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

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-HT_2A inverse agonists, e.g., M100907 and ACP-103, and atypical APDs, which are more potent 5-HT_2A than D₂ antagonists, e.g., clozapine and lurasidone, are more effective than selective D₂ 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 D₂ and 5-HT_2A 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-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. Conclusions: Multiple 5-HT receptors contribute to effective treatments to reverse adverse effects of NMDA-RA which model psychosis and cognitive impairment.