lsp4-2022 and Disease-Models--Animal

Rett syndrome and MECP2 Duplication syndrome are neurodevelopmental disorders attributed to loss-of-function mutations in, or duplication of, the gene encoding methyl-CpG-binding protein 2 (MeCP2), respectively. We recently reported decreased expression and function of the metabotropic glutamate receptor 7 (mGlu

Topics: Allosteric Regulation; Animals; Anxiety; Benzoxazoles; Disease Models, Animal; Excitatory Amino Acid Agonists; Fear; Learning; Mental Retardation, X-Linked; Mice; Phenotype; Phosphinic Acids; Receptors, Metabotropic Glutamate

Metabotropic glutamate receptors and muscarinic M. In the present studies, subactive doses of mGlu. 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.. 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 D. Based on our results, the simultaneous activation of M

Topics: Amphetamine; Animals; Antipsychotic Agents; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Male; Mice; Motor Activity; Phosphinic Acids; Receptor, Muscarinic M4; Receptors, Metabotropic Glutamate; Rodentia; Schizophrenia

Considering that ligands of metabotropic glutamate and GABA receptors may exert beneficial effects on schizophrenia, we assessed the actions of the first mGlu>4-selective orthosteric agonist, LSP4-2022, in several tests reflecting positive, negative, and cognitive symptoms of schizophrenia. Moreover, we investigated the possible involvement of GABAB receptors in LSP4-2022-induced actions. Hyperactivity induced by MK-801 or amphetamine and DOI-induced head twitches in mice were used as the models of positive symptoms. The social interaction test, modified forced swim test (FST), and novel object recognition (NOR) test were used as the models of negative and cognitive symptoms of schizophrenia. LSP4-2022 inhibited hyperactivity (in a dose-dependent manner, 0.5-2 mg/kg) induced by MK-801 or amphetamine and DOI-induced head twitches. In mGlu4 receptor knockout mice, LSP4-2022 was not effective. However, it reversed MK-801-induced impairment in the social interaction test and the MK-801-induced increase of immobility in the modified FST. In the NOR test, LSP4-2022 was active at a dose of 2 mg/kg. GABAB receptor antagonist, CGP55845 (10 mg/kg), reversed LSP4-2022-induced effects in hyperactivity and head twitch tests. At the same time, the simultaneous administration of subeffective doses of LSP4-2022 (0.1 mg/kg) and a positive allosteric modulator of GABAB receptor PAM, GS39783 (0.1 mg/kg), induced clear antipsychotic-like effects in those two tests. Such an interaction between mGlu4 and GABAB receptors was not observed in the social interaction and NOR tests. Therefore, we suggest that the activation of the mGlu

Topics: Amphetamine; Animals; Antipsychotic Agents; Cyclopentanes; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Excitatory Amino Acid Agonists; GABA Agents; Male; Mice, Knockout; Motor Activity; Phosphinic Acids; Pyrimidines; Receptors, GABA-B; Receptors, Metabotropic Glutamate; Recognition, Psychology; Schizophrenia; Social Behavior

Numerous data have indicated that metabotropic glutamate (mGlu) receptor ligands may be potentially useful as novel antidepressant drugs (ADs). The Group III mGlu receptor has not been explored much because of the limited access to selective ligands, but some behavioral studies have indicated that modulating group III mGlu receptors may result in benefits for the therapy of depression. Here, we investigated the potential antidepressant-like effects of a new mGlu4 selective orthosteric agonist, LSP4-2022. We found that the drug induced pro-depressant effects in the tail suspension test (TST) and the forced swim test (FST) in mice at doses that did not change the locomotor activity of the animals. Additional experiments that used knock-out (KO) mice and aimed to verify the selectivity of LSP4-2022 revealed that the drug induced strong pro-depressant-like effects in mGlu7 KO mice but did not affect the behavior of mGlu4 KO mice in the TST, suggesting that the activation of the mGlu4 receptor plays a role in producing the pro-depressant activity of the tested drug. The results of our study indicate that the inhibition rather than activation of mGlu4 receptors might induce antidepressant effects, but this hypothesis should be verified using a selective mGlu4 receptor antagonist, which is currently not available.

Topics: Animals; Antidepressive Agents, Tricyclic; Depressive Disorder; Disease Models, Animal; Excitatory Amino Acid Agonists; Frontal Lobe; Hippocampus; Imipramine; Male; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Phosphinic Acids; Psychotropic Drugs; Receptors, Metabotropic Glutamate