title: Serotonin (5-HT)1A receptor agonism and 5-HT7 receptor antagonism ameliorate the subchronic phencyclidine-induced deficit in executive functioning in mice.
abstract: BACKGROUND
  Reversal learning (RL), a type of executive function, dependent on prefrontal cortical function, is impaired in rodents by subchronic (sc) treatment with the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), a widely studied model of cognitive impairment in schizophrenia (CIS).
  
  
  OBJECTIVE
  The principal objective of this study was to determine the ability of serotonin (5-HT)1A partial agonism and 5-HT7 receptor antagonism to improve RL in scPCP-treated mice.
  
  
  METHODS
  Male C57BL/6J mice were trained on an operant RL (ORL) task, then received PCP, 10 mg/kg, or saline, bid, for 7 days, followed by a 7-day washout period.
  
  
  RESULTS
  scPCP significantly diminished the percent correct responding, increased total incorrect trials, and total incorrect responses, in the reversal phase performance of the ORL task. Pre-treatment with the selective 5-HT1A partial agonist, tandospirone, or the selective 5-HT7 antagonist, SB269970, but not the 5-HT7 agonist, AS 19, reversed the scPCP-induced deficit in RL. Pre-treatment with atypical antipsychotic drug lurasidone, which is a 5-HT1A partial agonist and 5-HT7 antagonist, as well as a 5-HT2A and dopamine (D)2 antagonist, also reversed RL deficit in the scPCP-treated mice. Furthermore, the selective 5-HT1A antagonist, WAY100635, blocked the ability of lurasidone to reverse the scPCP-induced RL deficit.
  
  
  CONCLUSIONS
  These results indicate that 5-HT7 antagonism and 5-HT1A partial agonism contribute to restoration of RL in scPCP-treated mice. It is suggested that these two mechanisms are effective in restoring RL by decreasing excessive GABAergic inhibition of cortical pyramidal neurons following withdrawal of scPCP treatment.
authors.affiliation: Department of Psychiatry and Behavioral Science, Northwestern University, Feinberg School of Medicine, 303E Chicago Ave, Ward Building 7-101, Chicago, IL, 60611, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Rajagopal
authors.affiliation: Department of Psychiatry and Behavioral Science, Northwestern University, Feinberg School of Medicine, 303E Chicago Ave, Ward Building 7-101, Chicago, IL, 60611, USA.
authors.forename: Bill W
authors.initials: BW
authors.lastname: Massey
authors.affiliation: Department of Psychiatry and Behavioral Science, Northwestern University, Feinberg School of Medicine, 303E Chicago Ave, Ward Building 7-101, Chicago, IL, 60611, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Michael
authors.affiliation: Department of Psychiatry and Behavioral Science, Northwestern University, Feinberg School of Medicine, 303E Chicago Ave, Ward Building 7-101, Chicago, IL, 60611, USA. h-meltzer@northwestern.edu.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy; D056344:Executive Function / Q000187:drug effects* / Q000502:physiology; D054833:Isoindoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010622:Phencyclidine / Q000008:administration & dosage / Q000633:toxicity*; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology; D011985:Receptors, Serotonin / Q000502:physiology; D012193:Reversal Learning / Q000187:drug effects* / Q000502:physiology; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D054833:Isoindoles; D010636:Phenols; D010879:Piperazines; D011743:Pyrimidines; D011985:Receptors, Serotonin; C404922:SB 269970; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists; D013449:Sulfonamides; C104425:serotonin 7 receptor; D044282:Receptor, Serotonin, 5-HT1A; C055267:tandospirone; D010622:Phencyclidine
keywords: 5-HT1A; 5-HT7; GABA; Lurasidone; PCP; Phencyclidine; Reversal learning; SB269970; Schizophrenia; Tandospirone