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

Abstract

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.

• Authors: Lakshmi Rajagopal, Bill W Massey, Eric Michael, Herbert Y Meltzer
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 233 Issue 4 Pg. 649-60 (Feb 2016) ISSN: 1432-2072 [Electronic] Germany
• PMID: 26558619 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Isoindoles
• Phenols
• Piperazines
• Pyrimidines
• Receptors, Serotonin
• SB 269970
• Serotonin 5-HT1 Receptor Agonists
• Serotonin Antagonists
• Sulfonamides
• serotonin 7 receptor
• Receptor, Serotonin, 5-HT1A
• tandospirone
• Phencyclidine

Topics

• Animals
• Cognition Disorders (chemically induced, drug therapy)
• Executive Function (drug effects, physiology)
• Isoindoles (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Phencyclidine (administration & dosage, toxicity)
• Phenols (pharmacology, therapeutic use)
• Piperazines (pharmacology)
• Pyrimidines (pharmacology)
• Reaction Time (drug effects, physiology)
• Receptor, Serotonin, 5-HT1A (physiology)
• Receptors, Serotonin (physiology)
• Reversal Learning (drug effects, physiology)
• Serotonin 5-HT1 Receptor Agonists (pharmacology, therapeutic use)
• Serotonin Antagonists (pharmacology, therapeutic use)
• Sulfonamides (pharmacology, therapeutic use)