Effect of levodopa chronic administration on behavioral changes and fos expression in basal ganglia in rat model of PD

Abstract

To study behavioral character and changes of neuronal activity in the basal ganglia of rat model of levodopa-induced dyskinesia, unilateral 6-hydroxydopamine lesioned rat model of Parkinson disease (PD) was treated with levodopa/benserazide twice daily for 4 weeks and the behavior observed on the 1st, 3rd, 4th, 7th, 9th, 10th, 14th, 21st and 28th day. The animals were sacrificed and immunohistochemical technique was used to measure the changes of Fos expression in the caudate putamen (CPU), globus pallidus (GP) and sensorimotor area of cerebral cortex 2 h after the last treatment. The results showed that pulsatile treatment with a subthreshold dose of levodopa gradually induced abnormal involuntary movement (AIM), including stereotypy (limb dyskinesia, axial dystonia and masticatory dyskinesia) towards the side contralateral to the dopamine-denervated striatum and increased contraversive rotation. The motor pattern of each subtype was highly stereotypic across individual rats, and the proportion of each subtype was not consistent among individual rats. Fos positive nuclei in the CPU and GP were increased by levodopa acute administration, and more remarkably in the CPU, but not in the cerebral cortex. After repeated levodopa treatment, Fos positive nuclei were reduced remarkably in the CPU, but were increased in the GP and cerebral cortex. It was concluded that the neural mechanisms underlying levodopa induced AIM in rat model of PD was very similar to those seen in levodopa-induced dyskinesia (LID) in PD patients and MPTP-lesioned monkeys, and increased striatopallidal neuronal activity might be involved in occurrence of LID.

Keywords

dyskinesia / levodopa / Parkinson disease / immediate early gene

References

[1] ThomasJ, WangJ, TakubaH, et al.. A 6-OHDA induced selective Parkinsonian rat model: further biochemical and behavioural characterization. Exp Neurol, 1994, 126(2): 159-159

[2] LeeC S, CenciM A, SchulzerM., et al.. Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesia in a rat model of Parkinson disease. Brain, 2000, 12(7): 1365-1365

[3] OlssonM, NikkahG, BentlageC, et al.. Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test. J Neurosci, 1995, 15(5): 3863-3863

[4] PapaS, BoldryR, EngberT M, et al.. Reversal of levodopa-induced motor fluctuations in experimental Parkinsonism by NMDA receptor blockade. Brain Res, 1995, 701(1): 13-13

[5] HenryB, CrossmanA R, BrotchieJ M. Characterization of enhanced behavioral responses to L-dopa following repeated administration in the 6-hydroxydopamine-lesioned rat model of Parkinsion disease. Exp Neurol, 1998, 151(2): 334-334

[6] OhJ D, VaughanC L, ChaseT N. Effect of dopamine denervation and dopamine agonist administration on serine phosphorylation of striatal nmda receptor subunits. Brain Res, 1999, 821(2): 433-433

[7] HenryB, FoxS H, CrossmanA R, et al.. μ⁻ and δ-opioid receptor antagonists reduced levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson disease. Exp Neurol, 2001, 171(1): 139-139

[8] PapaS M, ChaseT N. Levodopa-induced dyskinesias improved by a glutamate antagonist in Parkinsionian monkeys. Ann Neurol, 1996, 39(5): 574-574