title: Combined serotonin (5-HT)1A agonism, 5-HT(2A) and dopamine D₂ receptor antagonism reproduces atypical antipsychotic drug effects on phencyclidine-impaired novel object recognition in rats.
abstract: Subchronic administration of an N-methyl-D-aspartate receptor (NMDAR) antagonist, e.g. phencyclidine (PCP), produces prolonged impairment of novel object recognition (NOR), suggesting they constitute a hypoglutamate-based model of cognitive impairment in schizophrenia (CIS). Acute administration of atypical, e.g. lurasidone, but not typical antipsychotic drugs (APDs), e.g. haloperidol, are able to restore NOR following PCP (acute reversal model). Furthermore, atypical APDs, when co-administered with PCP, have been shown to prevent development of NOR deficits (prevention model). Most atypical, but not typical APDs, are more potent 5-HT(2A) receptor inverse agonists than dopamine (DA) D2 antagonists, and have been shown to enhance cortical and hippocampal efflux and to be direct or indirect 5-HT(1A) agonists in vivo. To further clarify the importance of these actions to the restoration of NOR by atypical APDs, sub-effective or non-effective doses of combinations of the 5-HT(1A) partial agonist (tandospirone), the 5-HT(2A) inverse agonist (pimavanserin), or the D2 antagonist (haloperidol), as well as the combination of all three agents, were studied in the acute reversal and prevention PCP models of CIS. Only the combination of all three agents restored NOR and prevented the development of PCP-induced deficit. Thus, this triple combination of 5-HT(1A) agonism, 5-HT(2A) antagonism/inverse agonism, and D2 antagonism is able to mimic the ability of atypical APDs to prevent or ameliorate the PCP-induced NOR deficit, possibly by stimulating signaling cascades from D1 and 5-HT(1A) receptor stimulation, modulated by D2 and 5-HT(2A) receptor antagonism.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, 303 East Chicago Ave #12-013, Chicago, IL 60611, USA; Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan. Electronic address: yoshihiro-oyamada@ds-pharma.co.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Oyamada
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, 303 East Chicago Ave #12-013, Chicago, IL 60611, USA; Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan. Electronic address: masakuni-horiguchi@ds-pharma.co.jp.
authors.forename: Masakuni
authors.initials: M
authors.lastname: Horiguchi
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, 303 East Chicago Ave #12-013, Chicago, IL 60611, USA. Electronic address: lakshmi.rajagopal@northwestern.edu.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Rajagopal
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, 303 East Chicago Ave #12-013, Chicago, IL 60611, USA; Sumitomo Dainippon Pharma Co., Ltd., 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan. Electronic address: masanori-miyauchi@ds-pharma.co.jp.
authors.forename: Masanori
authors.initials: M
authors.lastname: Miyauchi
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, 303 East Chicago Ave #12-013, Chicago, IL 60611, USA. Electronic address: h-meltzer@northwestern.edu.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D054833:Isoindoles / Q000494:pharmacology; D008569:Memory Disorders / Q000188:drug therapy* / Q000378:metabolism; D010622:Phencyclidine; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011897:Random Allocation; D020318:Rats, Long-Evans; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects* / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D012565:Schizophrenic Psychology; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D054833:Isoindoles; D010879:Piperazines; D010880:Piperidines; D011743:Pyrimidines; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D058825:Serotonin 5-HT1 Receptor Agonists; D058826:Serotonin 5-HT2 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C055267:tandospirone; D014508:Urea; D010622:Phencyclidine; D006220:Haloperidol; C510793:pimavanserin
keywords: 5-HT(1A); 5-HT(2A); Antipsychotic; D(2); NOR; Phencyclidine