Individual contribution of metabotropic glutamate receptor (mGlu) 2 and 3 to c-Fos expression pattern evoked by mGlu2/3 antagonism

Abstract

Objectives and materials and methods The aims of the present study were (1) to determine the neuronal activation pattern elicited by the group II mGlu antagonist LY341495 and (2) to evaluate the contribution of each group II mGlu subtype by using wild-type (WT) and knockout (KO) mice lacking either mGlu2 or mGlu3. c-Fos expression was used as a marker of neuronal activation. Results and discussion In WT mice, LY341495 induced widespread c-Fos expression in 68 out of 92 brain areas, including limbic areas such as the amygdala, septum, prefrontal cortex, and hippocampus. LY341495-induced cFos response was markedly decreased in the medial part of the central amygdala (CeM) and lateral septum (LS) in mGlu3-KO mice, as well as in the lateral parabrachial nucleus (LPB) in both KO strains. In the majority of investigated areas, LY341495-induced c-Fos expression was similar in KO and WT mice. Analysis of the cellular and subcellular distribution of mGlu2 and mGlu3 revealed a prevailing presence of mGlu3-immunoreactivity in the CeM in glial processes and in postsynapstic neuronal elements, whereas only rare presynaptic axon terminals were found immunoreactive for mGlu2. Conclusion In conclusion, our data indicate that group II mGlu blockade increases neuronal activation in a variety of brain areas, including many stress-and anxiety-related areas. The activation of two key brain areas, the CeM and LS, is mediated via mGlu3, while activation in the LPB involves both subtypes. Moreover, in the majority of investigated areas, LY341495-mediated neuronal activation appears to require a complex cross talk between group II mGlu subtypes or the action of LY341495 on additional receptors.

Developmental expression of mGlu2 and mGlu3 in the mouse brain

“…Here we show striking mGlu2 expression in the mouse dentate gyrus pyramidal layer, with minimal mGlu3 mRNA detected in this region, in agreement with another recent study in adult rat CNS (Gu et al, 2008). Subtle differences in response to mGlu2/3 antagonists have been demonstrated across mouse strains (Linden et al, 2005; Hetzenauer et al, 2008), and thus strain-, or indeed species-specific differences may account for the inconsistency between studies.…”

“…Consistent with this, global knockouts of these receptors in mice demonstrate specific functions; mGlu2 appears to be critical for the antipsychotic-like effects of mGlu2/3 ligands (Spooren et al, 2000), while both subtypes appear to be involved in the anxiolytic actions of mGlu2/3 antagonists (Linden et al, 2005). Meanwhile mGlu3, but not mGlu2, appear to underlie the cellular response to mGlu2/3 antagonists in the centromedial amygdala and ventral lateral septal nucleus (Hetzenauer et al, 2008). Thus the results of this study provide further evidence for understanding how distinct and overlapping mGlu2 and mGlu3 circuits contribute to the behavioral outcomes of genetic or pharmacological targeting of class II mGlu.…”

“…This is largely due to the fact that mGlu2 and mGlu3 are highly conserved, and subtype-specific ligands have only recently been identified (Sheffler et al, 2010; Cid et al, 2012). Attempts to dissociate mGlu2 from mGlu3 suggest distinct roles and interactions for each subtype (Spooren et al, 2000; Linden et al, 2005; Hetzenauer et al, 2008). The temporal expression of mGlu2 and mGlu3 and the role of these receptors in brain development is also not well understood, and a systematic analysis of mGlu2 and mGlu3 expression across development has not previously been conducted in species used as model systems for CNS disorders.…”

N-acetylaspartylglutamate Inhibits Heroin Self-Administration and Heroin-Seeking Behaviors Induced by Cue or Priming in Rats

“…The PR reinforcement schedule required animals to increase active nose-poking progressively for each successive infusion in the following series, within a self-administration session. The progression of ratio was calculated as follows for 28 reinforcements [28]: 1,2,4,6,9,12,15,20,25,32,40,50,62,77,95,118,145,178,219,268,328,402,603,737,901,1102, and 1347. The last ratio successfully completed was registered as the break-point for that session [28].…”

Effects of microinjections of Group II metabotropic glutamate agents into the amygdala on sleep

“…There is also evidence from immunohistochemical (Gale et al, 2004; Hetzenauer et al, 2008; Petralia et al, 1996) and radioligand binding (Wright et al, 2001) studies of low to moderate expression of mGlu II receptors in the CNA. Therefore, in this study, we microinjected into BA and CNA various dosages of an mGlu II agonist (LY37) and antagonist (LY34) and determined their effects on sleep.…”