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

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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.

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Abbreviations

AAPD:

Atypical antipsychotic drug

CIAS:

Cognitive impairment in schizophrenia

DA:

Dopamine

EF:

Executive functioning

FR:

Fixed ratio

GABA:

Gamma amino butyric acid

mPFC:

Medial prefrontal cortex

NMDAR:

N-methyl-d-aspartate receptor

NOR:

Novel object recognition

ORL:

Operant reversal learning

PCP:

Phencyclidine

RL:

Reversal learning

sc:

Subchronic

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Acknowledgments

We thank Dr. Sunoh Kwon for his assistance with drug preparations and Mr. Daniel Barrett Share for editorial assistance.

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Science, Northwestern University, Feinberg School of Medicine, 303E Chicago Ave, Ward Building 7-101, Chicago, IL, 60611, USA

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

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  1. Lakshmi Rajagopal
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  2. Bill W. Massey
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Correspondence to Herbert Y. Meltzer.

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Conflict of interest

Herbert Y Meltzer has received grant support from and been a consultant to Sumitomo Dainippon, Sunovion, Janssen, Novartis, ACADIA, Ferrosan, Roche, Takeda, Pfizer, Eli Lilly, EnVivo, Reviva, Alkermes, Astellas, Jazz, Solvay, SureGene, and Bristol Myers Squibb. Herbert Y Meltzer has been a consultant to Lundbeck and Teva. Herbert Y Meltzer is a shareholder of ACADIA, SureGene, and Astra Zeneca. Lakshmi Rajagopal, Bill Massey, and Eric Michael do not have any conflict of interest.

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This research is supported by a grant from Sumitomo Dainippon Pharma Co., Ltd.

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Rajagopal, L., Massey, B.W., Michael, E. et al. Serotonin (5-HT)1A receptor agonism and 5-HT7 receptor antagonism ameliorate the subchronic phencyclidine-induced deficit in executive functioning in mice. Psychopharmacology 233, 649–660 (2016). https://doi.org/10.1007/s00213-015-4137-1

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