Author: Cristiano, Nunzia ; Brabet, Isabelle ; Tora, Amelie ; Goupil-Lamy, Anne ; Flor, Peter J. ; Pin, Jean-Philippe ; Goudet, Cyril ; Acher, Francine C. ; Glatthar, Ralf ; Bertrand, Hugues-Olivier ; McCort-Tranchepain, Isabelle ; Cabayé, Alexandre

Metabotropic glutamate (mGlu) receptors play a key role in modulating most synapses in the brain. The mGlu7 receptors inhibit presynaptic neurotransmitter release and offer therapeutic possibilities for post-traumatic stress disorders or epilepsy. Screening campaigns provided mGlu7-specific allosteric modulators as the inhibitor XAP044 (Gee et al. J. Biol. Chem. 2014). In contrast to other mGlu receptor allosteric modulators, XAP044 does not bind in the transmembrane domain but to the extracellular domain of the mGlu7 receptor and not at the orthosteric site. Here, we identified the mode of action of XAP044, combining synthesis of derivatives, modeling and docking experiments, and mutagenesis. We propose a unique mode of action of these inhibitors, preventing the closure of the Venus flytrap agonist binding domain. While acting as a noncompetitive antagonist of L-AP4, XAP044 and derivatives act as apparent competitive antagonists of LSP4-2022. These data revealed more potent XAP044 analogues and new possibilities to target mGluRs.

01 Jan 2020·Genes, Brain and Behavior

Metabotropic glutamate receptor subtype 7 controls maternal care, maternal motivation and maternal aggression in mice

Article

Author: Peterlik, Daniel ; Flor, Peter J. ; Bauer, Angelika ; Bosch, Oliver J. ; Gryksa, Katharina ; Uschold‐Schmidt, Nicole ; Mittmann, Laura

AbstractThe group III metabotropic glutamate receptor subtype 7 (mGlu7) is an important regulator of glutamatergic and GABAergic neurotransmission and known to mediate emotionality and male social behavior. However, a possible regulatory role in maternal behavior remains unknown to date. Adequate expression of maternal behavior is essential for successful rearing and healthy development of the young. By understanding genetic and neural mechanisms underlying this important prosocial behavior, we gain valuable insights into possible dysregulations. Using genetic ablation as well as pharmacological modulation, we studied various parameters of maternal behavior in two different mouse strains under the influence of mGlu7. We can clearly show a regulatory role of mGlu7 in maternal behavior. Naïve virgin female C57BL/6 mGlu7 knockout mice showed more often nursing postures and less spontaneous maternal aggression compared to their heterozygous and wildtype littermates. In lactating C57BL/6 wildtype mice, acute central activation of mGlu7 by the selective agonist AMN082 reduced arched back nursing and accelerated pup retrieval without affecting maternal aggression. In addition, in lactating CD1 wildtype mice the selective mGlu7 antagonist XAP044 increased both pup retrieval and maternal aggression. With respect to receptor expression levels, mGlu7 mRNA expression was higher in lactating vs virgin C57BL/6 mice in the prefrontal cortex, but not hypothalamus or hippocampus. In conclusion, these findings highlight a significant role of the mGlu7 receptor subtype in mediating maternal behavior in mice. Region‐dependent studies are warranted to further extend our knowledge on the specific function of the brain glutamate system in maternal behavior.

01 Mar 2018·Neuropharmacology

Role of mGlu7 receptor in morphine rewarding effects is uncovered by a novel orthosteric agonist

Article

Author: Florence Noble ; Francine Acher ; Corinne Canestrelli ; Zuzana Hajasova ; Nicolas Marie

Opiate dependence is a major health issue and despite the existence of opioid substitution treatment, relapse frequently occurs. Group III metabotropic glutamate (mGlu) receptors has received much attention as a putative target in ethanol and cocaine addiction, but no data on opiate addiction exist. So we investigated the role of group III mGlu receptors in morphine rewarding effects through the expression and the reinstatement of conditioned place preference (CPP) using a newly synthesized mGlu4/mGlu7 receptor orthosteric agonist, LSP2-9166. We found that LSP2-9166 blocked morphine CPP expression and reinstatement after extinction. Blockade of CPP expression with LSP2-9166 was abolished when using XAP044, a mGlu7 antagonist. We also found that LSP2-9166 at the dose active for blocking morphine reward was devoid of any effect on locomotion, hedonic state, spatial memory, anxiety or depression. Altogether our data demonstrated that group III mGlu receptors, and more specifically mGlu7, might be a valuable target in opiate addiction.

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Indication	Highest Phase	Country/Location	Organization	Date
Epilepsy	Preclinical	France	Universite Paris Cite	01 May 2024
Stress Disorders, Post-Traumatic	Preclinical	France	Universite Paris Cite	01 May 2024

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