Psychopharmacology

, Volume 191, Issue 3, pp 783–792 | Cite as

Neonatal exposure to epidermal growth factor induces dopamine D2-like receptor supersensitivity in adult sensorimotor gating

  • Hidekazu Sotoyama
  • Hisaaki Namba
  • Nobuyuki Takei
  • Hiroyuki Nawa
Original Investigation

Abstract

Rational

Abnormality in the neurotrophic factor for dopamine neurons, epidermal growth factor (EGF), is associated with schizophrenia. Thus, rats treated with EGF as neonates are used as a putative animal model for schizophrenia showing impaired prepulse inhibition (PPI) and other cognitive deficits in the adult stage.

Objectives

To elucidate the abnormal behavioral traits of this animal model, the EGF effects on the dopaminergic system were analyzed pharmacologically and biochemically at the adult stage.

Results

We examined the effects of subthreshold doses of dopamine agonists on PPI in this model. A non-selective dopamine agonist, apomorphine (0.1 mg/kg), decreased PPI in EGF-treated rats, but not in controls. Further, a D2-like receptor agonist, quinpirole (0.01 and 0.03 mg/kg), similarly decreased PPI in EGF-treated rats but had no effect in the control animals. In contrast, a D1-like receptor agonist, SKF38393 (3 and 10 mg/kg), had no effect on PPI in both groups. To explore the molecular mechanism underlying the change in sensorimotor gating, we assessed D1 and D2 receptors expression in the prefrontal cortex, striatum and hippocampus and their downstream signaling. Although there were no significant differences in basal receptor levels, quinpirole administration significantly enhanced phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP response element binding protein (CREB) in the striatum of EGF-treated rats.

Conclusion

These results suggest that circulating EGF in the early development substantially influences D2 receptor-dependent regulation of sensorimotor gating.

Keywords

EGF ErbB1 Dopamine Quinpirole D2-like receptor PPI ERK Striatum 

Abbreviations

ANOVA

analysis of variance

EGF

epidermal growth factor

ERK

extracellular signal-regulated kinase

CREB

cyclic adenosine monophosphate response element binding protein

PBS

phosphate-buffered saline

TBS

Tris-buffered saline

PPI

prepulse inhibition

TGFα

transforming growth factor alpha

HB-EGF

heparin-binding EGF-like growth factor

SDS

sodium dodecylsulfate

BSA

bovine serum albumin

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Hidekazu Sotoyama
    • 1
  • Hisaaki Namba
    • 1
  • Nobuyuki Takei
    • 1
  • Hiroyuki Nawa
    • 1
    • 2
  1. 1.Department of Molecular NeurobiologyBrain Research Institute, Niigata UniversityNiigataJapan
  2. 2.Brain Research InstituteCenter for Transdisciplinary Research, Niigata UniversityNiigataJapan

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