title: Effect of S-COMT deficiency on behavior and extracellular brain dopamine concentrations in mice.
abstract: BACKGROUND
  Catechol-O-methyltransferase (COMT) has soluble (S-COMT) and membrane bound (MB-COMT) isoforms. Our aims were to assess the behavioral phenotype of S-COMT mutant mice and to clarify the role of MB-COMT in dopamine metabolism in different brain areas.
  
  
  METHODS
  Behavioral phenotype of the S-COMT mutant mice was assessed using a test battery designed to describe anxiety phenotype, spontaneous locomotor activity, sensorymotor gating, social behavior, and pain sensitivity. Microdialysis was used to explore the effect of S-COMT deficiency on extracellular dopamine under an L: -dopa load (carbidopa /L: -dopa 30/10 mg/kg i.p.).
  
  
  RESULTS
  In behavioral tests, mature adult S-COMT mutants that only possessed MB-COMT exhibited enhanced acoustic startle without alterations in sensorimotor gating. They also showed barbering of vibrissae and nonaggressive social dominance, suggesting a change in their social interactions. In addition, S-COMT deficiency slightly and sex-dependently affected spinal pain reflex and the effect of morphine on hot-plate latency. In microdialysis studies under L: -dopa load, S-COMT mutants of both sexes had higher accumbal dopamine levels, but male S-COMT mutant mice showed paradoxically lower prefrontal cortical dopamine concentrations than wild-type animals. S-COMT deficiency induced the accumulation of 3,4-dihydroxyphenylacetic acid in all brain areas, which was accentuated after L: -dopa loading. The lack of S-COMT decreased extracellular homovanillic acid levels. However, after L: -dopa loading, homovanillic acid concentrations in the prefrontal cortex of S-COMT mutants were similar to those of wild-type mice.
  
  
  CONCLUSIONS
  A lack of S-COMT has a notable, albeit small, brain-area and sex-dependent effect on the O-methylation of dopamine and 3,4-dihydroxyphenylacetic acid in the mouse brain. It also induces subtle changes in mouse social interaction behaviors and nociception.
authors.affiliation: Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland. anne.tammimaki@fimnet.fi
authors.forename: Anne
authors.initials: A
authors.lastname: Tammimäki
authors.forename: Mikko
authors.initials: M
authors.lastname: Käenmäki
authors.forename: Oleg
authors.initials: O
authors.lastname: Kambur
authors.forename: Natalia
authors.initials: N
authors.lastname: Kulesskaya
authors.forename: Tiina
authors.initials: T
authors.lastname: Keisala
authors.forename: Eeva
authors.initials: E
authors.lastname: Karvonen
authors.forename: J Arturo
authors.initials: JA
authors.lastname: García-Horsman
authors.forename: Heikki
authors.initials: H
authors.lastname: Rauvala
authors.forename: Pekka T
authors.initials: PT
authors.lastname: Männistö
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism*; D002230:Carbidopa / Q000008:administration & dosage; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D004298:Dopamine / Q000378:metabolism*; D004338:Drug Combinations; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D007980:Levodopa / Q000008:administration & dosage; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D009154:Mutation; D010641:Phenotype; D055139:Sensory Gating / Q000235:genetics; D012737:Sex Factors; D012930:Social Dominance
chemical_list: D004338:Drug Combinations; C009265:carbidopa, levodopa drug combination; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; D002394:Catechol O-Methyltransferase; D002230:Carbidopa; D004298:Dopamine