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.
Highlights
The ErbB family of receptor tyrosine kinases consists of four members; ErbB1-4 subunits form homo- or hetero-dimer complexes to transduce their signals
Rats and mice transiently exposed to epidermal growth factor (EGF) as neonates exhibit several behavioral deficits relevant to schizophrenia, including startle responses, prepulse inhibition (PPI), latent inhibition and social interaction, and were employed for this evaluation study of ErbB inhibitors.[6,27,37,38,39]
We found that ZD1839 decreased pulsealone acoustic startle responses in EGF rats (Figure 1a); a two-way repeated ANOVA with the subject factors of EGF
Summary
The ErbB family of receptor tyrosine kinases consists of four members; ErbB1-4 subunits form homo- or hetero-dimer complexes to transduce their signals. The upregulation of ErbB1 and ErbB4 expression is found in the forebrain of schizophrenia patients.[1,22] Despite the neuropathological implication of ErbB signaling in the brain diseases involving dopaminergic dysfunction,[23] the therapeutic potential of ErbB modulators (activators and inhibitors) remains to be explored
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