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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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