title: The effects of a 5-HT5A receptor antagonist in a ketamine-based rat model of cognitive dysfunction and the negative symptoms of schizophrenia.
abstract: Serotonin (5-HT) receptors still represent promising targets for the development of novel multireceptor or stand-alone antipsychotic drugs with a potential to ameliorate cognitive impairments and negative symptoms in schizophrenia. The 5-HT5A receptor, one of the least known members of the serotonin receptor family, has also drawn attention in this regard. Although the antipsychotic efficacy of 5-HT5A antagonists is still equivocal, recent experimental data suggest the cognitive-enhancing activity of this strategy. The aim of the present study was to evaluate pro-cognitive and pro-social efficacies of the 5-HT5A receptor antagonist in a rat pharmacological model of schizophrenia employing the administration of the NMDA receptor antagonist, ketamine. The ability of SB-699551 to reverse ketamine-induced cognitive deficits in the attentional set-shifting task (ASST) and novel object recognition task (NORT) was examined. The compound's efficacy against ketamine-induced social withdrawal was assessed in the social interaction test (SIT) and in the social choice test (SCT). The results demonstrated the efficacy of SB-699551 in ameliorating ketamine-induced impairments on the ASST and NORT. Moreover, the tested compound also enhanced set-shifting performance in cognitively unimpaired control rats and improved object recognition memory in conditions of delay-induced natural forgetting. The pro-social activity of SB-699551 was demonstrated on both employed paradigms, the SIT and SCT. The present study suggests the preclinical efficacy of a strategy based on the blockade of 5-HT5A receptors against schizophrenia-like cognitive deficits and negative symptoms. The utility of this receptor as a target for improvement of cognitive and social dysfunctions warrants further studies.
authors.affiliation: Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland. Electronic address: nikifor@if-pan.krakow.pl.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Nikiforuk
authors.affiliation: Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Hołuj
authors.affiliation: Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kos
authors.affiliation: Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Popik
mesh_terms: D000818:Animals; D002755:Choice Behavior / Q000187:drug effects; D060825:Cognitive Dysfunction / Q000139:chemically induced* / Q000188:drug therapy* / Q000523:psychology; D018691:Excitatory Amino Acid Antagonists; D007398:Interpersonal Relations; D007649:Ketamine; D008297:Male; D018697:Nootropic Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D021641:Recognition, Psychology / Q000187:drug effects; D012559:Schizophrenia / Q000139:chemically induced* / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D012919:Social Behavior
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018697:Nootropic Agents; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C078730:serotonin 5 receptor; D007649:Ketamine
keywords: 5-HT(5A) receptor; Animal models; Asociality; Cognition; Cognitive flexibility; NMDA receptor