Abstract | RATIONALE: OBJECTIVES: In the present studies, subactive doses of mGlu4 and M4 activators (LSP4-2022 and VU152100, respectively) were administered to investigate the mutual interaction between mGlu4 and M4 receptors in animal models of schizophrenia. METHODS: The behavioral tests used were MK-801-induced hyperactivity, (±)-2.5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced head twitches, the modified forced swim test, and MK-801-induced disruptions of social interactions and novel object recognition. DOI-induced spontaneous excitatory postsynaptic currents (sEPSCs) in brain slices and positron emission tomography (PET) in were used to establish the ability of these compounds to modulate the glutamatergic and dopaminergic systems. Rotarod was used to assess putative adverse effects. RESULTS: The mutual administration of subactive doses of LSP4-2022 and VU152100 exerted similar antipsychotic-like efficacy in animals as observed for active doses of both compounds, indicating their additive actions. VU152100 inhibited the DOI-induced frequency (but not amplitude) of sEPSCs in the frontal cortex, confirming presynaptic regulation of glutamate release. Both compounds reversed amphetamine-induced decrease in D2 receptor levels in the striatum, as measured with [18F] fallypride. The compounds did not induce any motor impartments when measured in rotarod test. CONCLUSIONS: Based on our results, the simultaneous activation of M4 and mGlu4 receptors is beneficial in reversing MK-801- and amphetamine-induced schizophrenia-related changes in animals.
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Authors | Paulina Cieślik, Monika Woźniak, Jerri M Rook, Mohammed N Tantawy, P Jeffrey Conn, Francine Acher, Krzysztof Tokarski, Magdalena Kusek, Andrzej Pilc, Joanna M Wierońska |
Journal | Psychopharmacology
(Psychopharmacology (Berl))
Vol. 235
Issue 10
Pg. 2897-2913
(Oct 2018)
ISSN: 1432-2072 [Electronic] Germany |
PMID | 30054675
(Publication Type: Journal Article)
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Chemical References |
- Antipsychotic Agents
- Excitatory Amino Acid Agonists
- LSP4-2022
- Phosphinic Acids
- Receptor, Muscarinic M4
- Receptors, Metabotropic Glutamate
- Dizocilpine Maleate
- Amphetamine
- metabotropic glutamate receptor 4
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Topics |
- Amphetamine
(toxicity)
- Animals
- Antipsychotic Agents
(pharmacology, therapeutic use)
- Disease Models, Animal
- Dizocilpine Maleate
(toxicity)
- Dose-Response Relationship, Drug
- Excitatory Amino Acid Agonists
(pharmacology, therapeutic use)
- Male
- Mice
- Motor Activity
(drug effects, physiology)
- Phosphinic Acids
(pharmacology, therapeutic use)
- Receptor, Muscarinic M4
(agonists, metabolism)
- Receptors, Metabotropic Glutamate
(agonists, metabolism)
- Rodentia
- Schizophrenia
(chemically induced, drug therapy, metabolism)
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