AbstractThe N-methyl-d-aspartate receptor (NMDAR) antagonists, phencyclidine (PCP), dizocilpine (MK-801), or ketamine, given subchronically (sc) to rodents and primates, produce prolonged deficits in cognitive function, including novel object recognition (NOR), an analog of human declarative memory, one of the cognitive domains impaired in schizophrenia. Atypical antipsychotic drugs (AAPDs) have been reported to improve declarative memory in some patients with schizophrenia, as well as to ameliorate and prevent the NOR deficit in rodents following scNMDAR antagonist treatment. While the efficacy of AAPDs to improve cognitive impairment in schizophrenia (CIS) is limited, at best, and controversial, single doses of all currently available AAPDs so far tested transiently restore NOR in rodents following scNMDAR antagonist treatment. Typical antipsychotic drugs (APDs), e.g. haloperidol and perphenazine, are ineffective in this rodent model, and may be less effective as treatments of some domains of CIS. Serotonergic mechanisms, including, but not limited to serotonin (5-HT)2A and 5-HT7 antagonism, 5-HT1A, and GABA(A) agonism, contribute to the efficacy of the AAPDs in the scNMDAR antagonist rodent models, which are relevant to the loss of GABA interneuron/hyperglutamate hypothesis of the etiology of CIS. The ability of sub-effective doses of the atypical APDs to ameliorate NOR in the scNMDAR-treated rodents can be restored by the addition of a sub-effective dose of the 5-HT1A partial agonist, tandospirone, or the 5-HT7 antagonist, SB269970. The mGluR2/3 agonist, LY379268, which itself is unable to restore NOR in the scNMDAR-treated rodents, can also restore NOR when given with lurasidone, an AAPD. Enhancing cortical and hippocampal dopamine and acetylcholine efflux, or both, may contribute to the restoration of NOR by the atypical APDs. Importantly, co-administration of lurasidone, tandospirone, or SB269970, with PCP, to rodents, at doses 5–10 fold greater than those acutely effective to restore NOR following scNMDAR treatment, prevents the effect of scPCP to produce an enduring deficit in NOR. This difference in dosage may be relevant to utilizing AAPDs to prevent the onset of CIS in individuals at high risk for developing schizophrenia. The scNMDAR paradigm may be useful for identifying possible means to treat and prevent CIS.