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

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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.

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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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Acknowledgements

This study was supported by a grant-in-aid for Creative Scientific Research from the Japan Society for the Promotion of Science, Core Research for Evolutional Science and Technology from the Japan Science and Technology Corporation, a grant for the promotion of Niigata University Research Projects (H. N.) and a research fund from Astrazeneca Pharmaceuticals.

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Correspondence to Hiroyuki Nawa.

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Sotoyama, H., Namba, H., Takei, N. et al. Neonatal exposure to epidermal growth factor induces dopamine D2-like receptor supersensitivity in adult sensorimotor gating. Psychopharmacology 191, 783–792 (2007). https://doi.org/10.1007/s00213-006-0595-9

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  • DOI: https://doi.org/10.1007/s00213-006-0595-9

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