Opposing efficacy of group III mGlu receptor activators, LSP1-2111 and AMN082, in animal models of positive symptoms of schizophrenia

Abstract

RationaleSeveral studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new and efficient way to achieve antipsychotic-like activity.ObjectivesHere, we decided to investigate the possible role of the group III mGlu receptor ligands, LSP1-2111, the group III mGlu receptor orthosteric agonist, preferentially stimulating mGlu4 receptors especially in low doses, and AMN082, the mGlu7 receptor positive modulator. We used MK-801- and amphetamine-induced hyperactivity tests, as well as DOI-induced head twitches in mice as models for positive symptoms of psychosis. The C57Bl/6J mGlu7 receptor knockout mice were used to confirm that AMN082-induced effect was receptor specific. A non-selective antagonist of the group II/III mGlu receptors, LY341495, was used to block LSP1-2111-induced effects.ResultsLSP1-2111 (1, 2, and 5 mg kg−1) dose dependently inhibited both MK-801- and amphetamine-induced hyperactivities. Moreover, the drug antagonized DOI-induced head twitches. The effects of the drug were antagonized by LY341495 administration (1.5 mg kg-1, i.p.). In contrast, AMN082 (3 and 6 mg kg−1) had no effect on amphetamine-induced hyperactivity but induced an enhancement of MK-801-induced hyperactivity and DOI-induced head twitches in mice. In C57Bl/6J mGlu7 receptor knockout animals (KO), those effects of AMN082 were not observed. Moreover, mGlu7 KO animals were less sensitive for DOI-induced effect than their wild type littermates.ConclusionsAltogether, we propose that among group III mGlu receptors, mGlu4 receptor may be a promising target for the development of novel antipsychotic drugs.

Role of mGluR4 in acquisition of fear learning and memory

“…The optimal pharmacological effect of a dose of 5 mg/kg is in agreement with other behavioral measures (Wieronska et al, 2010, 2012). Consistent with the opposite effects seen in mGluR4 −/− versus WT and LSP1-2111-treated versus vehicle-treated WT mice, analysis of microarray data of amygdala tissues from mGluR4 −/− versus WT and from WT mice treated with a mGluR4 agonist versus vehicle revealed a significant overlap in pattern of gene expression.…”

“…However, in contrast to LSP1-2111, AMN082 enhances extinction of conditioned fear (Fendt et al, 2008). Interestingly, opposing effects of mGluR4 and mGluR7 are also seen in animal models of positive symptoms of schizophrenia (Wieronska et al, 2012). …”

Characterization of the Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 ADX88178 in Rodent Models of Neuropsychiatric Disorders

“…For a decade, studies involving pharmacological manipulation of mGlu 5 and mGlu 2/3 receptors led the field of mGlu receptors as potential novel targets for schizophrenia (Conn et al, 2009), although recent preclinical evidence also implies the mGlu 4 receptor could be a viable target for all domains of schizophrenia. For example, mGlu 4 receptor activators were active in rodent models relevant for positive, negative, and cognitive symptoms of schizophrenia (Pałucha-Poniewiera et al, 2008;Wiero nska et al, 2012Wiero nska et al, , 2013Sławi nska et al, 2013b). It has been hypothesized that activation of mGlu 4 receptors localized on glutamatergic terminals of the thalamocortical neurons (Corti et al, 2002) can counteract glutamatergic (Liu et al, 2008).…”

“…For example, it has been shown that LSP1-2111 [(2S)-2-amino-4-[hydroxy [hydroxy(4-hydroxy-3-methoxy-5-nitro-phenyl)methyl]phosphoryl] butanoic acid], an orthosteric agonist with 30-fold higher potency at the mGlu 4 receptor compared with other group III receptors, has an anxiolytic-and antipsychotic-like profile in several rodent models (Wiero nska et al, 2012. Additionally, (2)-PHCCC [N-phenyl-7-(hydroxyimino)cyclopropa [b] chromen-1a-carboxamide], a mGlu 4 receptor positive allosteric modulator (PAM), showed anticonflict efficacy in the rat Vogel test when administered to the basolateral amygdala (Stachowicz et al, 2004).…”

Targeting metabotropic glutamate receptors for novel treatments of schizophrenia

“…In addition to efficacy in models of the positive symptoms of schizophrenia, both LSP1-2111 and LSP4-2022 have efficacy in models of negative symptoms and cognitive deficits [191, 192]. Furthermore, the mGlu 4 -selective PAMs Lu AF21934 [193], Lu AF32615 [194], and ADX88178 [195] displayed similar promise in models of all three symptom clusters of schizophrenia [196, 197], providing further support for potential therapeutic utility of selective mGlu 4 activators.…”