title: Role of serine racemase in behavioral sensitization in mice after repeated administration of methamphetamine.
abstract: BACKGROUND
  The N-methyl-D-aspartate (NMDA) receptors play a role in behavioral abnormalities observed after administration of the psychostimulant, methamphetamine (METH). Serine racemase (SRR) is an enzyme which synthesizes D-serine, an endogenous co-agonist of NMDA receptors. Using Srr knock-out (KO) mice, we investigated the role of SRR on METH-induced behavioral abnormalities in mice.
  
  
  RESULTS
  Evaluations of behavior in acute hyperlocomotion, behavioral sensitization, and conditioned place preference (CPP) were performed. The role of SRR on the release of dopamine (DA) in the nucleus accumbens after administration of METH was examined using in vivo microdialysis technique. Additionally, phosphorylation levels of ERK1/2 proteins in the striatum, frontal cortex and hippocampus were examined using Western blot analysis. Acute hyperlocomotion after a single administration of METH (3 mg/kg) was comparable between wild-type (WT) and Srr-KO mice. However, repeated administration of METH (3 mg/kg/day, once daily for 5 days) resulted in behavioral sensitization in WT, but not Srr-KO mice. Pretreatment with D-serine (900 mg/kg, 30 min prior to each METH treatment) did not affect the development of behavioral sensitization after repeated METH administration. In the CPP paradigm, METH-induced rewarding effects were demonstrable in both WT and Srr-KO mice. In vivo microdialysis study showed that METH (1 mg/kg)-induced DA release in the nucleus accumbens of Srr-KO mice previously treated with METH was significantly lower than that of the WT mice previously treated with METH. Interestingly, a single administration of METH (3 mg/kg) significantly increased the phosphorylation status of ERK1/2 in the striatum of WT, but not Srr-KO mice.
  
  
  CONCLUSIONS
  These findings suggest first, that SRR plays a role in the development of behavioral sensitization in mice after repeated administration of METH, and second that phosphorylation of ERK1/2 by METH may contribute to the development of this sensitization as seen in WT but not Srr-KO mice.
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
authors.forename: Mao
authors.initials: M
authors.lastname: Horio
authors.forename: Mami
authors.initials: M
authors.lastname: Kohno
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujita
authors.forename: Tamaki
authors.initials: T
authors.lastname: Ishima
authors.forename: Ran
authors.initials: R
authors.lastname: Inoue
authors.forename: Hisashi
authors.initials: H
authors.lastname: Mori
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D059333:Central Nervous System Sensitization / Q000187:drug effects* / Q000235:genetics*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008694:Methamphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D019998:Racemases and Epimerases / Q000235:genetics*; D012201:Reward; D000099300:Serine Racemase
chemical_list: D000697:Central Nervous System Stimulants; D004298:Dopamine; D048049:Extracellular Signal-Regulated MAP Kinases; D008694:Methamphetamine; D019998:Racemases and Epimerases; D000099300:Serine Racemase