Hispidulin attenuates the social withdrawal in isolated disrupted-in-schizophrenia-1 mutant and chronic phencyclidine-treated mice.

Hispidulin is a flavonoid isolated from Clerodendrum inerme that was found to remit intractable motor tics. Previously, we have found that hispidulin attenuates hyperlocomotion and the disrupted prepulse inhibition (PPI) induced by methamphetamine and N-methyl-d-aspartate (NMDA) receptor blockers, two phenotypes of schizophrenia resembling positive symdromes. Hispidulin can inhibit catechol-O-methyltransferase (COMT), a dopamine-metabolizing enzyme in the prefrontal cortex (PFC) that is important for social interaction. Here, we investigated whether hispidulin would affect social withdrawal, one dimension of negative symptoms in schizophrenia.We examined whether acute administration of hispidulin would attenuate social withdrawal in two mouse models, juvenile isolated disrupted-in-schizophrenia-1 mutant (mutDISC1) mice and chronic phencyclidine (PCP)-treated naïve mice.

In chronic PCP-treated mice, hispidulin (10 mg/kg, i.p.) attenuated social withdrawal in a manner prevented by a dopamine D₁ receptor (D₁ R) antagonist (SCH 23390, 0.02 mg/kg, i.p.) and mimicked by a selective COMT inhibitor, OR-486 (10 mg/kg, i.p.). Hispidulin increased extracellular dopamine levels in the PFC of chronic PCP-treated mice. In isolated mutDISC1 mice, hispidulin also rescued social withdrawal. In both models, intra-PFC microinjection of a D₁ R agonist (SKF81297: 10 nmol/mouse/bilateral) reversed the impairment of Ser⁸⁹⁷ phosphorylation at the NR1 subunit of NMDA receptors, suggesting the association between NR1 Ser⁸⁹⁷ -phosphorylation and D₁ R activation in the PFC exits in both models.

Hispidulin rescues social withdrawal by activating D₁ Rs indirectly through elevated dopamine levels in the PFC by COMT inhibition. This nature of hispidulin renders it a potential novel therapeutic candidate for negative symptoms in schizophrenia.