title: RP5063, an atypical antipsychotic drug with a unique pharmacologic profile, improves declarative memory and psychosis in mouse models of schizophrenia.
abstract: Various types of atypical antipsychotic drugs (AAPDs) modestly improve the cognitive impairment associated with schizophrenia (CIAS). RP5063 is an AAPD with a diverse and unique pharmacology, including partial agonism at dopamine (DA) D2, D3, D4, serotonin (5-HT)1A, and 5-HT2Areceptors (Rs), full agonism at α4β2nicotinic acetylcholine (ACh)R (nAChR), and antagonism at 5-HT2B, 5-HT6, and 5-HT7Rs. Most atypical APDs are 5-HT2Ainverse agonists. The efficacy of RP5063 in mouse models of psychosis and episodic memory were studied. RP5063 blocked acute phencyclidine (PCP)-as well as amphetamine-induced hyperactivity, indicating antipsychotic activity. Acute administration of RP5063 significantly reversed subchronic (sc)PCP-induced impairment in novel object recognition (NOR), a measure of episodic memory, but not reversal learning, a measure of executive function. Co-administration of a sub-effective dose (SED) of RP5063 with SEDs of a 5-HT7R antagonist, a 5-HT1BR antagonist, a 5-HT2AR inverse agonist, or an α4β2nAChR agonist, restored the ability of RP5063 to ameliorate the NOR deficit in scPCP mice. Pre-treatment with a 5-HT1AR, a D4R, antagonist, but not an α4β2nAChR antagonist, blocked the ameliorating effect of RP5063. Further, co-administration of scRP5063 prior to each dose of PCP prevented the effect of PCP to produce a deficit in NOR for one week. RP5063, given to scPCP-treated mice for one week restored NOR for one week only. Acute administration of RP5063 significantly increased cortical DA efflux, which may be critical to some of its cognitive enhancing properties. These results indicate that RP5063, by itself, or as an adjunctive treatment has a multifaceted basis for improving some cognitive deficits associated with schizophrenia.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Rajagopal
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Sunoh
authors.initials: S
authors.lastname: Kwon
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Michael
authors.affiliation: Reviva Pharmaceuticals, Inc., 3900 Freedom Circle, Suite 101, Santa Clara, CA 95054, USA.
authors.forename: Laxminarayan
authors.initials: L
authors.lastname: Bhat
authors.affiliation: Reviva Pharmaceuticals, Inc., 3900 Freedom Circle, Suite 101, Santa Clara, CA 95054, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Cantillon
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: h-meltzer@northwestern.edu.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology; D011618:Psychotic Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D011897:Random Allocation; D012193:Reversal Learning / Q000187:drug effects / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D012565:Schizophrenic Psychology
chemical_list: D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D018377:Neurotransmitter Agents; D000661:Amphetamine; D010622:Phencyclidine; D004298:Dopamine
keywords: Acetylcholine; Cognition; Dopamine; RP5063 antipsychotic; Serotonin