mGlu5-GABAB interplay in animal models of positive, negative and cognitive symptoms of schizophrenia

Abstract

Diverse preclinical studies exploiting the modulation of the GABAergic and/or glutamatergic system in brain via metabotropic receptors suggest their potential therapeutic utility. GS39783 and CDPPB, positive allosteric modulators of GABAB and mGlu5 receptors, were previously shown to reverse behavioral phenotypes in animal models to mimic selected (predominantly positive) symptoms of schizophrenia. In the present study we investigated the activity of selected GABAB (GS39783 and CGP7930) and mGlu5 (CDPPB) positive allosteric modulators. We focused mainly on the aspects of their efficacy in the models of negative and cognitive symptoms of schizophrenia. We used modified swim test, social interactions (models of negative symptoms) and novel object recognition (model of cognitive disturbances). The activity of the compounds was also tested in haloperidol-induced catalepsy test. The mutual interaction between GABAB/mGlu5 ligands was investigated as well. In the second part of the study, DHPG-induced PI hydrolysis in the presence of GABAB receptor antagonist (SKF97541), and SKF97541-induced inhibition of cAMP formation in the presence of DHPG, was performed. Both mGlu5 and GABAB receptor modulators effectively reversed MK-801-induced deficits in behavioral models of schizophrenia. Moreover, the concomitant administration of sub-effective doses of CDPPB and GS39783 induced a clear antipsychotic-like effect in all the procedures used, except DOI-induced head twitches. The concomitant administration of group I mGlu and GABAB agonists did not displayed any synergistic effects in vitro. Summing up, an activation of both types of receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious toward positive, negative and cognitive symptoms.

Involvement of GABABReceptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu4Receptor, LSP4-2022

“…The GABAergic system plays an important role in the development of schizophrenia because according to the GABAergic theory of psychosis, the deficit in GABA synthesis was observed in postmortem studies of schizophrenic patients [ 41 ]. Our previous publications showed that GABA B receptor agonists/PAMs were effective in the animal models of positive symptoms [ 18 ] as well as in those of negative and cognitive symptoms [ 19 ]. We also showed that the concomitant stimulation of GABA B and mGlu 5 receptors with subeffective doses of selective PAMs of those receptors (GS39783 and CDPPB, respectively) induced clear antipsychotic-like effects in the animal models of schizophrenia [ 19 ].…”

“…Our previous publications showed that GABA B receptor agonists/PAMs were effective in the animal models of positive symptoms [ 18 ] as well as in those of negative and cognitive symptoms [ 19 ]. We also showed that the concomitant stimulation of GABA B and mGlu 5 receptors with subeffective doses of selective PAMs of those receptors (GS39783 and CDPPB, respectively) induced clear antipsychotic-like effects in the animal models of schizophrenia [ 19 ]. This interplay between mGlu 5 and GABA B receptors was evident in the models of negative and cognitive symptoms, but not in the model of positive symptoms of schizophrenia, such as the DOI-induced head twitches [ 19 ].…”

“…The GABA B receptor is thought to regulate the release of glutamate in the same way as mGlu 4 and mGlu 7 receptor. Previously, we showed that positive allosteric modulators of the GABA B receptor, such as GS39783 and CGP7930, were active in the animal models of schizophrenia [ 18 , 19 ]. Therefore, it is possible that the mGlu 4 and GABA B receptors may act concomitantly regulating the release of glutamate and thus exerting antipsychotic action.…”

Negative Allosteric Modulators of mGlu7 Receptor as Putative Antipsychotic Drugs

“…The modified forced swim test was performed according to the method introduced by Noda ( Noda et al, 1995 , 1997 ; Wierońska et al, 2015a ; Woźniak et al, 2016a ). The swim tests were performed in a glass cylinder (height, 20 cm; internal diameter, 15 cm) containing 11 cm of water maintained at 23–24°C.…”

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities

“…Together, these two neurotransmitters constitute more than 90% of all neurotransmission. If this homeostasis is disturbed it could lead to anxiety disorders (Wieronska et al, 2015).…”