2013.05.08
ErbB inhibitors ameliorate behavioral impairments of an animal model for schizophrenia: implication of their dopamine-modulatory actions
（Transl Psychiatry (2013) 3, e252; doi:10.1038/tp.2013.29）
Mizuno M1,2,3, Sotoyama H1,3, Namba H1, Shibuya M1, Eda T1, Wang R1, Okubo T1, Nagata K2, Iwakura Y1, Nawa H1.
1Department of Molecular Neurobiology, Brain Research Institute, Niigata University
2Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi
3These authors contributed equally to this work.
Abstract
Ligands for ErbB receptors, including epidermal growth factor (EGF) and neuregulin-1, have a neurotrophic activity on midbrain dopaminergic neurons and are implicated in the pathophysiology of schizophrenia. Although ErbB kinase inhibitors ameliorate behavioral deficits of the schizophrenia model that was established by hippocampal lesioning of rat pups, the antipsychotic action of ErbB kinase inhibitors and its general applicability to other models are not fully characterized. Using a different animal model, here, we examined whether and how ErbB kinase inhibitors ameliorate the behavioral endophenotypes relevant to schizophrenia. The animal model for schizophrenia was prepared by exposing neonatal rats to the cytokine EGF. Intraventricular infusion of the ErbB1 inhibitors ZD1839 and PD153035 in these animals ameliorated the deficits in startle response and prepulse inhibition in a dose-dependent manner. The deficits of latent inhibition of fear learning were also alleviated by ZD1839 with its limited effects on body weight gain or locomotor activity. ZD1839 infusion also decreased the busting activity of nigral dopamine (DA) neurons and reduced pallidal DA metabolism, a result that mimics the anti-dopaminergic profile of risperidone and haloperidol in this brain region. ErbB inhibitors appear to have anti-dopaminergic actions to alleviate some of the behavioral deficits common to animal models for schizophrenia.
