Several studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new, efficient way to achieve antipsychotic-like effects. Such an activity was shown for mGlu2/3 and mGlu5 receptor agonists/positive modulators, as well as for ACPT-I or LSP1-2111, a non-selective mGlu group III receptors orthosteric agonists. Herein, we report the pharmacological actions of Lu AF21934 and Lu AF32615, a novel, selective and brain-penetrant positive allosteric modulators (PAMs) of the mGlu4receptor with proven anxiolytic, but not antidepressant-like activity, in several tests reflecting positive, negative and cognitive symptoms of schizophrenia in rodents. MK-801- and amphetamine-induced hyperactivities, as well as DOI-induced head twitches in mice were used as models for positive symptoms. Furthermore, the effect of Lu AF21934 on DOI-induced frequency of spontaneous excitatory postsynaptic currents (EPSCs) in slices from mouse brain frontal cortices was investigated. The MK-801 induced disruption of social interaction and of spatial delayed alternation in rats were used as models for negative and cognitive symptoms, respectively. Lu AF21934 (0.1, 0.5, 2 and 5 mg/kg) and Lu AF32615 (2, 5 and 10 mg/kg) dose-dependently inhibited both MK-801 and amphetamine-induced hyperactivities. Concomitantly, Lu AF 21935, an inactive enantiomer of Lu AF21934, was not effective. Moreover, the drugs antagonized DOI-induced head twitches in mice. DOI-induced increased frequency of spontaneous EPSCs was also decreased by Lu AF21395 and Lu AF32615. The MK-801-induced disruption in the social interaction test, measured as number of episodes and total time of episodes between two rats, was abolished by Lu AF21394 at a dose of 0.5 mg/kg and Lu AF32615 at a dose of 10 mg/kg. In the delayed spatial alternation test, the effective doses of Lu AF21934 were 1 and 2 mg/kg, and the AF32615 was active at a dose of 10 mg/kg. Altogether, we propose that mGlu4 receptor can be consider as promising target for the development of novel antipsychotic drugs, acting as a positive allosteric modulators of the receptor.
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