Blonanserin reverses the phencyclidine (PCP)-induced impairment in novel object recognition (NOR) in rats: Role of indirect 5-HT_1A partial agonism

Blonanserin is an atypical antipsychotic drug (APD) which, compared to other atypical APDs, is a relatively selective serotonin (5-HT)_2A and dopamine D₂ antagonist. Comparing blonanserin with more broadly acting atypical APDs could be useful to test the contributions of actions at other monoamine receptors, e.g. 5-HT_1A receptors, to the reversal of PCP-induced novel object recognition (NOR) deficit. In this study, we tested the effect of blonanserin alone, and in combination with 5-HT_1A agents, on NOR deficit induced by subchronic treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP; 2mg/kg), b.i.d., for 7 days. Blonanserin, 1mg/kg, but not 0.3mg/kg, improved the PCP-induced NOR deficit. However, at 1mg/kg, object exploration was diminished. Co-administration of sub-effective doses of blonanserin (0.3mg/kg) and the 5-HT_1A partial agonist, tandospirone (0.2mg/kg), significantly reversed the NOR deficit without diminishing activity during the acquisition or retention periods. The combination of WAY100635 (0.6mg/kg), a 5-HT_1A antagonist, and blonanserin (1mg/kg), also diminished object exploration which prevented assessment of the effect of this combination on NOR. WAY100635 (0.6mg/kg) blocked the ameliorating effect of risperidone (0.1mg/kg), another atypical APD with low affinity for 5-HT_1A receptors, but did not impair exploration. These results suggest that blonansein and risperidone, atypical APDs which lack a direct action on 5-HT_1A receptors require 5-HT_1A receptor stimulation to reverse the subchronic PCP-induced NOR deficit and provide a support for clinical trial of blonanserin in combination with tandospirone to ameliorate cognitive impairment in schizophrenia and to have fewer side effects.