Use of MGLUR2 and MGLUR3 knockout mice to explore in vivo receptor specificity of the MGLUR2/3 selective antagonist LY341495.

LY341495 is a metabotropic glutamate receptor (mGluR) antagonist showing selectivity to mGluR2/3 but having measurable antagonist efficacy across all mGluR subtypes at 10-1000 fold higher concentrations. In vivo in rodents it increases locomotor activity and wakefulness, enhances cognition and modulates emotions. It also induces widespread neuronal activation measured as c-Fos expression. To further investigate the receptor subtypes through which LY341495 might act in vivo we analyzed how its effects are altered in mGluR2-knockout (KO) and mGluR3-KO brains. In most regions, LY341495 (3 mg/kg, i.p., 2.5 h) -induced c-Fos expression was not altered in either KO brain. However, in mGluR3-KO mice, LY341495 was almost inactive in the central extended amygdala [central nucleus of the amygdala, lateral (CeL) and bed nucleus of the stria terminalis, laterodorsal (BSTLD)], suggesting that acute blockade of mGluR3 is activating these neurons in wildtype brain. In the ventrolateral nucleus of the thalamus (VL), LY341495 produced a significantly enhanced response in mGluR3-KO mice and attenuated response in mGluR2-KO mice. We also analyzed locomotion in familiar environment and found that locomotor activity was dose-dependently increased by LY341495 (1-30 mg/kg, i.p.) regardless of the genotype. In unfamiliar environment, both KO strains showed enhanced sensitivity to LY341495 in reducing locomotor habituation. Together our results indicate that certain effects of LY341495 may not be mediated by a blockade of either mGluR2 or mGluR3, but may involve other mGluR subtypes. Alternatively, functions of mGluR2 and mGluR3 may be redundant, resulting similar effects irrespective the receptor subtype being antagonized in vivo by LY341495.