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

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.

• Authors: Joanna M Wierońska, Katarzyna Stachowicz, Francine Acher, Tomasz Lech, Andrzej Pilc
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 220 Issue 3 Pg. 481-94 (Apr 2012) ISSN: 1432-2072 [Electronic] Germany
• PMID: 21952670 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminobutyrates
• Amphetamines
• Antipsychotic Agents
• Benzhydryl Compounds
• LSP1 2111
• N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride
• Phosphinic Acids
• Receptors, Metabotropic Glutamate
• metabotropic glutamate receptor 7
• Dizocilpine Maleate
• 4-iodo-2,5-dimethoxyphenylisopropylamine
• Dextroamphetamine
• metabotropic glutamate receptor 4

Topics

• Aminobutyrates (administration & dosage, pharmacology)
• Amphetamines (toxicity)
• Animals
• Antipsychotic Agents (administration & dosage, pharmacology)
• Benzhydryl Compounds (administration & dosage, pharmacology)
• Dextroamphetamine (toxicity)
• Disease Models, Animal
• Dizocilpine Maleate (toxicity)
• Dose-Response Relationship, Drug
• Drug Delivery Systems
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phosphinic Acids (administration & dosage, pharmacology)
• Receptors, Metabotropic Glutamate (agonists, genetics, metabolism)
• Schizophrenia (drug therapy, physiopathology)