Serotonin (5-HT)_1A receptor agonism and 5-HT₇ receptor antagonism ameliorate the subchronic phencyclidine-induced deficit in executive functioning in mice

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-HT_1A 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-HT_1A partial agonist and 5-HT₇ antagonist, as well as a 5-HT_2A and dopamine (D)₂ antagonist, also reversed RL deficit in the scPCP-treated mice. Furthermore, the selective 5-HT_1A antagonist, WAY100635, blocked the ability of lurasidone to reverse the scPCP-induced RL deficit. Conclusions: These results indicate that 5-HT₇ antagonism and 5-HT_1A 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.