title: MK-801 and amphetamine result in dissociable profiles of cognitive impairment in a rodent paired associates learning task with relevance for schizophrenia.
abstract: BACKGROUND
  Paired associates learning (PAL) has been suggested to be predictive of functional outcomes in first episode psychosis and of conversion from mild cognitive impairment to Alzheimer's disease. An automated touch screen-based rodent PAL (rPAL) task has been developed and is sensitive to manipulations of the dopaminergic and glutamatergic system. Accordingly, rPAL when used with pharmacological models of schizophrenia, like NMDA receptor blockade with MK-801 or dopaminergic stimulation with amphetamine, may have utility as a translational model of cognitive impairment in schizophrenia.
  
  
  OBJECTIVE
  The purpose of this study was to determine if amphetamine- and MK-801-induced impairment represent distinct models of cognitive impairment by testing their sensitivity to common antipsychotics and determine the relative contributions of D1 versus D2 receptors on performance of PAL.
  
  
  METHODS
  Rats were trained in rPAL and were then treated with MK-801, amphetamine, risperidone, haloperidol, quinpirole, SK-82958, or SCH-23390 alone and in combination.
  
  
  RESULTS
  While both amphetamine and MK-801 caused clear impairments in accuracy, MK-801 induced a profound "perseverative" type behavior that was more pronounced when compared to amphetamine. Moreover, amphetamine-induced impairments, but not the effects of MK-801, could be reversed by antipsychotics as well as the D1 receptor antagonist SCH-23390, suggesting a role for both the D1 and D2 receptor in the amphetamine impairment model.
  
  
  CONCLUSIONS
  These data suggest that amphetamine and MK-801 represent dissociable models of impairment in PAL, dependent on different underlying neurobiology. The ability to distinguish dopaminergic versus glutamatergic effects on performance in rPAL makes it a unique and useful tool in the modeling of cognitive impairments in schizophrenia.
authors.affiliation: Department of Neuroscience, Janssen Research and Development, 30 Turnhoutseweg, 2340, Beerse, Belgium. johnctalpos@gmail.com.
authors.forename: John
authors.initials: J
authors.lastname: Talpos
authors.affiliation: Department of Neuroscience, Janssen Research and Development, 30 Turnhoutseweg, 2340, Beerse, Belgium.
authors.forename: Nancy
authors.initials: N
authors.lastname: Aerts
authors.affiliation: Department of Neuroscience, Janssen Research and Development, 30 Turnhoutseweg, 2340, Beerse, Belgium.
authors.forename: Jason
authors.initials: J
authors.lastname: Waddell
authors.affiliation: Department of Neuroscience, Janssen Research and Development, 30 Turnhoutseweg, 2340, Beerse, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
mesh_terms: D000661:Amphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003072:Cognition Disorders / Q000139:chemically induced* / Q000523:psychology; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D010153:Paired-Associate Learning / Q000187:drug effects*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D012565:Schizophrenic Psychology
chemical_list: D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016291:Dizocilpine Maleate; D000661:Amphetamine
keywords: Dopamine receptor; Memory; NMDA receptor; Operant; PAL; Schizophrenia; Touch screen