Study of Novel Selective mGlu2 Agonist in the Temporo-Ammonic Input to CA1 Neurons Reveals Reduced mGlu2 Receptor Expression in a Wistar Substrain with an Anxiety-Like Phenotype

Abstract

Group II metabotropic receptors (mGluRs) regulate central synaptic transmission by modulating neurotransmitter release. However, the lack of pharmacological tools differentiating between mGlu2 and mGlu3 receptors has hampered identification of the roles of these two receptor subtypes. We have used LY395756 [(1SR,2SR,4RS,5RS,6SR)-2-amino-4-methylbicyclo[3.1.0]-hexane2,6-dicarboxylic], an agonist at mGlu2 receptors and an antagonist at mGlu3 receptors in cell lines, to investigate the roles of these receptors in the temporo-ammonic path from entorhinal cortex to CA1-stratum lacunosum moleculare in rat hippocampal slices. Surprisingly, the degree of inhibition of the field EPSP induced by LY395756 fell into two distinct groups, with EC 50 values of Ͻ1 M and Ͼ100 M. In "sensitive" slices, LY395756 had additive actions with a mixed mGlu2/mGlu3 agonist, DCG-IV [(2S,2ЈR,3ЈR)-2-(2Ј,3Ј-dicarboxycyclopropyl)glycine], whereas in "insensitive" slices, LY395756 reduced the effect of DCG-IV, with an IC 50 of ϳ1 M. This separation into sensitive and insensitive slices could be explained by LY395756 acting as an mGlu2 agonist and mGlu3 antagonist, respectively, a finding supported by data from mice lacking these receptors. The heterogeneity was correlated with differences in expression levels of mGlu2 receptors within our Wistar colony and other Wistar substrains. The initial search for a behavioral correlate indicated that rats lacking mGlu2 receptors showed anxiety-like behavior in open-field and elevated plus maze assays. These findings have implications for rat models of psychiatric disease and are especially pertinent given that mGlu2 receptors are targets for compounds under development for anxiety.

Characterisation of an mGlu8 receptor-selective agonist and antagonist in the lateral and medial perforant path inputs to the dentate gyrus

“…Furthermore, we also demonstrate selective mGlu8 antagonism by (RS)-a-methyl-3,4-dicarboxyphenylglycine (MDCPG) (Thomas et al, 2001) in the LPP. In order to directly assess the non-selective effects of DCPG, we used slices from mice lacking mGlu8, mGlu2, mGlu4 or mGlu7 receptors, as well as from a rat strain lacking functional mGlu2 receptors (Ceolin et al, 2011). The present investigation has demonstrated that submicromolar concentrations of DCPG are selective for mGlu8 receptors but that higher concentrations lead to activation of mGlu2 receptors, thus complicating the interpretation of some in vivo studies.…”

“…We sought to further investigate the effects of DCPG in a substrain of Wistar rat identified as lacking mGlu2 receptor expression (Ceolin et al, 2011). For these experiments, Hsd:Wi rats were ordered from Harlan (UK), and western blot analyses were performed on the remaining hippocampal slices from each animal following electrophysiological recording, in order to estimate mGlu2 receptor expression levels.…”

LY395756, an mGluR2 agonist and mGluR3 antagonist, enhances NMDA receptor expression and function in the normal adult rat prefrontal cortex, but fails to improve working memory and reverse MK801-induced working memory impairment

“…LY395756 (LY39) is a novel compound that serves as both an mGluR2 agonist and mGluR3 antagonist (K i = 0.165 and 0.302 μM, respectively) (Ceolin et al, 2011; Lucas et al, 2013). We ewcently observed that LY39 also exhibited a strong effect on AMPAR expression in cultured neurons (Wang et al, 2013).…”

Persistent nociception induces anxiety-like behavior in rodents: Role of endogenous neuropeptide S

“…Another study in mice revealed the antinociceptive effect of NPS on inflammatory pain [44]. The amygdala has been implicated in the integration of pain and mood disorders [3; 8; 12; 61]. NPS-responsive neurons express NPSR and are concentrated in the amygdala [11; 59].…”