Blonanserin differs from other
antipsychotic drugs, such as
risperidone and
olanzapine, and exhibits a higher affinity for
dopamine-D2/3 receptors than for
serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effect of
blonanserin on the social deficit observed in an animal model of
schizophrenia and sought to elucidate the molecular mechanism underlying its action. Mice received
phencyclidine (PCP: 10 mg/kg/day, s.c.), a non-competitive
N-methyl-d-aspartate (
NMDA) receptor antagonist, once a day for 14 consecutive days. We then evaluated the sociability, using a social interaction test, and the expression of GluN1 subunit, an essential subunit of the
NMDA receptors, in these mice.
Blonanserin significantly ameliorated the PCP-induced social deficit, whereas
olanzapine and
haloperidol did not. This effect of
blonanserin was antagonized by
7-OH-DPAT, a
dopamine-D3 receptor agonist, and
SCH23390, a
dopamine-D1 receptor antagonist. However, the ameliorating effect of
blonanserin was not inhibited by DOI, a
serotonin 5-HT2A receptor agonist. The PCP-induced social deficit was also ameliorated by U99194, a
dopamine-D3 receptor antagonist and
SKF38393, a
dopamine-D1 receptor agonist, being effects antagonized by
7-OH-DPAT or
SCH23390.
Blonanserin significantly inhibited the decrease in the phosphorylation levels of GluN1 at Ser897 by
protein kinase A (PKA) in the prefrontal cortex (PFC) in PCPadministered mice. These results suggest that activation of
NMDA receptors due to Ser897-phosphorylation of GluN1 subunit, which is a step linked to
dopamine-D1 receptor-PKA signaling through
dopamine-D3 receptor antagonism in the PFC, is required for the ameliorating effect of
blonanserin on the PCP-induced social deficit. These findings also provide in vivo evidence that
blonanserin antagonism of the dopamine-D3 receptors may be useful as a novel treatment strategy and that the dopamine-D3 receptors can be a novel therapeutic target molecule for the social deficit observed in
schizophrenia.