The role of 5-HT1A receptors in phencyclidine (PCP)-induced novel object recognition (NOR) deficit in rats

Atypical antipsychotic drugs (APDs), many of which are direct or indirect serotonin (5-HT)(1A) agonists, and tandospirone, a 5-HT1A partial agonist, have been reported to improve cognition in schizophrenia. We tested the effect of 5-HT1A agonism, alone, and in combination with other psychotropic agents, including the atypical APD, lurasidone, in reversing the deficit in novel object recognition (NOR) induced by subchronic treatment with the non-competitive NMDA receptor antagonist, phencyclidine (PCP) (2 mg/kg, b.i.d., for 7 days). Subchronic treatment with PCP induced a persistent NOR deficit. Lurasidone (0.1 mg/kg), a potent 5-HT1A partial agonist, 5-HT2A antagonist, and weaker D-2 antagonist, tandospirone (0.6 mg/kg), and the selective post-synaptic 5-HT1A agonist, F15599 (0.16 mg/kg), ameliorated the subchronic PCP-induced-NOR deficit. The 5-HT1A antagonist, WAY100635 (0.6 mg/kg), blocked the ameliorating effects of tandospirone and lurasidone. The combination of sub-effective doses of tandospirone (0.2 mg/kg) and lurasidone (0.03 mg/kg) also reversed the PCP-induced NOR-deficit. Buspirone, a less potent partial 5-HT1A agonist than tandospirone, was less effective. Co-administration of tandospirone (0.2 mg/kg) and pimavanserin (3 mg/kg), a relatively selective 5-HT2A receptor inverse agonist, did not reverse the effect of sub-chronic PCP on NOR. The D-2 antagonist, haloperidol, blocked the ameliorating effect of tandospirone on the PCP-induced deficit in NOR. These results indicate that 5-HT1A agonism is adequate to ameliorate the PCP-induced impairment in NOR and suggest further study of utilizing the combination of a 5-HT1A agonist and an atypical APD to ameliorate some types of cognitive impairment in schizophrenia.