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Coordinated and Spatial Upregulation of Arc in Striatonigral Neurons Correlates with L-Dopa-Induced Behavioral Sensitization in Dyskinetic Rats

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Coordinated and Spatial Upregulation of Arc in Striatonigral Neurons Correlates with L-Dopa-Induced Behavioral Sensitization in Dyskinetic Rats J Neuropathol Exp Neurol Vol. 64, No. 11 Copyright Ó 2005 by the American Association of Neuropathologists, Inc. November 2005 pp. 936–947 ORIGINAL ARTICLE Coordinated and Spatial Upregulation of Arc in Striatonigral Neurons Correlates With L-Dopa-Induced Behavioral Sensitization in Dyskinetic Rats Ve´ronique Sgambato-Faure, PhD, Virginie Buggia, MSc, Francxois Gilbert, MSc, Daniel Le´vesque, PhD, Alim-Louis Benabid, MD, PhD, and Francxois Berger, MD, PhD Downloaded from https://academic.oup.com/jnen/article/64/11/936/2916615 by guest on 30 September 2021 remains the best symptomatic treatment (6). However, its long- Abstract term use is commonly associated with side effects such as Although oral administration of L-Dopa remains the best therapy motor fluctuations and abnormal involuntary movements, for Parkinson disease, its long-term administration causes the appear- namely L-Dopa-induced dyskinesia (LID) (7–10; for review, ance of abnormal involuntary movements such as dyskinesia. Although [11]). The genesis of LID is not fully understood, but major persistent striatal induction of some genes has already been asso- factors include degree of presynaptic nigral denervation (12– ciated with such pathologic profiles in hemiparkinsonian rats, molec- 15); onset, dose, and manner of administration of L-Dopa (16); ular and cellular mechanisms underlying such long-term adaptations sensitization of dopaminergic receptors and their pulsatile remain to be elucidated. In this study, using a rat model of L-Dopa- stimulation (17, 18); imbalance between the output structures induced dyskinesia, we report that activity regulated cytoskeletal (Arc)- of basal ganglia (3, 4); as well as alteration of activity and associated protein is strongly upregulated in the lesioned striatum and discharge pattern of neurons of basal ganglia (19, 20). that the extent of its induction further varies according to the However, the precise mechanisms by which chronic L-Dopa occurrence or absence of locomotor sensitization. Moreover, Arc is leads to such long-term motor alterations require elucidation. preferentially induced, along with FosB, nur77, and homer-1a, in From experimental studies using animal models of LID striatonigral neurons, which express mRNA encoding the precursor (i.e. dopaminergic-lesioned animals chronically treated with of dynorphin. Given the likely importance of Arc in the regulation of L-Dopa given intermittently to simulate dosing schedules in cytoskeleton during synaptic plasticity, its upregulation supports the parkinsonian patients), it has been shown that abnormal in- hypothesis that a relationship exists between cytoskeletal modifica- formation storage in the corticostriatal pathways correlates with tions and the longlasting action of chronically administrated L-Dopa. LID (21). Moreover, it has been shown that in the striatum, Key Words: Arc, Dynorphin, Dyskinesia, homer-1a, L-Dopa, persistent molecular alterations noticeably related to glutamate Locomotor sensitization, nur77. signaling are involved in LID (22, 23). Many of these gene modulations are observed in striatonigral-projecting cells of the striatum, suggesting that dynorphin-containing cells may INTRODUCTION be associated with the development of behavioral sensitization Parkinson disease (PD) is a neurologic disorder that occurs in animal models of PD after L-Dopa treatment, characterized by an extensive loss of dopaminergic neurons although the involvement of opioid receptors is still a matter in the substantia nigra pars compacta (1, 2). The loss of of debate (24–29). Often compared with an aberrant form of dopamine within the striatum disturbs the functional organi- motor learning (30, 31), LID might also involve synaptic re- zation of the basal ganglia networks by causing an imbalance modeling. Among the cytoskeleton-related genes, the activity- between the 2 efferent striatal output pathways (direct: regulated cytoskeletal (Arc)-associated gene is of particular striatonigral; indirect: striatopallido–subthalamonigral) (3). interest. Initially identified in differential screens for seizure- Dopamine deficiency causes the motor symptoms of PD such stimulated hippocampal mRNA (32, 33), Arc mRNA rapidly as akinesia, rigidity, and tremor (3, 4). Despite the intense localizes to discrete dendritic regions that have received direct development of new therapeutic approaches (5), administra- synaptic stimulation (34, 35). Moreover, Arc is required for tion of the natural dopamine precursor levodopa (L-Dopa) still long-term potentiation as well as memory in the hippocampus (36–38). In the present study, we asked whether chronic L-Dopa From Inserm U318 (VS-F, VB, A-LB, FB), Laboratoire de Neurosciences Pre´cliniques, CHU Pavillon B, Grenoble, France; and Centre de recherche increased the expression of Arc and whether its L-Dopa-driven en Neuroscience (FG, DL), CHUL, Sainte Foy, Que´bec, Canada. induction could be correlated with dyskinesia or behavioral Send correspondence and reprint requests to: Ve´ronique Sgambato-Faure, sensitization. Using hemiparkinsonian rats that were chron- PhD, INSERM U704, Dynamique des Re´seaux Neuronaux, 2280 Rue de ically treated with L-Dopa and developed dyskinetic profiles, la Piscine, BP53, 38041 Grenoble cedex 9, France; E-mail: veronique. [email protected] we observed that a strong upregulation of Arc at both gene and This work was supported by grants from Institut National de la Sante´ et de la protein levels, in response to L-Dopa administration in the Recherche Me´dicale. dopaminergic-depleted striatum, was spatially coincident with 936 J Neuropathol Exp Neurol Volume 64, Number 11, November 2005 J Neuropathol Exp Neurol Volume 64, Number 11, November 2005 Arc Correlates With L-Dopa-Induced Motor Behavior that of the FosB-like proteins, homer-1a, nur77 (also known as practice. Rats were observed individually after each injection. nerve growth factor-inducible B [NGFI-B]), and preprodynor- Another small group of hemiparkinsonian rats (n = 3) were phin (PPDyn) mRNA levels, in the striatal subregion according treated for a 3-week period with lower doses of L-Dopa to the subtype of motor behavior displayed. Moreover, we (10 mg/kg) and benserazide (2 mg/kg). For pharmacologic observed that Arc is colocalized with PPDyn mRNA in neurons studies, 4 groups of hemiparkinsonian rats (n = 12) were treated of the direct striatonigral pathway. Finally, we found that with L-Dopa (at 50 mg/kg plus benserazide at 10 mg/kg) L-Dopa-induced motor behavioral response and Arc upregulation twice daily for 10 days as follows: administration of L-Dopa are not affected by a modulation of opioid receptor activity. alone, coadministration of L-Dopa plus naloxone dihydro- Altogether, these findings highlight a possible involvement of chloride (at 10 mg/kg), coadministration of L-Dopa plus Arc in the development or maintenance of LID and locomotor U-50,488H (trans-3,4-di-chloro-N-methyl-N[2]-[(1-pyrrolidinyl) sensitization and further support a role for cytoskeletal remod- cyclohexyl] benzeneacetamide methane-sulfonate salt) (at eling in the regulation of such long-term motor alterations. 1 mg/kg), and administration of L-Dopa plus an acute Downloaded from https://academic.oup.com/jnen/article/64/11/936/2916615 by guest on 30 September 2021 injection of nor-binaltorphimine di-hydrochloride (20 mg/kg) 1 hour before L-Dopa on the last day of treatment. MATERIALS AND METHODS The animal experimental protocols performed in this study strictly conformed to the guidelines of the French Agriculture Motor Behavior Analysis and Forestry Ministry and were approved by INSERM. Briefly, individual rats were observed daily in their home cage 1 hour after the injection, when the response to L-Dopa Lesion Surgery was maximal. Movements were considered as dyskinetic when Male adult Wistar rats, weighing 260 to 300 g, were both of the following criteria were fulfilled: induction by maintained on a 12-hour light/dark cycle with food and tap L-Dopa of repetitive and abnormal movements of the body water available ad libitum. All animals in this study were contralateral to the lesion. Abnormal involuntary movements anesthetized with chloral hydrate (400 mg/kg) and subjected to were subdivided into 3 subtypes: forelimb dyskinesia, orolin- unilateral 6-OHDA lesion in the left substantia nigra pars gual dyskinesia, and axial dyskinesia (40). The severity of each compacta (SNc) using a conventional stereotaxic instrument dyskinesia subtype was evaluated for each animal by assigning (David Kopf, Phymep, Paris, France). The lesions were per- a rating scale (0–4) (14, 41). Locomotor sensitization was also formed according to a standard procedure. Briefly, 12 mgof evaluated by counting the number of contralateral rotations per 6-OHDA-HCl (Sigma, Saint Quentin Fallavier, France) dis- minute. Finally, animals were videotaped during the treatment solved in 0.1% ascorbate saline were injected in the left SNc at and before death. the following coordinates (according to the atlas of Paxinos and Watson (39)) in millimeters and relative to Bregma and Tissue Preparation cortical surface: A = 5.3; L = 2.1; H = 7.8. To preserve norad- Two or 24 hours after the last L-Dopa injection, animals renergic fibers, all animals were intraperitoneally (IP) injected received a lethal dose of chloral hydrate and were killed by with desipramine-HCl (25 mg/kg; Sigma) at least 30 minutes intracardiac perfusion of RingerÕs solution followed by 4% before 6-OHDA injection. paraformaldehyde in 0.1 M Na2HPO4/NaH2PO4 buffer,
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