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Psychopharmacology (Berl). 2012 Apr;220(3):481-94. doi: 10.1007/s00213-011-2502-2. Epub 2011 Sep 28.

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

Author information

1
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.

PMID:
21952670
PMCID:
PMC3299972
DOI:
10.1007/s00213-011-2502-2
[Indexed for MEDLINE]
Free PMC Article

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