TY - JOUR
T1 - Hispidulin attenuates the social withdrawal in isolated disrupted-in-schizophrenia-1 mutant and chronic phencyclidine-treated mice
AU - Mouri, Akihiro
AU - Lee, Hsin Jung
AU - Mamiya, Takayoshi
AU - Aoyama, Yuki
AU - Matsumoto, Yurie
AU - Kubota, Hisayoshi
AU - Huang, Wei Jan
AU - Chiou, Lih Chu
AU - Nabeshima, Toshitaka
N1 - Publisher Copyright:
© 2020 The British Pharmacological Society
PY - 2020/7/1
Y1 - 2020/7/1
N2 - Background and Purpose: Hispidulin is a flavonoid isolated from Clerodendrum inerme that was found to inhibit intractable motor tics. Previously, we found that hispidulin attenuates hyperlocomotion and the disrupted prepulse inhibition induced by methamphetamine and N-methyl-d-aspartate (NMDA) receptor antagonists, two phenotypes of schizophrenia resembling positive symptoms. Hispidulin can inhibit 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 of the negative symptoms of schizophrenia. Experimental Approach: We examined whether acute administration of hispidulin would attenuate social withdrawal in two mice models, juvenile isolated disrupted-in-schizophrenia-1 mutant (mutDISC1) mice and chronic phencyclidine (PCP)-treated naïve mice. Key Results: In chronic PCP-treated mice, hispidulin (10 mg·kg−1, i.p.) attenuated social withdrawal similar to that observed with dopamine D1 receptor antagonist (SCH-23390, 0.02 mg·kg−1, i.p.) and was mimicked by the selective COMT inhibitor, OR-486 (10 mg·kg−1, i.p.). Hispidulin increased extracellular dopamine levels in the PFC of chronic PCP-treated mice. In isolated mutDISC1 mice, hispidulin also reversed social withdrawal. In both models, intra-PFC microinjection of a D1 agonist (SKF-81297: 10 nmol/mouse/bilateral) reversed the impairment of Ser897phosphorylation at the GluN1 subunit of NMDA receptors, suggesting the association between GluN1 Ser897-phosphorylation and D1 activation in the PFC exits in both models. Conclusions and Implications: Hispidulin attenuated social withdrawal by activating D1 receptors indirectly through elevated dopamine levels in the PFC by COMT inhibition. This nature of hispidulin suggests that it a potential novel therapeutic candidate for the treatment of negative symptoms in schizophrenia.
AB - Background and Purpose: Hispidulin is a flavonoid isolated from Clerodendrum inerme that was found to inhibit intractable motor tics. Previously, we found that hispidulin attenuates hyperlocomotion and the disrupted prepulse inhibition induced by methamphetamine and N-methyl-d-aspartate (NMDA) receptor antagonists, two phenotypes of schizophrenia resembling positive symptoms. Hispidulin can inhibit 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 of the negative symptoms of schizophrenia. Experimental Approach: We examined whether acute administration of hispidulin would attenuate social withdrawal in two mice models, juvenile isolated disrupted-in-schizophrenia-1 mutant (mutDISC1) mice and chronic phencyclidine (PCP)-treated naïve mice. Key Results: In chronic PCP-treated mice, hispidulin (10 mg·kg−1, i.p.) attenuated social withdrawal similar to that observed with dopamine D1 receptor antagonist (SCH-23390, 0.02 mg·kg−1, i.p.) and was mimicked by the selective COMT inhibitor, OR-486 (10 mg·kg−1, i.p.). Hispidulin increased extracellular dopamine levels in the PFC of chronic PCP-treated mice. In isolated mutDISC1 mice, hispidulin also reversed social withdrawal. In both models, intra-PFC microinjection of a D1 agonist (SKF-81297: 10 nmol/mouse/bilateral) reversed the impairment of Ser897phosphorylation at the GluN1 subunit of NMDA receptors, suggesting the association between GluN1 Ser897-phosphorylation and D1 activation in the PFC exits in both models. Conclusions and Implications: Hispidulin attenuated social withdrawal by activating D1 receptors indirectly through elevated dopamine levels in the PFC by COMT inhibition. This nature of hispidulin suggests that it a potential novel therapeutic candidate for the treatment of negative symptoms in schizophrenia.
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U2 - 10.1111/bph.15043
DO - 10.1111/bph.15043
M3 - Article
C2 - 32133633
AN - SCOPUS:85082838622
SN - 0007-1188
VL - 177
SP - 3210
EP - 3224
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 14
ER -