title: 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.
authors: Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, Kraków 31-343, Poland. Electronic address: wierons@if-pan.krakow.pl.
authors: Joanna M
authors: JM
authors: Wierońska
authors: Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, Kraków 31-343, Poland.
authors: Natalia
authors: N
authors: Kłeczek
authors: Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, Kraków 31-343, Poland.
authors: Monika
authors: M
authors: Woźniak
authors: Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, Kraków 31-343, Poland.
authors: Piotr
authors: P
authors: Gruca
authors: Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, Kraków 31-343, Poland.
authors: Magdalena
authors: M
authors: Łasoń-Tyburkiewicz
authors: Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, Kraków 31-343, Poland.
authors: Mariusz
authors: M
authors: Papp
authors: Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, Kraków 31-343, Poland.
authors: Piotr
authors: P
authors: Brański
authors: Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, Kraków 31-343, Poland.
authors: Grzegorz
authors: G
authors: Burnat
authors: Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, Kraków 31-343, Poland; Department of Drug Management, Faculty of Health Sciences, Jagiellonian University Medical College, Kraków 31-531, Poland.
authors: Andrzej
authors: A
authors: Pilc
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D003072:Cognition Disorders / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000627:therapeutic use; D058786:GABA-B Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D018690:Excitatory Amino Acid Agonists; D058786:GABA-B Receptor Agonists; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D018080:Receptors, GABA-B
keywords: Cognitive symptoms; GABA; Glutamate; Negative; Positive; Schizophrenia