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-HT1A 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-HT1A agents, on NOR deficit induced by subchronic treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP 2 mgkg), b.i.d., for 7 days. Blonanserin, 1mgkg, but not 0.3mgkg, improved the PCP-induced NOR deficit. However, at 1mgkg, object exploration was diminished. Co-administration of sub-effective doses of blonanserin (0.3 mgkg) and the 5-HT1A partial agonist, tandospirone (0.2 mgkg), significantly reversed the NOR deficit without diminishing activity during the acquisition or retention periods. The combination of WAY100635 (0.6 mgkg), a 5-HT1A antagonist, and blonanserin (1 mgkg), also diminished object exploration which prevented assessment of the effect of this combination on NOR. WAY100635 (0.6 mgkg) blocked the ameliorating effect of risperidone (0.1 mgkg), another atypical APD with low affinity for 5-HT1A receptors, but did not impair exploration. These results suggest that blonansein and risperidone, atypical APDs which lack a direct action on 5-HT1A receptors require 5-HT1A 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.