Chronic Levodopa Administration Followed by a Washout Period Increased Number and Induced Phenotypic Changes in Striatal Dopaminergic Cells in MPTP-Monkeys.docVIP

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Chronic Levodopa Administration Followed by a Washout Period Increased Number and Induced Phenotypic Changes in Striatal Dopaminergic Cells in MPTP-Monkeys.doc

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Chronic Levodopa Administration Followed by a Washout Period Increased Number and Induced Phenotypic Changes in Striatal Dopaminergic Cells in MPTP-Monkeys

ChronicLevodopaAdministrationFollowedbya WashoutPeriodIncreasedNumberandInduced PhenotypicChangesinStriatalDopaminergicCellsin MPTP-Monkeys CarlaDiCaudo,MarioRiverol,In?aki-CarrilMundin?ano,CristinaOrdon?ez,Mar?′aHerna′ndez, IreneMarcilla,Maria-RosarioLuquin* LaboratoryofRegenerativeTherapyandDepartmentofNeurology,DivisionofNeuroscience,UniversityofNavarra,Pamplona,Spain Abstract InadditiontothemediumspinyneuronsthemammalianstriatumcontainsasmallpopulationofGABAergicinterneurons that are immunoreactive for tyrosine hydroxylase (TH), which dramatically increases after lesions to the nigrostriatal pathway and striatal delivery of neurotrophic factors. The regulatory effect of levodopa (L-Dopa) on the number and phenotype of these cells is less well understood. Eleven macaques (Macaca fascicularis) were included. Group I (n=4) received 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and L-Dopa; Group II (n=4) was treated with MPTP plus vehicleandGroupIII(n=3)consistofintactanimals(controlgroup).L-Dopaandvehicleweregivenfor1yearandanimals sacrificed 6 months later. Immunohistochemistry against TH was used to identify striatal and nigral dopaminergic cells. Doubleandtriplelabelingimmunofluorescencewasperformedtodetecttheneurochemicalcharacteristicsofthestriatal TH-ircellsusingantibodiesagainst:TH,anti-glutamatedecarboxylase(GAD67)anti-calretinin(CR)anti-dopadecarboxylase (DDC)andanti-dopamineandcyclicAMP-regulatedphosphoprotein(DARPP-32).ThegreatestdensityofTH-irstriatalcells wasdetectedinthestriatumoftheL-Dopatreatedmonkeysandparticularlyinitsassociativeterritory.Noneofthestriatal TH-ircellexpressedDARPP-32indicatingtheyareinterneurons.ThepercentagesofTH-ircellsthatexpressedGAD67and DDCwasapproximately50%.Interestingly,wefoundthatintheL-DopagroupthenumberofTH/CRexpressingcellswas significantlyreduced.WeconcludethatchronicL-Dopaadministrationproducedalong-lastingincreaseinthenumberof TH-ircells,evenafterawashoutperiodof6months.L-Dopaalsomodifiedthephenotypeofthesec