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

Herbert Y. Meltzer, Masakuni Horiguchi, Bill W. Massey

Research output: Contribution to journalReview article

88 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)289-305
Number of pages17
JournalPsychopharmacology
Volume213
Issue number2-3
DOIs
StatePublished - Feb 1 2011

Fingerprint

N-Methylaspartate
N-Methyl-D-Aspartate Receptors
Psychotic Disorders
Serotonin
Antipsychotic Agents
Locomotion
Serotonin 5-HT2 Receptor Agonists
Receptor, Serotonin, 5-HT2C
Dizocilpine Maleate
Serotonin 5-HT1 Receptor Agonists
Serotonin 5-HT2 Receptor Antagonists
Receptor, Serotonin, 5-HT2A
Phencyclidine
Receptor, Serotonin, 5-HT1A
Aptitude
Clozapine
Serotonin Receptors
Ketamine
Cognitive Dysfunction
Schizophrenia

Keywords

  • 5-HT
  • 5-HT
  • Cognition
  • Dopamine
  • Glutamate
  • NMDA
  • Novel object recognition
  • Phencyclidine
  • Schizophrenia
  • Serotonin

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment",
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 na{\"i}ve 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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The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment. / Meltzer, Herbert Y.; Horiguchi, Masakuni; Massey, Bill W.

In: Psychopharmacology, Vol. 213, No. 2-3, 01.02.2011, p. 289-305.

Research output: Contribution to journalReview article

TY - JOUR

T1 - The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment

AU - Meltzer, Herbert Y.

AU - Horiguchi, Masakuni

AU - Massey, Bill W.

PY - 2011/2/1

Y1 - 2011/2/1

N2 - 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.

AB - 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.

KW - 5-HT

KW - 5-HT

KW - Cognition

KW - Dopamine

KW - Glutamate

KW - NMDA

KW - Novel object recognition

KW - Phencyclidine

KW - Schizophrenia

KW - Serotonin

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U2 - 10.1007/s00213-010-2137-8

DO - 10.1007/s00213-010-2137-8

M3 - Review article

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