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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Blonanserin ameliorates social deficit through dopamine-D-3 receptor antagonism in mice administered phencyclidine as an animal model of schizophrenia
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Blonanserin ameliorates social deficit through dopamine-D-3 receptor antagonism in mice administered phencyclidine as an animal model of schizophrenia

机译：Blonanserin通过小鼠的小鼠施用的Phenyclidine作为精神分裂症的动物模型，通过多巴胺-D-3受体拮抗作用来改善社会缺陷

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Blonanserin differs from other antipsychotic drugs, such as risperidone and olanzapine, and exhibits a higher affinity for dopamine-D-2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D-3 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-o-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-D-3 receptor agonist, and SCH23390, a dopamine-D-1 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-D-3 receptor antagonist and SKF38393, a dopamine-D-1 receptor agonist, being effects antagonized by 7-OH-DPAT or SCH23390. Blonanserin significantly inhibited the decrease in the phosphorylation levels of GluN1 at Ser(897) by protein kinase A (PKA) in the prefrontal cortex (PFC) in PCP-administered mice. These results suggest that activation of NMDA receptors due to Ser(897)-phosphorylation of GluN1 subunit, which is a step linked to dopamine-D-1 receptor-PKA signaling through dopamine-D-3 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-D-3 receptors may be useful as a novel treatment strategy and that the dopamine-D-3 receptors can be a novel therapeutic target molecule for the social deficit observed in schizophrenia.
机译：Blonanserin与其他抗精神病药物不同，例如Risperidone和Olanzapine，并且对多巴胺-D-2/3受体表现出更高的亲和力，而不是血清素5-HT2A受体。我们调查了多巴胺-D-3受体参与Blonanserin对精神分裂症动物模型中观察到的社会缺陷的影响，并试图阐明其行动的分子机制。小鼠接受了Phencyclidine（PCP：10mg / kg /天，S.），一种连续14天的非竞争性N-甲基-O-天冬氨酸（NMDA）受体拮抗剂。然后，我们使用社交相互作用试验评估社交性，以及这些小鼠中NMDA受体的必需亚基的Glun1亚基的表达。 Blonanserin显着改善了PCP诱发的社会赤字，而奥兰扎和氟哌​​啶醇则没有。将Blonanserin的这种效果由7-OH-DPAT，多巴胺-D-3受体激动剂和SCH23390，DOPamine-D-1受体拮抗剂拮抗。然而，Blonanserin的改善效果不受DOI抑制的血清素5-HT2A受体激动剂。 PCP诱导的社会缺陷由U99194，多巴胺-D-3受体拮抗剂和SKF38393，多巴胺-D-1受体激动剂，由7-OH-DPAT或SCH23390拮抗作用。 Blonanserin在PCP-施用的小鼠中显着抑制SER（897）的蛋白激酶A（PKA）在SER（897）中的磷酸化水平的降低。这些结果表明，由于PFC中通过多巴胺-D-3受体拮抗多达多巴胺-D-3受体拮抗多功能-DOP-D-1受体-PKa信号传导，这些结果表明，抗NMDA受体的激活Blonanserin对PCP引起的社会赤字的改善作用。这些发现还提供体内证据，即多巴胺-D-3受体的Blonanserin拮抗剂可用作新的治疗策略，并且多巴胺-D-3受体可以是精神分裂症中观察到的社会缺陷的新疗法靶分子。

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