Pallidal hyperdopaminergic innervation underlying D2 receptor-dependent behavioral deficits in the schizophrenia animal model established by EGF.
Epidermal growth factor (EGF) is one of the ErbB receptor ligands implicated in schizophrenia neuropathology as well as in dopaminergic development. Based on the immune inflammatory hypothesis for schizophrenia, neonatal rats are exposed to this cytokine and later develop neurobehavioral abnormality such as prepulse inhibition (PPI) deficit. Here we found that the EGF-treated rats exhibited persistent increases in tyrosine hydroxylase levels and dopamine content in the globus pallidus. Furthermore, pallidal dopamine release was elevated in EGF-treated rats, but normalized by subchronic treatment with risperidone concomitant with amelioration of their PPI deficits. To evaluate pathophysiologic roles of the dopamine abnormality, we administered reserpine bilaterally to the globus pallidus to reduce the local dopamine pool. Reserpine infusion ameliorated PPI deficits of EGF-treated rats without apparent aversive effects on locomotor activity in these rats. We also administered dopamine D1-like and D2-like receptor antagonists (SCH23390 and raclopride) and a D2-like receptor agonist (quinpirole) to the globus pallidus and measured PPI and bar-hang latencies. Raclopride (0.5 and 2.0 µg/site) significantly elevated PPI levels of EGF-treated rats, but SCH23390 (0.5 and 2.0 µg/site) had no effect. The higher dose of raclopride induced catalepsy-like changes in control animals but not in EGF-treated rats. Conversely, local quinpirole administration to EGF-untreated control rats induced PPI deficits and anti-cataleptic behaviors, confirming the pathophysiologic role of the pallidal hyperdopaminergic state. These findings suggest that the pallidal dopaminergic innervation is vulnerable to circulating EGF at perinatal and/or neonatal stages and has strong impact on the D2-like receptor-dependent behavioral deficits relevant to schizophrenia.
Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan.
Hidekazu
H
Sotoyama
Yingjun
Y
Zheng
Yuriko
Y
Iwakura
Makoto
M
Mizuno
Miho
M
Aizawa
Ksenia
K
Shcherbakova
Ran
R
Wang
Hisaaki
H
Namba
Hiroyuki
H
Nawa
D000375:Aging / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D002375:Catalepsy / Q000150:complications / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D004815:Epidermal Growth Factor / Q000008:administration & dosage / Q000494:pharmacology*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005917:Globus Pallidus / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D007398:Interpersonal Relations; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012110:Reserpine / Q000008:administration & dosage / Q000494:pharmacology; D018967:Risperidone / Q000494:pharmacology / Q000627:therapeutic use; D012559:Schizophrenia / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D014150:Antipsychotic Agents; D015415:Biomarkers; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D004815:Epidermal Growth Factor; D012110:Reserpine; D014446:Tyrosine 3-Monooxygenase; D018967:Risperidone; D004298:Dopamine