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

Wierońska JM, Stachowicz K, Acher F, Lech T, Pilc A - Psychopharmacology (Berl.) (2011)

Bottom Line: The effects of the drug were antagonized by LY341495 administration (1.5 mg kg(-1), i.p.).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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, Poland. wierons@if-pan.krakow.pl

ABSTRACT

Rationale: Several 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.

Objectives: Here, 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.

Results: LSP1-2111 (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.

Conclusions: Altogether, 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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Related in: MedlinePlus

The effect of AMN082 on DOI-induced head twitches in mice (a) and the effect of DOI on the mGlu7 KO C57Bl/6J mice during a 20-min session and the lack of AMN082 effect after administration to mGlu7 KO animals (b). AMN082 was given in the dose of 6 mg kg−1, 60 min before DOI administration. Values represent the mean number of head twitches ±SEM. **p < 0.01 and *p < 0.05 vs. DOI-treated group, #p < 0.01 vs. WT animals
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Fig8: The effect of AMN082 on DOI-induced head twitches in mice (a) and the effect of DOI on the mGlu7 KO C57Bl/6J mice during a 20-min session and the lack of AMN082 effect after administration to mGlu7 KO animals (b). AMN082 was given in the dose of 6 mg kg−1, 60 min before DOI administration. Values represent the mean number of head twitches ±SEM. **p < 0.01 and *p < 0.05 vs. DOI-treated group, #p < 0.01 vs. WT animals

Mentions: The effect of AMN082 on DOI-induced head twitches in Albino Swiss and C57Bl/6J mGlu7 KO and WT mice AMN082, given in doses 3 and 6 mg kg−1, did not antagonize the DOI-induced effect; the highest dose of 6 mg kg−1 significantly enhanced the effect of DOI [F(2.17) = 8.11, p < 0.01] (Fig. 8a). The experiments with mGlu7 knockout animals revealed that the lack of the receptor resulted in the decreased number of DOI-induced head twitches by approximately 61% of the control (p < 0.01). AMN082, given in the highest dose of 6 mg kg−1, enhanced the effect of DOI in WT animals but did not evoke any effect in mGlu7 KO mice (Fig. 8b).Fig. 8


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

Wierońska JM, Stachowicz K, Acher F, Lech T, Pilc A - Psychopharmacology (Berl.) (2011)

The effect of AMN082 on DOI-induced head twitches in mice (a) and the effect of DOI on the mGlu7 KO C57Bl/6J mice during a 20-min session and the lack of AMN082 effect after administration to mGlu7 KO animals (b). AMN082 was given in the dose of 6 mg kg−1, 60 min before DOI administration. Values represent the mean number of head twitches ±SEM. **p < 0.01 and *p < 0.05 vs. DOI-treated group, #p < 0.01 vs. WT animals
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3299972&req=5

Fig8: The effect of AMN082 on DOI-induced head twitches in mice (a) and the effect of DOI on the mGlu7 KO C57Bl/6J mice during a 20-min session and the lack of AMN082 effect after administration to mGlu7 KO animals (b). AMN082 was given in the dose of 6 mg kg−1, 60 min before DOI administration. Values represent the mean number of head twitches ±SEM. **p < 0.01 and *p < 0.05 vs. DOI-treated group, #p < 0.01 vs. WT animals
Mentions: The effect of AMN082 on DOI-induced head twitches in Albino Swiss and C57Bl/6J mGlu7 KO and WT mice AMN082, given in doses 3 and 6 mg kg−1, did not antagonize the DOI-induced effect; the highest dose of 6 mg kg−1 significantly enhanced the effect of DOI [F(2.17) = 8.11, p < 0.01] (Fig. 8a). The experiments with mGlu7 knockout animals revealed that the lack of the receptor resulted in the decreased number of DOI-induced head twitches by approximately 61% of the control (p < 0.01). AMN082, given in the highest dose of 6 mg kg−1, enhanced the effect of DOI in WT animals but did not evoke any effect in mGlu7 KO mice (Fig. 8b).Fig. 8

Bottom Line: The effects of the drug were antagonized by LY341495 administration (1.5 mg kg(-1), i.p.).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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacology, Polish Academy of Sciences, 31-343, Kraków, Poland. wierons@if-pan.krakow.pl

ABSTRACT

Rationale: Several 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.

Objectives: Here, 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.

Results: LSP1-2111 (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.

Conclusions: Altogether, we propose that among group III mGlu receptors, mGlu4 receptor may be a promising target for the development of novel antipsychotic drugs.

Show MeSH
Related in: MedlinePlus