title: Predictive validity of a MK-801-induced cognitive impairment model in mice: implications on the potential limitations and challenges of modeling cognitive impairment associated with schizophrenia preclinically.
abstract: Cognitive impairment associated with schizophrenia (CIAS) is a major and disabling symptom domain of the disease that is generally unresponsive to current pharmacotherapies. Critically important to the discovery of novel therapeutics for CIAS is the utilization of preclinical models with robust predictive validity. We investigated the predictive validity of MK-801-induced memory impairments in mouse inhibitory avoidance (MK-IA) as a preclinical model for CIAS by investigating compounds that have been tested in humans, including antipsychotics, sodium channel blocker mood stabilizers, and putative cognitive enhancers. The atypical antipsychotic clozapine, as well as risperidone and olanzapine (see Brown et al., 2013), had no effect on MK-801-induced memory impairments. For sodium channel blockers, carbamazepine significantly attenuated memory impairments induced by MK-801, whereas lamotrigine had no effect. Nicotine, donepezil, modafinil, and xanomeline all significantly attenuated MK-801-induced memory impairments, but the magnitude of effects and the dose-responses observed varied across compounds. Clinically, only acute administration of nicotine has demonstrated consistent positive effects on CIAS, while inconsistent results have been reported for lamotrigine, donepezil, and modafinil; atypical antipsychotics produce only moderate improvements at best. A positive clinical signal has been observed with xanomeline, but only in a small pilot trial. The results presented here suggest that the MK-IA model lacks robust predictive validity for CIAS as the model is likely permissive and may indicate false positive signals for compounds and mechanisms that lack clear clinical efficacy for CIAS. Our findings also highlight the potential limitations and challenges of using NMDA receptor antagonists in rodents to model CIAS.
authors.affiliation: Neuroscience Discovery, AbbVie, 1 North Waukegan Rd., North Chicago, IL 60064, United States. Electronic address: jordan.brown@abbvie.com.
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Brown
authors.affiliation: Neuroscience Discovery, AbbVie, 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Rueter
authors.affiliation: Neuroscience Discovery, AbbVie, 1 North Waukegan Rd., North Chicago, IL 60064, United States.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001362:Avoidance Learning / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced* / Q000150:complications / Q000188:drug therapy* / Q000523:psychology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005189:False Positive Reactions; D007266:Inhibition, Psychological; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use; D011237:Predictive Value of Tests; D011619:Psychotropic Drugs / Q000494:pharmacology / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000150:complications* / Q000188:drug therapy; D012565:Schizophrenic Psychology; D026941:Sodium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D014150:Antipsychotic Agents; D018697:Nootropic Agents; D011619:Psychotropic Drugs; D016194:Receptors, N-Methyl-D-Aspartate; D026941:Sodium Channel Blockers; D016291:Dizocilpine Maleate
keywords: Antipsychotics; CIAS; CNS; Cognition; Cognitive enhancers; DHEA; FDA; IA; IP; Inhibitory avoidance; MK-801; MK-801 inhibitory avoidance; MK-IA; N-methyl-d-aspartate; NMDA; Naive-IA; PANSS; PCP; Positive and Negative Syndrome Scale; Schizophrenia; U.S. Food and Drug Administration; central nervous system; cognitive impairment associated with schizophrenia; dehydroepiandrosterone; inhibitory avoidance; intraperitoneal; naive inhibitory avoidance; phencyclidine