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The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment

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Abstract

Objective

To review the evidence that agents which preferentially affect serotonin (5-HT) attenuate the ability of N-methyl-D-aspartate (NMDA) receptor non-competitive antagonists (NMDA-RA), e.g., phencyclidine (PCP), dizocilpine (MK-801), and ketamine, to stimulate locomotor activity (LA), and to impair novel object recognition (NOR).

Rationale

NMDA-RA-induced increased LA and impairment of NOR are widely used models of the pathophysiology of schizophrenia, the mechanism of action of antipsychotic drugs (APDs), and the identification of novel treatments. Serotonin (5-HT) plays an important role in attenuating these effects of NMDA-RA.

Results

Selective 5-HT2A inverse agonists, e.g., M100907 and ACP-103, and atypical APDs, which are more potent 5-HT2A than D2 antagonists, e.g., clozapine and lurasidone, are more effective than selective D2 receptor antagonists to attenuate NMDA-RA-induced increased LA. 5-HT2A inverse agonists alone are not effective to improve NMDA-RA-impaired NOR, but augment the effects of atypical, but not typical APDs, to improve NOR. The 5-HT1A receptor partial agonist tandospirone alone and the 5-HT1A agonist effects of atypical APDs may substitute for, or contribute to, the effects of D2 and 5-HT2A receptor antagonism to reverse the NMDA-RA impairment in NOR. 5-HT6 and 5-HT7 receptor antagonists may also attenuate these NMDA-RA-induced behaviors. 5-HT2C receptor inverse agonist, but not neutral antagonists, block NOR in naïve rats and the effects of atypical APDs to restore NOR in PCP-treated rats, suggesting the importance of the constitutive activity of 5-HT2C receptors in NOR.

Conclusions

Multiple 5-HT receptors contribute to effective treatments to reverse adverse effects of NMDA-RA which model psychosis and cognitive impairment.

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Acknowledgment

The authors wish to acknowledge the assistance of Dr. Shikha Snigdha in the preparation of this manuscript. Preparation of this research and some of the research cited in NOR was supported by a grant from Dainippon Sumitomo Pharma Co., Ltd.

Potential Conflicts of Interest

HYM receives grant support from Azur, Bioline, Dainippon Sumitomo, EnVivo, Eli Lilly, Janssen, Otsuka, and Roche. HYM has been a consultant to the above companies and to Astra Zeneca, Glaxo Smith Kline, and Merck.

MH is an employee of Dainippon Sumitomo Pharma Co., Ltd., and a visiting faculty at Vanderbilt.

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  1. Department of Psychiatry, Vanderbilt University School of Medicine, 1601 23rd Ave South, Nashville, TN, 37212, USA

    Herbert Y. Meltzer & Masakuni Horiguchi

  2. Dainippon Sumitomo Pharma Co., Ltd, Osaka, 564-0053, Japan

    Masakuni Horiguchi

  3. Department of Pharmacology, The University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA

    Bill W. Massey

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  1. Herbert Y. Meltzer
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Meltzer, H.Y., Horiguchi, M. & Massey, B.W. The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment. Psychopharmacology 213, 289–305 (2011). https://doi.org/10.1007/s00213-010-2137-8

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