The antipsychotic-like effects of positive allosteric modulators of metabotropic glutamate mGlu4 receptors in rodents

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.

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.

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) .

Conclusions and implications: We propose that activation by PAMs of the mGlu4 receptor is a promising approach to the discovery of novel antipsychotic drugs.