Using a rat model of hemiparkinsonism, we examined the time-course of D1 agonist, SKF-38393-induced changes in extracellular signaling regulated kinases 1/2 (ERK1/2) phosphorylation in the striatum and substantia nigra (SN). We unilaterally lesioned the rat median forebrain bundle with 6-hydroxydopamine. Dopaminergic lesioned rats were administered with SKF-38393 and perfused at 15, 30, 60, or 120 minutes after the drug. Immunohistochemical analysis of striatum and SN revealed, as expected, a loss of tyrosine hydroxylase and a decrease of substance P in lesioned rats. SKF-38393 induced a robust increase in phospho-ERK1/2 levels in the lesioned striatum, which peaked at 15 min and substantially declined by 120 min. We report for the first time that similar changes were observed in the SN. The time-dependent ERK 1/2 activation in the striatonigral neurons may play a role in the therapeutic and/or side effects such as dyskinesias related to the dopamine agonist treatment for Parkinson’s disease.
Y. Smith and J. Z. Kieval, “Anatomy of the Dopamine System In the Basal Ganglia,” Trends in Neuroscience, Vol. 23, Supplement 1, 2000, pp. S28-S33. doi:10.1016/S1471-1931(00)00023-9
S. C. Sealfon and C. W. Olanow, “Dopamine Receptors: From Structure to Behavior,” Trends in Neuroscience, Vol. 23, Supplement, 2000 pp. S34-S40. doi:10.1016/S1471-1931(00)00025-2
M. Lebel, P. Robinson and M. Cyr, “Canadian Association of Neurosciences Review: the Role of Dopamine Receptor Function in Neurodegenerative Diseases,” Canadian Journal of Neurological Sciences, Vol. 34, No. 1, 2007, pp. 18-29.
S. P. Onn, A. R. West and A. A. Grace, “Dopamine-Mediated Regulation of Striatal Neuronal and Network Interactions,” Trends in Neuroscience, Vol. 23, Supplement 1, 2000, pp. S48-S56.
A. M. Graybiel, C. W. Ragsdale Jr. and P. C. Emson, “Biochemical Anatomy of the Striatum,” Raven Press, New York, 1983, pp. 427-504.
J. D. Berke, R. F. Paletzki, G. J. Aronson, S. E. Hyman and C. R. Gerfen, “A Complex Program of Striatal Gene Expression Induced by Dopaminergic Stimulation,” Journal of Neuroscience, Vol. 18, No. 14, 1998, pp. 5301-5310.
C. R. Gerfen, “D1 Dopamine Receptor Supersensitivity in the Dopamine-Depleted Striatum: Animal Model of Parkinson’s Disease,” Neuroscientist, Vol. 9, No. 6, 2003, pp. 455-462. doi:10.1177/1073858403255839
K. A. Neve, J. K. Seamans and H. Trantham-Davidson, “Dopamine Receptor Signaling,” Journal of Receptor and Signal Transduction Research, Vol. 24, No. 3, 2004, pp. 165-205. doi:10.1081/RRS-200029981
J. W. Kebabian, “Brain Dopamine Receptors: 20 Years of Progress,” Neurochemical Research, Vol. 18, No. 1, 1993, pp. 101-104. doi:10.1007/BF00966928
C. R. Gerfen, T. M. Engber, L. C. Mahan, Z. Susel, T. N. Chase, F. J. Monsma and D. R. Sibley, “D1 and D2 Dopamine Receptor-Regulated Gene Expression of Striatonigral and Striatopallidal Neurons,” Science, Vol. 250, No. 4986, 1990, pp.1429-1432. doi:10.1126/science.2147780
C. R. Gerfen, “Molecular Effects of Dopamine on Striatal Projection Pathways,” Trends in Neuroscience, Vol. 23, Supplement 1, 2000, pp. S64-S70.
A. Nadjar, C. R. Gerfen and E. Bezard, “Priming for L-Dopa-Induced Dyskinesia in Parkinson’s Disease: A Feature Inherent to the Treatment or the Disease?” Progress in Neurobiology, Vol. 87, No. 1, 2009, pp. 1-9. doi:10.1016/j.pneurobio.2008.09.013
G. S. Robertson, S. R. Vincent and H. C. Fibiger, “Striatonigral Projection Neurons Contain D1 Dopamine Receptor-Activated c-fos,” Brain Research, Vol. 523, No. 2, 1990, pp. 288-290. doi:10.1016/0006-8993(90)91498-6
H. Steiner and C. R. Gerfen, “Dynorphin Opioid Inhibition of Cocaine-Induced, D1 Dopamine Receptor-Mediated immediate-Early Gene Expression in the Striatum,” Journal of Comparative Neurology, Vol. 353, No. 2, 1995, pp. 200-212. doi:10.1002/cne.903530204
H. Steiner and C. R. Gerfen, “Dynorphin Regulates D1 Dopamine Receptor-Mediated Responses in the Striatum: Relative Contributions of Pre- and Postsynaptic Mechanisms in Dorsal and Ventral Striatum Demonstrated by Altered Immediate-Early Gene Induction,” Journal of Comparative Neurology, Vol. 376, No. 4, 1996, pp. 530-541. doi:10.1002/(SICI)1096-9861(19961223)376:4 3.0.CO;2-2
J. D. Sweatt, “The Neuronal MAP Kinase Cascade: A Biochemical Signal Integration System Subserving Synaptic Plasticity and Memory,” Journal of Neurochemistry, Vol. 76, No. 1, 2001, pp. 1-10. doi:10.1046/j.1471-4159.2001.00054.x
G. M. Thomas and R. L. Huganir, “MAPK Cascade Signaling and Synaptic Plasticity,” Nature Reviews Neuroscience, Vol. 5. No. 3, 2004, pp.173-183. doi:10.1038/nrn1346
D. Chuderland and R. Seger, “Protein-Protein Interactions in the Regulation of the Extracellular Signal-Regulated Kinase,” Molecular Biotechnology, Vol. 29, No. 1, 2005, pp. 57-74. doi:10.1385/MB:29:1:57
G. Pearson, F. Robinson, T. Gibson, B. E. Xu, M. Karandikar, K. Berman and M. H. Cobb, “Mitogen-Activated Protein (MAP) Kinase Pathways: Regulation and Physiological Functions,” Endocrinology Reviews, Vol. 22, No. 2, 2001, pp. 153-183. doi:10.1210/er.22.2.153
G. R. Post and J. H. Brown, “G Protein-Coupled Receptors and Signaling Pathways Regulating Growth Responses,” FASEB Journal, Vol. 10, No. 7, 1996, pp. 741-749.
P. Rogue and A. N. Malviya, “Regulation of Signaling Pathways to the Nucleus by Dopaminergic Receptors,” Cell Signal, Vol. 6, No. 7, 1994, pp. 725-733. doi:10.1016/0898-6568(94)00044-1
S. Maudsley, B. Martin and L. M. Luttrell, “The Origins of Diversity and Specificity in G Protein-Coupled Receptor Signaling,” Journal of Pharmacology and Experimental Therapeutics, Vol. 314, No. 2, 2005, pp. 485-494. doi:10.1124/jpet.105.083121
R. J. Kelleher III, A. Govindarajan, H. Y. Jung, H. Kang and S. Tonegawa, “Translational Control by MAPK signaling in Long-Term Synaptic Plasticity and Memory,” Cell, Vol. 116, No. 3, 2004, pp. 467-479. doi:10.1016/S0092-8674(04)00115-1
L. Pozzi, K. Hakansson, A. Usiello, A. Borgkvist, M. Lindskog, P. Greengard and G. Fisone, “Opposite Regulation by Typical and Atypical Anti-Psychotics of ERK1/2, CREB and Elk-1 Phosphorylation in Mouse Dorsal Striatum,” Journal of Neurochemistry, Vol. 86, No. 2, 2003, pp. 451-459. doi:10.1046/j.1471-4159.2003.01851.x
J. Chen, M. Rusnak, R. R. Luedtke and A. Sidhu, “D1 Dopamine Receptor Mediates Dopamine-Induced Cytotoxicity via the ERK Signal Cascade,” Journal of Biological Chemistry, Vol. 279, No. 38, 2004, pp. 393173-9330. doi:10.1074/jbc.M403891200
J. McDaid, M. P. Graham and T. C. Napier, “Methamphetamine-Induced Sensitization Differentially Alters pCREB and Delta FosB throughout the Limbic Circuit of the Mammalian Brain,” Molecular Pharmacology, Vol. 70, No. 6, 2006, pp. 2064-2074. doi:10.1124/mol.106.023051
L. Zhang, D. Lou, H. Jiao, D. Zhang, X. Wang, Y. Xia, J. Zhang and M. Xu, “Cocaine-Induced Intracellular Signaling and Gene Expression Are Oppositely Regulated by the Dopamine D1 and D3 Receptors,” Journal of Neuroscience, Vol. 24, No. 13, 2004, pp. 3344-3354.
D. Tardito, J. Perez, E. Tiraboschi, L. Musazzi, G. Racagni and M. Popoli, “ Signaling Pathways Regulating Gene Expression, Neuroplasticity, and Neurotrophic Mechanisms in the Action of Antidepressants: A Critical Overview,” Pharmacological Reviews, Vol. 58, No.1, 2006, pp. 115-134.
E. Valjent, V. Pascoli, P. Svenningsson, S. Paul, H. Enslen, J. C. Corvol, A. Stipanovich, J. Caboche, P. J. Lombroso, A. C. Nairn, P. Greengard, D. Herve and J. A. Girault, “Regulation of a Protein Phosphatase Cascade Allows Convergent Dopamine and Glutamate Signals to Activate ERK in the Striatum,” Proceedings of National Academy of Sciences USA, Vol. 102, No. 2, 2005, pp. 491-496. doi:10.1073/pnas.0408305102
N. Pavon, A. B. Martin, A. Mendialdua and R. Moratalla, “ERK Phosphorylation and FosB Expression Are Associated with L-DOPA-Induced Dyskinesia in Hemiparkinsonian Mice,” Biological Psychiatry, Vol. 59, No. 1, 2006, pp. 64-74. doi:10.1016/j.biopsych.2005.05.044
C. R. Gerfen, S. Miyachi, R. Paletzki and P. Brown, “D1 Dopamine Receptor Supersensitivity in the Dopamine-Depleted Striatum Results from a Switch in the Regulation of ERK1/2/MAP Kinase,” Journal of Neuroscience, Vol. 22, No. 12, 2002, pp. 5042-5054.
D. S. Kim, R. D. Palmiter, A. Cummins and C. R. Gerfen, “Reversal of Supersensitive Striatal Dopamine D1 Receptor Signaling and Extracellular Signal-Regulated Kinase Activity in Dopamine-Deficient Mice,” Neuroscience, Vol. 137, No. 4, 2006, pp. 1381-1388. doi:10.1016/j.neuroscience.2005.10.054
S. T. Papadeas, B. L. Blake, D. J. Knapp and G. R. Breese, “Sustained Extracellular Signal-Regulated Kinase 1/2 Phosphorylation in Neonate 6-Hydroxydopamine-Lesioned Rats after Repeated D1-Dopamine Receptor Agonist Administration: Implications for NMDA Receptor Involvement,” Journal of Neuroscience, Vol. 24, No. 26, 2004, pp. 5863-5876. doi:10.1523/JNEUROSCI.0528-04.2004
S. P. Sivam and C. Moreno, “Dopamine Agonist Mediated Striatonigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease,” Society of Neuroscience Abstracts, Washington DC, 2008.
G. Paxinos and C. Watson, “The Rat Brain in Stereotaxic Coordinates,” Elsevier Academic Press, New York, 2005.
G. R. Breese, A. A. Baumeister, T. J. McCown, S. G. Emerick, G. D. Frye, K Crotty and R. A. Mueller, “Behavioral Differences between Neonatal and Adult 6-Hydrocydopamine-Treated Rats to Dopamine Agonists: Relevance to Neurological Symptoms in Clinical Syndromes with Reduced Brain Dopamine,” Journal of Pharmacology and Experimental Therapeutics, Vol. 231, No. 2, 1984, pp. 343-354.
S. J. Li, S. P. Sivam, J. F. McGinty, Y. S. Huang and J. S. Hong, “Dopaminergic Regulation of Tachykinin Metabolism in the Striatonigral Pathway,” Journal of Pharmacology and Experimental Therapeutics, Vol. 243, No. 2, 1987, pp. 792-798.
L. K. Nisenbaum, W. R. Crowley and S. T. Kitai, “Partial Striatal Dopamine Depletion Differentially Affects Striatal Substance P and Enkephalin Messenger RNA Expression,” Molecular Brain Research, Vol. 37, No. 1-2, 1996, pp. 209-216. doi:10.1016/0169-328X(95)00317-L
S. P. Sivam, G. R. Breese, J. E. Krause, T. C. Napier, M. A. Mueller and J. S. Hong, “Neonatal and Adult 6-Hydroxydopamine-Induced Lesions Differentially Alter Tachykinin and Enkephalin Gene Expression,” Journal of Neurochemistry, Vol. 49, No.5, 1987, pp. 1623-1633. doi:10.1111/j.1471-4159.1987.tb01036.x
J. E. Westin, L. Vercammen, E. M. Strome, C. Konradi and M. A. Cenci, “Spatiotemporal Pattern of Striatal ERK1/2 Phosphorylation in a Rat Model of L-DOPA-induced Dyskinesia and the Role of Dopamine D1 Receptors,” Biological Psychiatry, Vol. 62, No. 7, 2007, pp. 800-810. doi:10.1016/j.biopsych.2006.11.032
E. Valjent, J. C. Corvol, J. M. Trzaskos, J. A. Girault and D. Herve, “Role of the ERK Pathway in Psychostimulant-Induced Locomotor Sensitization,” BMC Neuroscience, Vol. 7, No. 1, 2006, p. 20.
C. J. Marshall, “Specificity of Receptor Tyrosine Kinase Signaling: Transient versus Sustained Extracellular Signal-Regulated Kinase Activation,” Cell, Vol. 80, No. 2, 1995, pp. 179-185. doi:10.1016/0092-8674(95)90401-8
J. Chen, M. Rusnak, P. J. Lombroso and A. Sidhu, “Dopamine Promotes Striatal Neuronal Apoptotic Death via ERK Signaling Cascades,” European Journal of Neuroscience, Vol. 29, No. 2, 2009, pp. 287-306. doi:10.1111/j.1460-9568.2008.06590.x
L. Colucci-D'Amato, C. Perrone-Capano and U. di Porzio, “Chronic Activation of ERK and Neurodegenerative Diseases,” Bioessays, Vol. 25, No. 11, 2003, pp. 1085-1095. doi:10.1002/bies.10355
C. R. Gerfen and W. S. Young III, “Distribution of Striatonigral and Striatopallidal Peptidergic Neurons in Both Path and Matrix Compartments: An in Situ Hybridization Histochemistry and Fluorescent Retrograde Tracing Study,” Brain Research, Vol. 460, No. 1, 1988, pp. 161-167. doi:10.1016/0006-8993(88)91217-6
S. M. Hersch, B. J. Ciliax, C. A. Gutekunst, H. D. Rees, C. J. Heilman, K. K. Yung, J. P. Bolam, E. Ince, H. Yi and A. I. Levey, “Electron Microscopic Analysis of D1 and D2 Dopamine Receptor Proteins in the Dorsal Striatum and their Synaptic Relationships with Motor Corticostriatal Afferents,” Journal of Neuroscience, Vol. 15, No. 7, 1995, pp. 5222-5237.
L, Pei, F. J. Lee, A. Moszczynska, B. Vukusic and F. Liu, “Regulation of Dopamine D1 Receptor Function by Physical Interaction with the NMDA Receptors,” Journal of Neuroscience, Vol. 24, No. 5, 2004, pp. 1149-1158. doi:10.1523/JNEUROSCI.3922-03.2004
G. L. Snyder, G. Fisone and P. Greengard, “Phosphorylation of DARPP-32 Is Regulated by GABA in Rat Striatum and Substantia Nigra,” Journal of Neurochemistry, Vol. 63, No. 5, 1994, pp. 1766-1771. doi:10.1046/j.1471-4159.1994.63051766.x
A. Saavedra, G. Baltazar and E. P. Duarte, “Driving GDNF Expression: The Green and the Red Traffic Lights,” Vol. 86, No. 3, 2008, pp. 186-215.
T. Gonzalez-Hernandez and M. Rodriguez, “Compartmental Organization and Chemical Profile of Dopaminergic and GABAergic Neurons in the Substantia Nigra of the Rat,” Journal of Comparative Neurology, Vol. 421, No. 1, 2000, pp. 107-135. doi:10.1002/(SICI)1096-9861(20000522)421:1 3.0.CO;2-F
K. K. Yung, J. P. Bolam, A. D. Smith, S. M. Hersch, B. J. Ciliax and A. I. Levey, “Immunocytochemical localization of D1 and D2 Dopamine Receptors in the Basal Ganglia of the Rat: Light and Electron Microscopy,” Neuroscience, Vol. 65, No. 3, 2008, pp. 709-730. doi:10.1016/0306-4522(94)00536-E
J. L. Bizon, J. C. Lauterborn and C. M. Gall, “Subpopulations of Striatal Interneurons Can Be Distinguished on the Basis of Neurotrophic Factor Expression,” Journal of Comparative Neurology, Vol. 408, No. 2, 1999, pp. 283-298. doi:10.1002/(SICI)1096-9861(19990531)408:2 3.0.CO;2-2
M. G. Rosales, D. Martinez-Fong, R. Morales, A. Nunez, G. Flores, J. L. Gongora-Alfaro, B. Floran and J. Aceves, “Reciprocal Interaction between Glutamate and Dopamine in the Pars Reticulata of the Rat Substantia Nigra: A Microdialysis Study,” Neuroscience, Vol. 80, No. 3, 1997, pp. 803-810. doi:10.1016/S0306-4522(97)00160-7
F. Windels and E. A. Kiyatkin, “GABAergic Mechanisms in Regulating the Activity State of Substantia Nigra Pars Reticulata Neurons,” Neuroscience, Vol. 140, No. 4, 2006, pp. 1289-1299. doi:10.1016/j.neuroscience.2006.03.064
T. Trevitt, B. Carlson, M. Correa, A. Keene, M. Morales and J. D. Salamone, “Interactions between Dopamine D1 Receptors and Gamma-Aminobutyric Acid Mechanisms in Substantia Nigra Pars Reticulata of the Rat: Neurochemical and Behavioral Studies,” Psychopharmacology, Vol. 159, No. 3, 2002, pp. 229-237. doi:10.1007/s002130100908
C. C. Ouimet, P. E. Miller, H. C. Hemmings Jr., S. I. Walaas and P. Greengard, “ DARPP-32, a Dopamine- and Adenosine 3':5'-Monophosphate-Regulated Phosphoprotein Enriched in Dopamine-Innervated Brain Regions. III. Immunocytochemical Iocalization,” Journal of Neuroscience, Vol. 4, No. 1, 1984, pp. 111-124.
P. Teismann, K. Tieu, O. Cohen, D. K. Choi, D. C. Wu, D. Marks, M. Vila, V. Jackson-Lewis and S. Przedborski, “Pathogenic Role of Glial Cells in Parkinson’s Disease,” Movement Disorders, Vol. 18, No. 2, 2003, pp. 121-129. doi:10.1002/mds.10332
A. Sajadi, J. C. Bensadoun, B. L. Schneider, C. Lo Bianco and P. Aebischer, “Transient Striatal Delivery of GDNF via Encapsulated Cells Leads to Sustained Behavioral Improvement in a Bilateral Model of Parkinson Disease,” Neurobiology of Disease, Vol. 22, No. 1, 2006, pp. 119-129. doi:10.1016/j.nbd.2005.10.006
P. Barroso-Chinea, I. Cruz-Muros, M. S. Aymerich, M. Rodriguez-Diaz, D. Afonso-Oramas, J. L. Lanciego and T. Gonzalez-Hernandez, “Striatal Expression of GDNF and Differential Vulnerability of Midbrain Dopaminergic Cells,” European Journal of Neuroscience, Vol. 21, No. 7, 2005, pp. 1815-1827. doi:10.1111/j.1460-9568.2005.04024.x
A. Sarabi, B. J. Hoffer, L. Olson and M. Morales, “GFRalpha-1 mRNA in Dopaminergic and Nondopaminergic Neurons in the Substantia Nigra and Ventral Tegmental Area,” Journal of Comparative Neurology, Vol. 441, No. 2, 2001, pp. 106-117. doi:10.1002/cne.1400
A. Saavedra, G. Baltazar, P. Santos, C.M. Carvalho and E. P. Duarte, “Selective Injury to Dopaminergic Neurons Up-Regulates GDNF in Substantia Nigra Postnatal Cell Cultures: Role of Neuron-Glia Crosstalk,” Neurobiology of Disease, Vol. 23, No. 3, 2006, pp. 533-542. doi:10.1016/j.nbd.2006.04.008
R. L. Miller, G. Y. Sun and A. Y. Sun, “Cytotoxicity of Paraquat in Microglial Cells: Involvement of PKC Delta- and ERK1/2-Dependent NADPH Oxidase,” Brain Research, Vol. 1167, 2007, pp. 129-139.
N. Lindgren, R. K. Leak, K. M. Carlson, A. D. Smith and M. J. Zigmond, “Activation of the Extracellular Signal-Regulated Kinases 1 and 2 by Glial Cell Line-Derived Neurotrophic Factor and Its Relation to Neuroprotection in a Mouse Model of Parkinson’s Disease,” Journal of Neuroscience Research, Vol. 86, No. 9, 2008, pp. 2039-2049. doi:10.1002/jnr.21641
H. Guo, Z. Tang, Y. Yu, L. Xu, G. Jin and J. Zhou, “Apomorphine Induces Trophic Factors that Support Fetal Rat Mesencephalic Dopaminergic Neurons in Cultures,” European Journal of Neuroscience, Vol. 16, No. 10, 2002, pp. 1861-1870. doi:10.1046/j.1460-9568.2002.02256.x
K. Ohta, S. Kuno, I. Mizuta, A. Fujinami, H. Matsui and M. Ohta, “Effects of Dopamine Agonists Bromocriptine, Pergolide, Cabergoline, and SKF-38393 on GDNF, NGF, and BDNF Synthesis in Cultured Mouse Astrocytes,” Life Sciences, Vol. 73, No. 5, 2003, pp. 617-626. doi:10.1016/S0024-3205(03)00321-7
N. Kinor, R. Geffen, E. Golomb, T. Zinman and G. Yadid, “Dopamine Increases Glial Cell Line-Derived Neurotrophic Factor in Human Fetal Astrocytes,” Glia, Vol. 33, No. 2, 2001, pp.143-150. doi:10.1002/1098-1136(200102)33:2 3.0.CO;2-3