Human COMT over-expression confers a heightened susceptibility to dyskinesia in mice

• Published in: Neurobiology of disease 2017-06, Vol.102, p.133-139
• Main Authors: Solís, Oscar, García-Montes, Jose-Rubén, Garcia-Sanz, Patricia, Herranz, Antonio S, Asensio, Maria-José, Kang, Gina, Hiroi, Noboru, Moratalla, Rosario
• Format: Article
• Language: English
• Subjects: 22q11.2; Abnormal involuntary movements; Animals; Antiparkinson Agents - pharmacology; Antiparkinson Agents - toxicity; Armadillo Domain Proteins - genetics; Armadillo Domain Proteins - metabolism; ARVCF; Catechol O-Methyltransferase - genetics; Catechol O-Methyltransferase - metabolism; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; COMT; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Disease Models, Animal; Disease Susceptibility; Dopamine; Dopamine - metabolism; Dyskinesia, Drug-Induced - metabolism; Humans; l-DOPA; Levodopa - pharmacology; Levodopa - toxicity; LID; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity - physiology; Neurology; Oxidopamine; Parkinsonian Disorders - drug therapy; Parkinsonian Disorders - metabolism; Phosphoproteins - genetics; Phosphoproteins - metabolism; Proto-Oncogene Proteins c-fos - metabolism; Serotonin - metabolism; Striatum; Thioredoxin Reductase 2 - genetics; Thioredoxin Reductase 2 - metabolism; TXNRD2
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2017.03.006

Abstract 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.