title: Activation of metabotropic glutamate 2/3 receptors attenuates methamphetamine-induced hyperlocomotion and increase in prefrontal serotonergic neurotransmission.
abstract: BACKGROUND
  Metabotropic glutamate (mGlu) 2/3 receptor agonists inhibit amphetamine- and phencyclidine-induced hyperlocomotion. The mechanism for the antipsychotic effect of mGlu2/3 receptor agonists was studied in a hypoglutamatergic model, but not a hyperdopaminergic model.
  
  
  OBJECTIVE
  To study the mechanism for the antipsychotic effect of the agonist in the hyperdopaminergic model, this study examined the effects of the selective mGlu2/3 receptor agonist MGS0028 on methamphetamine-induced hyperlocomotion and the increases in extracellular levels of serotonin, dopamine, noradrenaline, and glutamate in the prefrontal cortex and nucleus accumbens of mice.
  
  
  RESULTS
  Systemic administration of MGS0028 attenuated methamphetamine-induced hyperlocomotion in a dose-dependent manner. Microdialysis studies showed that MGS0028 significantly inhibited methamphetamine-induced increases in the extracellular serotonin, but not dopamine and noradrenaline, levels in the prefrontal cortex, and it did not affect methamphetamine-induced increases in the extracellular amine levels in the nucleus accumbens. Methamphetamine did not affect the glutamate release in the prefrontal cortex and nucleus accumbens. Local application of MGS0028 into the prefrontal cortex also attenuated methamphetamine-induced hyperlocomotion and increases in the extracellular serotonin levels in the prefrontal cortex. Moreover, MGS0028 did not affect methamphetamine-induced hyperlocomotion in the mice pretreated with p-chlorophenylalanine, a serotonin synthesis inhibitor.
  
  
  CONCLUSIONS
  Activation of prefrontal mGlu2/3 receptors inhibits the psychomotor stimulant effect of methamphetamine in mice, and the prefrontal serotonergic system may be involved in this effect. The finding provides evidence that prefrontal mGlu2/3 receptors are functionally coupled with the serotonergic system.
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ago
authors.forename: Ryota
authors.initials: R
authors.lastname: Araki
authors.forename: Koji
authors.initials: K
authors.lastname: Yano
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
authors.forename: Atsuro
authors.initials: A
authors.lastname: Nakazato
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Onoe
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Akemichi
authors.initials: A
authors.lastname: Baba
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takuma
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D003998:Dicarboxylic Acids / Q000494:pharmacology; D006948:Hyperkinesis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008694:Methamphetamine / Q000009:adverse effects*; D051379:Mice; D008815:Mice, Inbred Strains; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012701:Serotonin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D001643:Bridged Bicyclo Compounds; D003998:Dicarboxylic Acids; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D012701:Serotonin; D008694:Methamphetamine; C418124:MGS 0028