Serotonin (5-HT)1A receptor agonism and 5-HT7 receptor antagonism ameliorate the subchronic phencyclidine-induced deficit in executive functioning in mice

Lakshmi Rajagopal, Bill W. Massey, Eric Michael, Herbert Y. Meltzer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Rationale: 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.

Original languageEnglish (US)
Pages (from-to)649-660
Number of pages12
Issue number4
StatePublished - Feb 1 2016


  • 5-HT
  • 5-HT
  • GABA
  • Lurasidone
  • PCP
  • Phencyclidine
  • Reversal learning
  • SB269970
  • Schizophrenia
  • Tandospirone

ASJC Scopus subject areas

  • Pharmacology

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