The GABA B receptor agonist CGP44532 and the positive modulator GS39783 reverse some behavioural changes related to positive syndromes of psychosis in mice |
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| Authors: | Wierońska J M Kusek M Tokarski K Wabno J Froestl W Pilc A |
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| Affiliation: | 1Department of Neurobiology, Institute of Pharmacology PAS, 31-343 Kraków, Poland;2Department of Physiology, Institute of Pharmacology PAS, 31-343 Kraków, Poland;3AC Immune SA, EPFL PSE B, CH-1015 Lausanne, Switzerland;4Department of Drug Management, Medical College, Jagiellonian University, 31-531 Kraków, Poland |
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| Abstract: | BACKGROUND AND PURPOSEAn important role of GABAergic neurotransmission in schizophrenia was proposed a long time ago, but there is limited data to support this hypothesis. In the present study we decided to investigate GABAB receptor ligands in animal models predictive for the antipsychotic activity of drugs. The GABAB receptor antagonists {"type":"entrez-protein","attrs":{"text":"CGP51176","term_id":"875489595","term_text":"CGP51176"}}CGP51176 and {"type":"entrez-protein","attrs":{"text":"CGP36742","term_id":"877561962","term_text":"CGP36742"}}CGP36742, agonist {"type":"entrez-protein","attrs":{"text":"CGP44532","term_id":"875097404","term_text":"CGP44532"}}CGP44532 and positive allosteric modulator GS39783 were studied.EXPERIMENTAL APPROACHThe effects of all ligands were investigated in MK-801- and amphetamine-induced hyperactivity tests. The anti-hallucinogenic-like effect of the compounds was screened in the model of head twitches induced by (±)1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Furthermore, the effect of GS39783 and {"type":"entrez-protein","attrs":{"text":"CGP44532","term_id":"875097404","term_text":"CGP44532"}}CGP44532 on DOI-induced frequency of spontaneous excitatory postsynaptic currents (EPSCs) in slices from mouse brain frontal cortices was investigated. The anti-cataleptic properties of the compounds were also assessed.KEY RESULTSThe GABAB receptor activators {"type":"entrez-protein","attrs":{"text":"CGP44532","term_id":"875097404","term_text":"CGP44532"}}CGP44532 and GS39783 exhibited antipsychotic-like effects both in the MK-801- and amphetamine-induced hyperactivity tests, as well as in the head-twitch model in mice. Such effects were not observed for the GABAB receptor antagonists. DOI-induced increased frequency of spontaneous EPSCs was also decreased by the compounds. Moreover, {"type":"entrez-protein","attrs":{"text":"CGP44532","term_id":"875097404","term_text":"CGP44532"}}CGP44532 and GS39783 inhibited haloperidol-induced catalepsy and EPSCs.CONCLUSION AND IMPLICATIONSThese data suggest that selective GABAB receptor activators may be useful in the treatment of psychosis. |
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| Keywords: | GABAB receptor GABA schizophrenia amphetamine MK-801 |
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