The mGlu2 but not the mGlu3 receptor mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity.
BACKGROUND
Group II metabotropic glutamate receptors (mGluRs) comprise the mGluR2 and mGluR3 subtypes, the activation and modulation of which has been suggested to be beneficial for treating schizophrenia. Genetic association studies suggest limited association between mGluR2 and schizophrenia but some association between mGluR3 and schizophrenia. Conversely, pre-clinical studies suggest that mGluR2 may be responsible for mediating the antipsychotic activity of mGluR2/3 agonists, although to date, the role of mGluR3 has not been specifically assessed.


OBJECTIVE
The aim of this study is to use recently generated mGluR3 and mGluR2 knockout mice to investigate which of the group II mGluRs mediates the actions of the mGluR2/3 agonist, LY379268, in two mouse models predictive of antipsychotic activity.


METHODS
LY379268 (0.3-10 mg/kg SC), phencyclidine (PCP; 1-5 mg/kg IP), and amphetamine 1-10 mg/kg IP) were assessed on locomotor activity and behaviour in C57Bl/6J and transgenic mice. LY379268 was then assessed on PCP (5 mg/kg IP)- and amphetamine (2.5 mg/kg IP)-induced hyperactivity and behaviour in C57Bl/6J and transgenic mice.


RESULTS
PCP (5 mg/kg)-evoked hyperactivity and behavioural alterations, i.e. circling, falling, stereotypy and ataxia, as well as amphetamine (2.5 mg/kg)-evoked hyperactivity, were dose-dependently attenuated by LY379268 (0.3-3 mg/kg) in C57Bl/6J mice. One milligram per kilogram of LY379268 reversed PCP-evoked hyperactivity and behavioural alterations in wild-type (WT) and mGluR3 knockout mice but not in mice lacking mGluR2. Similarly, 3 mg/kg LY379268 reversed amphetamine-evoked hyperactivity in WT and mGluR3 knockout mice but not in mice lacking mGluR2.


CONCLUSIONS
The mGlu2 but not the mGlu3 receptor subtype mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity.
GlaxoSmithKline plc, Harlow, Essex, CM19 5AW, UK. marie.2.woolley-roberts@gsk.com
M L
ML
Woolley
D J
DJ
Pemberton
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S
Bate
C
C
Corti
D N C
DN
Jones
D000596:Amino Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006948:Hyperkinesis / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000235:genetics
D000596:Amino Acids; D014150:Antipsychotic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D000661:Amphetamine