Human COMT over-expression confers a heightened susceptibility to dyskinesia in mice.
Catechol-O-methyltransferase (COMT) degrades dopamine and its precursor l-DOPA and plays a critical role in regulating synaptic dopamine actions. We investigated the effects of heightened levels of COMT on dopamine-regulated motor behaviors and molecular alterations in a mouse model of dyskinesia. Transgenic mice overexpressing human COMT (TG) and their wildtype (WT) littermates received unilateral 6-OHDA lesions in the dorsal striatum and were treated chronically with l-DOPA for two weeks. l-DOPA-induced dyskinesia was exacerbated in TG mice without altering l-DOPA motor efficacy as determined by contralateral rotations or motor coordination. Inductions of FosB and phospho-acetylated histone 3 (molecular correlates of dyskinesia) were potentiated in the lesioned striatum of TG mice compared with their WT littermates. The TG mice had lower basal levels of dopamine in the striatum. In mice with lesions, l-DOPA induces a greater increase in the dopamine metabolite 3-methoxytyramine in the lesioned striatum of dyskinetic TG mice than in WT mice. The levels of serotonin and its metabolite were similar in TG and WT mice. Our results demonstrate that human COMT overexpression confers a heightened susceptibility to l-DOPA-induced dyskinesia and alters molecular and neurochemical responses in the lesioned striatum of mice.
Instituto Cajal, CSIC, Madrid 28002, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
Oscar
O
Solís
Instituto Cajal, CSIC, Madrid 28002, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
Jose-Rubén
JR
García-Montes
Instituto Cajal, CSIC, Madrid 28002, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
Patricia
P
Garcia-Sanz
Servicio de Neurobiología, Hospital Universitario Ramón y Cajal (IRYCIS), Madrid 28034, Spain.
Antonio S
AS
Herranz
Servicio de Neurobiología, Hospital Universitario Ramón y Cajal (IRYCIS), Madrid 28034, Spain.
Maria-José
MJ
Asensio
Department of Psychiatry and Behavioral Sciences, Dominick P. Purpura Department of Neuroscience, and Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Gina
G
Kang
Department of Psychiatry and Behavioral Sciences, Dominick P. Purpura Department of Neuroscience, and Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Noboru
N
Hiroi
Instituto Cajal, CSIC, Madrid 28002, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain. Electronic address: moratalla@cajal.csic.es.
Rosario
R
Moratalla
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000633:toxicity*; D051186:Armadillo Domain Proteins / Q000235:genetics / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004298:Dopamine / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D006801:Humans; D007980:Levodopa / Q000494:pharmacology / Q000633:toxicity*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D054482:Thioredoxin Reductase 2 / Q000235:genetics / Q000378:metabolism
C411307:ARVCF protein, human; D000978:Antiparkinson Agents; D051186:Armadillo Domain Proteins; D015815:Cell Adhesion Molecules; D010750:Phosphoproteins; D016760:Proto-Oncogene Proteins c-fos; D012701:Serotonin; D007980:Levodopa; D016627:Oxidopamine; C516127:TXNRD2 protein, human; D054482:Thioredoxin Reductase 2; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; D004298:Dopamine
22q11.2; ARVCF; Abnormal involuntary movements; COMT; Dopamine; LID; Striatum; TXNRD2; l-DOPA