Title : The mGlu4 receptors as target for novel antipsychotic drugs; Interactions with other neurotransmitter systems
The aim of our studies was to further investigate to antipsychotic potential of glutamate metabotropic receptor 4 (mGlu4) agonists and positive allosteric modulators (PAMs) as well as to investigate the interactions between mGlu4 receptor stimulators and 5-HT1A serotonin agonists in order to develop potential novel and efficacious ways to treat this devastating disease. The possibility that the mGlu4 receptors and 5-HT1A receptors may form dimers was also investigated. An orthosteric agonist of mGlu4 receptors was investigated in several rodent tests used to study antipsychotic-like activity of drugs, such as MK-801 and amphetamine-induced hyperactivity, DOI-induced head twitches, social interactions, modified forced swim test, and novel object recognition test.
Interactions of mGlu4 receptor agonists with serotonergic system was also evaluated. Moreover the in vivo microdialysis, the electrophysiological studies were also conducted. The potential dimerization of mGlu4 and 5-HT1A receptors was also investigated. The mGlu4 receptororthostericagonist LSP4-2022was effective in all preclinical tests of schizophrenia applied. In subsequent experiments it was shown that the administration of subeffective doses of LSP4-2022 may be intensified with the administration of the ligands of the other receptors. The co-administration of sub-effective dose of the 5-HT1A agonist (R)-(S)-8-OH-DPAT revealed the activity of ineffective doses of LSP4-2022, while the 5-HT1A antagonist WAY100635 reversed LSP4-2022-induced effects on MK-801-induced hyperactivity, DOI-induced head twitches, MK-801-induced disruptions of social interactions and novel object recognition. In the microdialysis studies MK-801 at a dose of 0.6 mg•kg−1 significantly increased cortical DA, 5-HT and Glu levels, reaching a maximal effect between 80 and 120 min after administration. LSP4-2022 reversed this effect and WAY100635 (5-HT1A antagonist) antagonized this LSP4-2022-induced effect. In the electrophysiological studies in slices from the mouse prefrontal cortex, LSP4-2022 reversed the DOI-induced changes in both the frequency and amplitude of the EPSCs, but the more robust effect on the frequency was observed. When mGlu4 and 5-HT1A receptor were co-expressed in the T-Rex 293 cells, the fluorescenceresonance energy transfer (FRET) studies revealed the close vicinity of both receptors. The experiments with the use of proximity ligation assay (PLA) conducted ona primary cultures of astrocytes or neurons have shown a positive PLA signal, which indicated that both receptors are placed in a close vicinity, which enables the potential dimerization of bot receptors. The efficacy shown by mGlu4 receptor activator in mechanistic and behavioral models of schizophrenia provides evidence for a potential role played by this receptor in the pathophysiology of this disease and suggests that mGlu4 receptor activators can become future antipsychotics.
Our results indicate that:
• Combined treatment based on the simultaneous stimulation of 5-HT1A and mGlu4 receptors may be considered as combinations active in psychosis
• Such combination may allow for lowering drug doses and achieving a greater efficacy.
• The study was supported by the National Science Centre grants No. 2012/6/06/A/NZ7/00014 (MAESTRO) given to A. Pilc.