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The antipsychotic-like effects of positive allosteric modulators of metabotropic glutamate mGlu4 receptors in rodents.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2013 Aug; Vol. 169 (8), pp. 1824-39. - Publication Year :
- 2013
-
Abstract
- Background and Purpose: Because agonists at metabotropic glutamate receptors exert beneficial effects in schizophrenia, we have assessed the actions of Lu AF21934 and Lu AF32615, two chemically distinct, selective and brain-penetrant positive allosteric modulators (PAMs) of the mGlu4 receptor, in several tests reflecting positive, negative and cognitive symptoms of schizophrenia in rodents.<br />Experimental Approach: Hyperactivity induced by MK-801 or amphetamine and head twitches induced by 2,5-dimethoxy-4-iodoamphetamine (DOI) in mice were used as models for positive symptoms. Disruption of social interaction and spatial delayed alternation tests induced by MK-801 in rats were used as models for negative and cognitive symptoms of schizophrenia, respectively.<br />Key Results: Lu AF21934 (0.1-5 mg·kg(-1) ) and Lu AF32615 (2-10 mg·kg(-1) ) dose-dependently inhibited hyperactivity induced by MK-801 or amphetamine. They also antagonized head twitches and increased frequency of spontaneous excitatory postsynaptic currents (EPSCs) in brain slices, induced by DOI. In mice lacking the mGlu4 receptor (mGlu4 (-/-) ) mice, Lu AF21934 did not antagonize DOI-induced head twitches. MK-801-induced disruption in the social interaction test was decreased by Lu AF21934 at 0.5 mg·kg(-1) and by Lu AF32615 at 10 mg·kg(-1) . In the delayed spatial alternation test, Lu AF21934 was active at 1 and 2 mg·kg(-1) , while Lu AF32615 was active at 10 mg·kg(-1) .<br />Conclusions and Implications: We propose that activation by PAMs of the mGlu4 receptor is a promising approach to the discovery of novel antipsychotic drugs.<br /> (© 2013 The British Pharmacological Society.)
- Subjects :
- Allosteric Regulation
Amphetamine
Animals
Disease Models, Animal
Dizocilpine Maleate
Dose-Response Relationship, Drug
Excitatory Postsynaptic Potentials drug effects
Hyperkinesis drug therapy
Male
Mice
Motor Activity drug effects
Rats
Schizophrenia chemically induced
Anilides pharmacology
Antipsychotic Agents pharmacology
Cyclohexanecarboxylic Acids pharmacology
Receptors, Metabotropic Glutamate drug effects
Schizophrenia drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5381
- Volume :
- 169
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 23714045
- Full Text :
- https://doi.org/10.1111/bph.12254