l-Dopa induced dyskinesias in Parkinsonian mice: Disease severity or l-Dopa history

Abstract

In Parkinson's disease, the efficacy of L-Dopa treatment changes over time, as dyskinesias emerge with previously beneficial doses. Using MitoPark mice, that models mitochondrial failure in dopamine (DA) neurons and mimics the progressive loss of dopamine observed in Parkinson’s disease, we found that the severity of DA denervation and associated adaptations in striatal neurotransmission at the time of initiation of L-Dopa treatment determines development of L-Dopa induced dyskinesias. We treated 20-week, and 28-week old MitoPark mice with L-Dopa (10 mg/kg i.p. twice a day) and found locomotor responses to be significantly different. While all MitoPark mice developed sensitization to L-Dopa treatment over time, 28-week old MitoPark mice with extensive striatal DA denervation developed abnormal involuntary movements rapidly and severely after starting L-Dopa treatment, as compared to a more gradual escalation of movements in 20-week old animals that started treatment at earlier stages of degeneration. Our data support that it is the extent of loss of DA innervation that determines how soon motor complications develop with L-Dopa treatment. Gene array studies of striatal neurotransmitter receptors revealed changes in mRNA expression levels for DA, serotonin, glutamate and GABA receptors in striatum of 28-week old MitoPark mice. Our results support that delaying L-Dopa treatment until Parkinson’s disease symptoms become more severe does not delay the development of L-Dopa-induced dyskinesias. MitoPark mice model genetic alterations known to impair mitochondrial function in a subgroup of Parkinson patients and provide a platform in which to study treatments to minimize the development of dyskinesia.

Altered glutamate release in the dorsal striatum of the MitoPark mouse model of Parkinson's disease

“…2). Initially, we looked at KCl-stimulated glutamate release in the dorsal striatum of MitoPark mice at 28 weeks of age, an age previously shown to develop LID in these mice (Shan et al, 2015). Glutamate release was measured by the amplitude of the electrochemical peak produced in response to pressure ejected 70 mM KCl (Farrand et al, 2015) which was applied locally in the dorsal striatum (Fig.…”

“…For example, previous studies have demonstrated that MitoPark mice are responsive to L-Dopa therapy with a differential response depending on disease state (Galter et al, 2010; Gellhaar et al, 2015). In addition, Shan et al, (2015) demonstrated behavioral evidence of striatal neuroplasticity in response to DAergic denervation, as well as in response to chronic L-Dopa therapy. Furthermore, it was determined that the extent of striatal DAergic denervation determines when motor complications develop with L-Dopa treatment (Shan et al, 2015).…”

“…In addition, Shan et al, (2015) demonstrated behavioral evidence of striatal neuroplasticity in response to DAergic denervation, as well as in response to chronic L-Dopa therapy. Furthermore, it was determined that the extent of striatal DAergic denervation determines when motor complications develop with L-Dopa treatment (Shan et al, 2015). This study also supported the notion that delaying L-Dopa therapy until behavioral symptoms become more severe did not delay the development of L-Dopa induced dyskinesia (LID).…”

“…This notion is further supported by studies showing that glutamate receptor antagonists alleviated LID (Paoletti et al, 2011; Nicoletti et al, 2011). MitoPark mice, which have been previously shown to develop LID, have increased mRNA expression of glutamate receptors in the dorsal striatum, which may be contributing to the formation of these behavioral abnormalities (Shan et al, 2015). Therefore, the current study was designed to assess glutamate release in the dorsal striatum of MitoPark mice, at an age in which LID was previously determined to be present (28 weeks; Shan et al, 2015).…”

“…MitoPark mice, which have been previously shown to develop LID, have increased mRNA expression of glutamate receptors in the dorsal striatum, which may be contributing to the formation of these behavioral abnormalities (Shan et al, 2015). Therefore, the current study was designed to assess glutamate release in the dorsal striatum of MitoPark mice, at an age in which LID was previously determined to be present (28 weeks; Shan et al, 2015). In addition, we also assessed various markers associated with the uptake and clearance of glutamate from the synaptic cleft to determine a potential mechanism by which glutamate may impact behavioral abnormalities.…”