title: Effects of the mGluR2/3 agonist LY379268 on ketamine-evoked behaviours and neurochemical changes in the dentate gyrus of the rat.
abstract: One of the functions of group II metabotropic glutamate receptors (mGluR2/3) is to modulate glutamate release. Thus, targeting mGluR2/3s might be a novel treatment for several psychiatric disorders associated with inappropriate glutamatergic neurotransmission, such as schizophrenia. In an effort to evaluate the antipsychotic properties of LY379268, a potent and selective mGluR2/3 agonist, we examined its effect on ketamine-evoked hyperlocomotion and sensorimotor gating deficit (PPI) in rats, an animal model of schizophrenia. We also measured the ex vivo tissue level of glutamate (Glu), dopamine (DA) and serotonin (5-HT) as well as the DA metabolites DOPAC and the major 5-HT metabolite HIAA to determine the neurochemical effects of ketamine (12 mg/kg) and LY379268 (1 mg/kg) in the dentate gyrus (DG). While LY379268 (1-3 mg/kg) reduced ketamine-evoked hyperlocomotion (12 mg/kg), it could not restore ketamine-evoked PPI deficits (4-12 mg/kg). In the DG we found that ketamine decreased Glu and DA levels, as well as HIAA/5-HT turnover, and that LY379268 could prevent ketamine effects on Glu level but not on monoamine transmission. These results may indicate that the inability of LY379268 to reverse PPI deficits is attributable to its lack of effect on ketamine-induced changes in monoamine transmission, but that LY379268 can prevent ketamine-evoked changes in glutamate, which is sufficient to block hyperlocomotion. In addition to the partial effectiveness of LY379268 in the ketamine model of schizophrenia, we observed a dual effect of LY379268 on anxious states, whereby a low dose of this compound (1 mg/kg) produced anxiolytic effects, while a higher dose (3 mg/kg) appeared to be anxiogenic. Additional work is needed to address a possible role of LY379268 in schizophrenia and anxiety treatment.
authors.affiliation: Department of Psychiatry, University Medical Center Groningen, and University of Groningen, The Netherlands. g.imre@med.umcg.nl
authors.forename: Gabor
authors.initials: G
authors.lastname: Imre
authors.forename: Amber
authors.initials: A
authors.lastname: Salomons
authors.forename: Minke
authors.initials: M
authors.lastname: Jongsma
authors.forename: Dirk S
authors.initials: DS
authors.lastname: Fokkema
authors.forename: Johan A
authors.initials: JA
authors.lastname: Den Boer
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ter Horst
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D018891:Dentate Gyrus / Q000473:pathology*; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009448:Neurochemistry / Q000379:methods*; D018377:Neurotransmitter Agents / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012701:Serotonin / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D014151:Anti-Anxiety Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C118218:LY 379268; D018377:Neurotransmitter Agents; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D012701:Serotonin; D007649:Ketamine