Quantitative autoradiographic study on receptor regulation in the basal ganglia in rat model of levodopa-induced motor complications

Abstract

In order to study neurotransmitter receptor regulation in the basal ganglia involved in the functional changes underlying levodopa-induced motor complications, quantitative autoradiography was used to observe receptor bindings of dopamine D1 and D2, N-methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) and amino butyric acid (GABA) in the basal ganglia of rats that had unilateral nigrostriatal lesions and had been chronically treated with levodopa until motor complications developed. The rats were randomly assigned to three groups: normal, denervated and treatment-complicated groups. The results showed that response duration to levodopa became progressively shorter and abnormal involuntary movement (AIM) score was progressively increased during the course of levodopa treatment. Chronic treatment augmented D1 receptors more than denervation, and reduced D2 receptors that were also increased by dopamine denervation. Striatal NMDA receptors were substantially up-regulated in the treatment-complicated group. Levodopa treatment did not change receptors of nigral AMPA, pallidal GABA, and subthalamic GABA, which remained the same as that in denervation group. However, chronic treatment reversed the increase of nigral GABA receptors caused by the lesion. It was concluded that a shortening of response duration and AIM mimicked levodopa-induced motor complications of Parkinson’s patients. These data suggested that up-regulation of dopamine D1 and NMDA receptors in the striatum leads to an imbalance of stimulation through the striatal output pathways, which is associated with levodopa-induced motor complications.

Keywords

levodopa-induced motor complications / Parkinson’s disease / glutamate receptors / GABA receptors / dopamine receptors / autoradiography

References

[1] JennerP.. Factors influencing the onset and persistence of dyskinesia in MPTP-treated primates. Ann Neurol, 2000, 47(4Suppl1): S90-S99

[2] FoxS.H., LangA.E.. Levodopa-related motor complications—phenomenology. Mov Disord, 2008, 23(Suppl3): S509-S514

[3] LuquinM.R., LagunaJ., ObesoJ.A.. Selective D2 receptor stimulation induces dyskinesia in parkinsonian monkeys. Ann Neurol, 1992, 31(5): 551-554

[4] CalabresiP., Di FilippoM., GhiglieriV., et al. . Molecular mechanisms underlying levodopa-induced dyskinesia. Mov Disord, 2008, 23(Suppl3): S570-S579

[5] YungK.K., BolamJ.P.. Localization of dopamine D1 and D2 receptors in the rat neostriatum: synaptic interaction with glutamate- and GABA-containing axonal terminals. Synapse, 2000, 38(4): 413-420

[6] MelaF., MartiM., DekundyA., et al. . Antagonism of metabotropic glutamate receptor type 5 attenuates l-DOPA-induced dyskinesia and its molecular and neurochemical correlates in a rat model of Parkinson’s disease. J Neurochem, 2007, 101(2): 483-497

[7] PapaS.M., EngberT.M., KaskA.M., et al. . Motor fluctuations in levodopa treated parkinsonian rats: relation to lesion extent and treatment duration. Brain Res, 1994, 662(1–2): 69-74

[8] LeeC.S., CenciM.A., SchulzerM., et al. . Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesia in a rat model of Parkinson’s disease. Brain, 2000, 123(Part7): 1365-1379

[9] PenneyJ.B.Jr, PanH.S., YoungA.B., et al. . Quantitative autoradiography of [³H]muscimol binding in rat brain. Science, 1981, 214(4524): 1036-1038

[10] 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(5Part2): 3863-3875

[11] BerkeJ.D., PaletzkiR.F., AronsonG.J., et al. . A complex program of striatal gene expression induced by dopaminergic stimulation. J Neurosci, 1998, 18(14): 5301-5310

[12] GerfenC.R.. Molecular effects of dopamine on striatal-projection pathways. Trends Neurosci, 2000, 23(10Suppl): S64-S70

[13] GuanQ., ZhanQ., HeY., et al. . Changes in the prodynorphin gene and DARPP-32 state in 6-OHDA-lesioned rats following long-term treatment with l-dopa. Neurosci Lett, 2007, 426(1): 64-68

[14] PicconiB., PisaniA., BaroneI., et al. . Pathological synaptic plasticity in the striatum: implications for Parkinson’s disease. Neurotoxicology, 2005, 26(5): 779-783

[15] AlbinR.L., YoungA.B., PenneyJ.B.. The functional anatomy of basal ganglia disorders. Trends Neurosci, 1989, 12(10): 366-375

[16] ObesoJ.A., Rodríguez-OrozM.C., Benitez-TeminoB., et al. . Functional Organization of the Basal Ganglia: therapeutic implications for Parkinson Disease. Mov Disord, 2008, 23(Suppl3): S548-S559

[17] Tallaksen-GreeneS.J., AlbinR.L.. Localization of AMPA-selective excitatory amino acid receptor subunits in identified populations of striatal neurons. Neuroscience, 1994, 61(3): 509-519

[18] PapaS.M., BoldryR.C., EngberT.M., et al. . Reversal of levodopa-induced motor fluctuations in experimental parkinsonism by NMDA receptor blockade. Brain Res, 1995, 701(1–2): 13-18

[19] PapaS.M., ChaseT.N.. Levodopa-induced dyskinesias improved by a glutamate antagonist in Parkinsonian monkeys. Ann Neurol, 1996, 39(5): 574-578

[20] HallettP.J., StandaertD.G.. Rationale for and use of NMDA receptor antagonists in Parkinson’s disease. Pharmacol Ther, 2004, 102(2): 155-174

[21] OhJ.D., RussellD.S., VaughanC.L., et al. . Enhanced tyrosine phosphorylation of striatal NMDA receptor subunits: effect of dopaminergic denervation and L-DOPA administration. Brain Res, 1998, 813(1): 150-159

[22] 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): 433-442

[23] FloresG., LiangJ.J., SierraA., et al. . Expression of dopamine receptors in the subthalamic nucleus of the rat: characterization using reverse transcriptase-polymerase chain reaction and autoradiography. Neuroscience, 1999, 91(2): 549-556

[24] MoratallaR., ElibolB., VallejoM., et al. . Network-level changes in expression of inducible Fos-Jun proteins in the striatum during chronic cocaine treatment and withdrawal. Neuron, 1996, 17(1): 147-156

[25] CenciM.A., TranbergA., AnderssonM., et al. . Changes in the regional and compartmental distribution of FosB- and JunB-like immunoreactivity induced in the dopamine-denervated rat striatum by acute or chronic L-dopa treatment. Neuroscience, 1999, 94(2): 515-527

[26] KhanS.M., SmithT.S., BennettJ.P., et al. . Effects of single and multiple treatments with L-dihydroxyphenylalanine L-DOPA) on dopamine receptor-G protein interactions and supersensitive immediate early gene responses in striata of rats after reserpine treatment or with unilateral nigrostriatal lesions. J Neurosci Res, 1999, 55(1): 71-79

[27] ImpeyS., SmithD.M., ObrietanK., et al. . Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nat Neurosci, 1998, 1(7): 595-601

[28] SilvaA.J., KoganJ.H., FranklandP.W., et al. . CREB and memory. Annu Rev Neurosci, 1998, 21: 127-148

[29] HiroiN., MarekG.J., BrownJ.R., et al. . Essential role of the fosB gene in molecular, cellular, and behavioral actions of chronic electroconvulsive seizures. J Neurosci, 1998, 18(17): 6952-6962

[30] SasnerM., BuonannoA.. Distinct N-methyl-D-aspartate receptor 2B subunit gene sequences confer neural and developmental specific expression. J Biol Chem, 1996, 271(35): 21316-21322