Summary
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.
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Jenner P. Factors influencing the onset and persistence of dyskinesia in MPTP-treated primates. Ann Neurol, 2000, 47(4 Suppl 1):S90–S99, discussion S99–S104
Fox SH, Lang AE. Levodopa-related motor complications—phenomenology. Mov Disord, 2008,23(Suppl 3): S509–S514
Luquin MR, Laguna J, Obeso JA. Selective D2 receptor stimulation induces dyskinesia in parkinsonian monkeys. Ann Neurol, 1992,31(5):551–554
Calabresi P, Di Filippo M, Ghiglieri V, et al. Molecular mechanisms underlying levodopa-induced dyskinesia. Mov Disord, 2008,23(Suppl 3):S570–S579
Yung KK, Bolam JP. 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
Mela F, Marti M, Dekundy A, 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
Papa SM, Engber TM, Kask AM, et al. Motor fluctuations in levodopa treated parkinsonian rats: relation to lesion extent and treatment duration. Brain Res, 1994,662(1–2): 69–74
Lee CS, Cenci MA, Schulzer M, et al. Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesia in a rat model of Parkinson’s disease. Brain, 2000,123(Part 7):1365–1379
Penney JB Jr, Pan HS, Young AB, et al. Quantitative autoradiography of [3H]muscimol binding in rat brain. Science, 1981,214(4524):1036–1038
Olsson M, Nikkah G, Bentlage C, 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 Part 2):3863–3875
Berke JD, Paletzki RF, Aronson GJ, et al. A complex program of striatal gene expression induced by dopaminergic stimulation. J Neurosci, 1998,18(14):5301–5310
Gerfen CR. Molecular effects of dopamine on striatal-projection pathways. Trends Neurosci, 2000,23(10 Suppl):S64–S70
Guan Q, Zhan Q, He Y, 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
Picconi B, Pisani A, Barone I, et al. Pathological synaptic plasticity in the striatum: implications for Parkinson’s disease. Neurotoxicology, 2005,26(5):779–783
Albin RL, Young AB, Penney JB. The functional anatomy of basal ganglia disorders. Trends Neurosci, 1989,12(10): 366–375
Obeso JA, Rodríguez-Oroz MC, Benitez-Temino B, et al. Functional Organization of the Basal Ganglia: therapeutic implications for Parkinson Disease. Mov Disord, 2008,23(Suppl 3):S548–S559
Tallaksen-Greene SJ, Albin RL. Localization of AMPA-selective excitatory amino acid receptor subunits in identified populations of striatal neurons. Neuroscience, 1994,61(3):509–519
Papa SM, Boldry RC, Engber TM, et al. Reversal of levodopa-induced motor fluctuations in experimental parkinsonism by NMDA receptor blockade. Brain Res, 1995,701(1–2):13–18
Papa SM, Chase TN. Levodopa-induced dyskinesias improved by a glutamate antagonist in Parkinsonian monkeys. Ann Neurol, 1996,39(5):574–578
Hallett PJ, Standaert DG. Rationale for and use of NMDA receptor antagonists in Parkinson’s disease. Pharmacol Ther, 2004,102(2):155–174
Oh JD, Russell DS, Vaughan CL, 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
Oh JD, Vaughan CL, Chase TN. Effect of dopamine denervation and dopamine agonist administration on serine phosphorylation of striatal NMDA receptor subunits. Brain Res, 1999,821(2):433–442
Flores G, Liang JJ, Sierra A, 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
Moratalla R, Elibol B, Vallejo M, 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
Cenci MA, Tranberg A, Andersson M, 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
Khan SM, Smith TS, Bennett JP, 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
Impey S, Smith DM, Obrietan K, et al. Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nat Neurosci, 1998,1(7): 595–601
Silva AJ, Kogan JH, Frankland PW, et al. CREB and memory. Annu Rev Neurosci, 1998,21:127–148
Hiroi N, Marek GJ, Brown JR, 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
Sasner M, Buonanno A. Distinct N-methyl-D-aspartate receptor 2B subunit gene sequences confer neural and developmental specific expression. J Biol Chem, 1996,271(35):21316–21322
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The two authors contributed equally to this work.
This project was supported by a grant from the National Natural Science Foundation of China (No. 30770753).
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Xu, Y., Zhang, Z., Qin, K. et al. Quantitative autoradiographic study on receptor regulation in the basal ganglia in rat model of levodopa-induced motor complications. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 29, 156–162 (2009). https://doi.org/10.1007/s11596-009-0204-3
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DOI: https://doi.org/10.1007/s11596-009-0204-3