title: Acute ketamine induces hippocampal synaptic depression and spatial memory impairment through dopamine D1/D5 receptors.
abstract: BACKGROUND
  Subanesthetic doses of ketamine have been reported to induce psychotic states that may mimic positive and negative symptoms as well as cognitive and memory deficits similar to those observed in schizophrenia. The cognitive and memory deficits are persistent, and their underlying cellular mechanisms remain unclear.
  
  
  OBJECTIVE
  We sought to investigate the roles of dopamine D1/D5 receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in hippocampal synaptic transmission and spatial memory impairment induced by ketamine.
  
  
  METHODS
  We examined the effects of subanesthetic ketamine on hippocampal synaptic transmission in freely moving rats. Spatial memory was tested with the Morris water maze. Pretreatment with the D1/D5 receptors antagonist SCH23390 or the AMPA receptors endocytosis interfering peptide Tat-GluR23Y was conducted to examine their capacities to reverse ketamine-induced electrophysiological and behavioral alterations. A series of behavioral observations, including locomotion, prepulse inhibition, and social interaction, were also conducted after ketamine treatment.
  
  
  RESULTS
  Ketamine induced synaptic depression lasting at least 4 h at hippocampal Schaffer collateral-CA1 synapses in freely moving rats and long-term spatial memory impairment. Both the effects were blocked by either SCH23390 or Tat-GluR23Y. Ketamine also elicited transient behavioral changes lasting less than 90 min, such as hyperlocomotion and prepulse inhibition deficits. These changes were ameliorated by SCH23390 but not by Tat-GluR23Y. Rats treated with ketamine showed social withdrawal that was also attenuated by either SCH23390 or Tat-GluR23Y.
  
  
  CONCLUSIONS
  Our results indicate that hippocampal synaptic depression is involved in ketamine-induced memory impairment, and this is modulated by D1/D5 receptors activation and AMPA receptors endocytosis.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms, and Laboratory of Learning and Memory, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Duan
authors.forename: Ji-Wei
authors.initials: JW
authors.lastname: Tan
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yuan
authors.forename: Jun
authors.initials: J
authors.lastname: Cao
authors.forename: Qi-Xin
authors.initials: QX
authors.lastname: Zhou
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
mesh_terms: D000778:Anesthetics, Dissociative / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D007649:Ketamine / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050641:Receptors, Dopamine D5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013037:Spatial Behavior / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D000778:Anesthetics, Dissociative; D001552:Benzazepines; D017447:Receptors, Dopamine D1; C534628:SCH 23390; D050641:Receptors, Dopamine D5; D007649:Ketamine