Peripheral administration of group III mGlu receptor agonist ACPT-I exerts potential antipsychotic effects in rodents

Pałucha-Poniewiera, Agnieszka; Kłodzińska, Aleksandra; Stachowicz, Katarzyna; Tokarski, Krzysztof; Hess, Grzegorz; Schann, Stéphan; Frauli, Mélanie; Neuville, Pascal; Pilc, Andrzej

doi:10.1016/j.neuropharm.2008.06.033

Cited by 48 publications

(59 citation statements)

References 42 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…For example, a nonselective group III receptor agonist, ACPT-I [(1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid], showed an anticonflict effect in the rat Vogel test following intrahippocampal administration (Stachowicz et al, 2006) and reduced anxiety-like reactivity in the mouse elevated plus maze (EPM) and stress-induced hyperthermia tests following intraperitoneal administration (Stachowicz et al, 2009). In addition, ACPT-I has been shown to have an antipsychotic-like profile in rodents, reducing MK-801 [(5S,10R)-(1)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine]-and amphetamine-induced hyperactivity in rats, DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in mice, and DOI-mediated excitatory postsynaptic potentials in the mouse cortex (Pałucha-Poniewiera et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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

Kalinichev

Poul

Boléa

et al. 2014

J Pharmacol Exp Ther

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There is growing evidence that activation of metabotropic glutamate receptor 4 (mGlu 4 ) leads to anxiolytic-and antipsychotic-like efficacy in rodent models, yet its relevance to depression-like reactivity remains unclear. Here, we present the pharmacological evaluation of ADX88178 [5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine], a novel potent, selective, and brain-penetrant positive allosteric modulator of the mGlu 4 receptor in rodent models of anxiety, obsessive compulsive disorder (OCD), fear, depression, and psychosis. ADX88178 dose-dependently reduced the number of buried marbles in the marble burying test and increased open-arm exploration in the elevated plus maze (EPM) test, indicative of anxiolyticlike efficacy. Target specificity of the effect in the EPM test was confirmed using male and female mGlu 4 receptor knockout mice. In mice, ADX88178 reduced the likelihood of conditioned freezing in the acquisition phase of the fear conditioning test, yet had no carryover effect in the expression phase. Also, ADX88178 dose-dependently reduced duration of immobility in the forced swim test, indicative of antidepressantlike efficacy. ADX88178 reduced DOI (2,5-dimethoxy-4-iodoamphetamine)-mediated head twitches (albeit with no dose-dependency), and MK-801 [(5S,10R)-(1)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]-induced locomotor hyperactivity in mice, but was inactive in the conditioned avoidance response test in rats. The compound showed good specificity as it had no effect on locomotor activity in mice and rats at efficacious doses. Thus, allosteric activation of mGlu 4 receptors can be a promising new therapeutic approach for treatment of anxiety, OCD, fear-related disorders, and psychosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Kalinichev

Poul

Boléa

et al. 2014

J Pharmacol Exp Ther

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“…The pan-group III agonist ACPT-I reduced PCP- and amphetamine-induced hyperlocomotion as well as DOI-induced head twitches [190], and these actions of ACPT-I are also observed with mGlu 4 -selective agonists, LSP1-2111 [191] (>30-fold selective for mGlu 4 vs. mGlu 8 ) and LSP4-2022 [192] (>100-fold selective for mGlu 4 vs. mGlu 7 ; >300-fold vs. mGlu 8 ). 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].…”

Section: Group III Mglu Receptors (Mglu4 Mglu7 and Mglu8)mentioning

confidence: 99%

Targeting metabotropic glutamate receptors for novel treatments of schizophrenia

2017

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Support for the N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis of schizophrenia has led to increasing focus on restoring proper glutamatergic signaling as an approach for treatment of this devastating disease. The ability of metabotropic glutamate (mGlu) receptors to modulate glutamatergic neurotransmission has thus attracted considerable attention for the development of novel antipsychotics. Consisting of eight subtypes classified into three groups based on sequence homology, signal transduction, and pharmacology, the mGlu receptors provide a wide range of targets to modulate NMDAR function as well as glutamate release. Recently, allosteric modulators of mGlu receptors have been developed that allow unprecedented selectivity among subtypes, not just groups, facilitating the investigation of the effects of subtype-specific modulation. In preclinical animal models, positive allosteric modulators (PAMs) of the group I mGlu receptor mGlu5 have efficacy across all three symptom domains of schizophrenia (positive, negative, and cognitive). The discovery and development of mGlu5 PAMs that display unique signal bias suggests that efficacy can be retained while avoiding the neurotoxic effects of earlier compounds. Interestingly, mGlu1 negative allosteric modulators (NAMs) appear efficacious in positive symptom models of the disease but are still in early preclinical development. While selective group II mGlu receptor (mGlu2/3) agonists have reached clinical trials but were unsuccessful, specific mGlu2 or mGlu3 receptor targeting still hold great promise. Genetic studies implicated mGlu2 in the antipsychotic effects of group II agonists and mGlu2 PAMs have since entered into clinical trials. Additionally, mGlu3 appears to play an important role in cognition, may confer neuroprotective effects, and thus is a promising target to alleviate cognitive deficits in schizophrenia. Although group III mGlu receptors (mGlu4/6/7/8) have attracted less attention, mGlu4 agonists and PAMs appear to have efficacy across all three symptoms domains in preclinical models. The recent discovery of heterodimers comprising mGlu2 and mGlu4 may explain the efficacy of mGlu4 selective compounds but this remains to be determined. Taken together, compounds targeting mGlu receptors, specifically subtype-selective allosteric modulators, provide a compelling alternative approach to fill the unmet clinical needs for patients with schizophrenia.

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“…The experiments with non-selective orthosteric agonist of group III mGlu receptors, ACPT-I (Acher et al 1997), demonstrated its anxiolytic, but not antidepressant, efficacy (Stachowicz et al 2009). The compound was also shown to induce antipsychotic-like effects in animal models of positive symptoms of the disease (Palucha-Poniewiera et al 2008). …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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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.

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Peripheral administration of group III mGlu receptor agonist ACPT-I exerts potential antipsychotic effects in rodents

Cited by 48 publications

References 42 publications

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

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

Targeting metabotropic glutamate receptors for novel treatments of schizophrenia

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

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