The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment.
Herbert Y. Meltzer, Masakuni Horiguchi, Bill W Massey
Psychopharmacology February 1, 2011 DOI: 10.1007/s00213-010-2137-8 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Serotonin |
| Key findings | Multiple serotonin receptors, particularly 5-HT(2A), 5-HT(1A), 5-HT(6), 5-HT(7), and 5-HT(2C), contribute to attenuating NMDA-RA-induced behaviors modeling psychosis and cognitive impairment. |
Abstract
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). 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. Selective 5-HT(2A) inverse agonists, e.g., M100907 and ACP-103, and atypical APDs, which are more potent 5-HT(2A) than D(2) antagonists, e.g., clozapine and lurasidone, are more effective than selective D(2) receptor antagonists to attenuate NMDA-RA-induced increased LA. 5-HT(2A) 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-HT(1A) receptor partial agonist tandospirone alone and the 5-HT(1A) agonist effects of atypical APDs may substitute for, or contribute to, the effects of D(2) and 5-HT(2A) receptor antagonism to reverse the NMDA-RA impairment in NOR. 5-HT(6) and 5-HT(7) receptor antagonists may also attenuate these NMDA-RA-induced behaviors. 5-HT(2C) 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-HT(2C) receptors in NOR. Multiple 5-HT receptors contribute to effective treatments to reverse adverse effects of NMDA-RA which model psychosis and cognitive impairment.
Comparable studies
Other narrative reviews on serotonin, most cited first.
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- Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile Psychopharmacology May 19, 2015
- Hippocampal serotonin depletion unmasks differences in the hyperlocomotor effects of phencyclidine and MK-801: quantitative versus qualitative analyses Frontiers in Pharmacology 2013
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- Preincubation with antipsychotic drugs protects against in vitro phencyclidine-mediated spontaneous neuronal network suppression. European Journal of Pharmacology September 5, 2025
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Cites 11
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