Combined serotonin (5-HT)1A agonism, 5-HT2A and dopamine D2 receptor antagonism reproduces atypical antipsychotic drug effects on phencyclidine-impaired novel object recognition in rats

Abstract Subchronic administration of an N-methyl- d -aspartate receptor (NMDAR) antagonist, e.g. phencyclidine (PCP), produces prolonged impairment of novel object recognition (NOR), suggesting they constitute a hypoglutamate-based model of cognitive impairment in schizophrenia (CIS). Acute administration of atypical, e.g. lurasidone, but not typical antipsychotic drugs (APDs), e.g. haloperidol, are able to restore NOR following PCP (acute reversal model). Furthermore, atypical APDs, when co-administered with PCP, have been shown to prevent development of NOR deficits (prevention model). Most atypical, but not typical APDs, are more potent 5-HT 2A receptor inverse agonists than dopamine (DA) D 2 antagonists, and have been shown to enhance cortical and hippocampal efflux and to be direct or indirect 5-HT 1A agonists in vivo. To further clarify the importance of these actions to the restoration of NOR by atypical APDs, sub-effective or non-effective doses of combinations of the 5-HT 1A partial agonist (tandospirone), the 5-HT 2A inverse agonist (pimavanserin), or the D 2 antagonist (haloperidol), as well as the combination of all three agents, were studied in the acute reversal and prevention PCP models of CIS. Only the combination of all three agents restored NOR and prevented the development of PCP-induced deficit. Thus, this triple combination of 5-HT 1A agonism, 5-HT 2A antagonism/inverse agonism, and D 2 antagonism is able to mimic the ability of atypical APDs to prevent or ameliorate the PCP-induced NOR deficit, possibly by stimulating signaling cascades from D 1 and 5-HT 1A receptor stimulation, modulated by D 2 and 5-HT 2A receptor antagonism.