Limits...
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.

Show MeSH

Related in: MedlinePlus

Effect of standard antipsychotic drugs, haloperidol, and clozapine on the MK-801-induced hyperactivity in mice (a). Clozapine and haloperidol were given 30 min before the MK-801 administration. LSP1-2111 abolished MK-801-induced effect when administered 45 min before MK-801 administration (b). LY341495 abolished the effect of the highest dose of LSP1-2111 (5 mg kg−1) when given 15 min prior LSP1-2111 (c). Locomotor activity was monitored every 10 min over an 80-min session immediately following an injection of psychostimulant agent. The data are presented as means ± SEM and analyzed by repeated measure ANOVA (inset the total activity of mice within the 80-min session was analyzed by one-way ANOVA [a, b] or two-way ANOVA [c]) #p < 0.001 vs. control group and *** p < 0.001, **p < 0.01, and *p < 0.05 vs. MK-801-treated group
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3299972&req=5

Fig3: Effect of standard antipsychotic drugs, haloperidol, and clozapine on the MK-801-induced hyperactivity in mice (a). Clozapine and haloperidol were given 30 min before the MK-801 administration. LSP1-2111 abolished MK-801-induced effect when administered 45 min before MK-801 administration (b). LY341495 abolished the effect of the highest dose of LSP1-2111 (5 mg kg−1) when given 15 min prior LSP1-2111 (c). Locomotor activity was monitored every 10 min over an 80-min session immediately following an injection of psychostimulant agent. The data are presented as means ± SEM and analyzed by repeated measure ANOVA (inset the total activity of mice within the 80-min session was analyzed by one-way ANOVA [a, b] or two-way ANOVA [c]) #p < 0.001 vs. control group and *** p < 0.001, **p < 0.01, and *p < 0.05 vs. MK-801-treated group

Mentions: The effect of MK-801 on locomotor activity in mice MK-801, in a dose of 0.3 mg kg−1, produced a robust increase in the ambulation scores within 80 min of the experimental session [F(1.16) = 60.5, p < 0.000001], and time–dose interaction was shown to be significant as well [F(7.96) = 13.18, p < 0.0000] (Fig. 3a). Repeated measure ANOVA revealed that the effects of reference compounds clozapine (10 mg kg-1) and haloperidol (0.25 mg kg−1) were shown to be statistically significant and inhibited the effect of MK-801 in a time-dependent manner [F(7.98) = 12.77, p < 0.0000, and F(7.98) = 17.79, p < 0.0000, respectively] (Fig. 3a).Fig. 3


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)

Effect of standard antipsychotic drugs, haloperidol, and clozapine on the MK-801-induced hyperactivity in mice (a). Clozapine and haloperidol were given 30 min before the MK-801 administration. LSP1-2111 abolished MK-801-induced effect when administered 45 min before MK-801 administration (b). LY341495 abolished the effect of the highest dose of LSP1-2111 (5 mg kg−1) when given 15 min prior LSP1-2111 (c). Locomotor activity was monitored every 10 min over an 80-min session immediately following an injection of psychostimulant agent. The data are presented as means ± SEM and analyzed by repeated measure ANOVA (inset the total activity of mice within the 80-min session was analyzed by one-way ANOVA [a, b] or two-way ANOVA [c]) #p < 0.001 vs. control group and *** p < 0.001, **p < 0.01, and *p < 0.05 vs. MK-801-treated group
© Copyright Policy
Related In: Results  -  Collection

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

Fig3: Effect of standard antipsychotic drugs, haloperidol, and clozapine on the MK-801-induced hyperactivity in mice (a). Clozapine and haloperidol were given 30 min before the MK-801 administration. LSP1-2111 abolished MK-801-induced effect when administered 45 min before MK-801 administration (b). LY341495 abolished the effect of the highest dose of LSP1-2111 (5 mg kg−1) when given 15 min prior LSP1-2111 (c). Locomotor activity was monitored every 10 min over an 80-min session immediately following an injection of psychostimulant agent. The data are presented as means ± SEM and analyzed by repeated measure ANOVA (inset the total activity of mice within the 80-min session was analyzed by one-way ANOVA [a, b] or two-way ANOVA [c]) #p < 0.001 vs. control group and *** p < 0.001, **p < 0.01, and *p < 0.05 vs. MK-801-treated group
Mentions: The effect of MK-801 on locomotor activity in mice MK-801, in a dose of 0.3 mg kg−1, produced a robust increase in the ambulation scores within 80 min of the experimental session [F(1.16) = 60.5, p < 0.000001], and time–dose interaction was shown to be significant as well [F(7.96) = 13.18, p < 0.0000] (Fig. 3a). Repeated measure ANOVA revealed that the effects of reference compounds clozapine (10 mg kg-1) and haloperidol (0.25 mg kg−1) were shown to be statistically significant and inhibited the effect of MK-801 in a time-dependent manner [F(7.98) = 12.77, p < 0.0000, and F(7.98) = 17.79, p < 0.0000, respectively] (Fig. 3a).Fig. 3

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