SN) results in a functional impairment of basal ganglia motor circuits, which leads, in turn, to a characteristic parkinsonian syndrome (Crossman, 1989; Jenner, 2008) including bradykinesia, resting tremor, rigidity, and impairment of posture and gait (Jankovic, 2008; Massano and Bhatia, 2012). The risk that a patient will develop dyskinesia depends on multiple factors including the degree of dopaminergic neurodegeneration (Obeso et al, 2000), the dose and duration of L-DOPA therapy (Hauser et al, 2006), the age of onset of PD (Kostic et al, 1991; Schrag, 2006), the presence or absence of resting tremor (Kipfer et al, 2011), and genetic factors such as genomic polymorphisms (Linazasoro, 2005). The occurrence of Frontiers in Behavioral Neuroscience www.frontiersin.org
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