Neonatal exposure to epidermal growth factor induces dopamine D2-like receptor supersensitivity in adult sensorimotor gating
- 112 Downloads
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.
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.
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.
These results suggest that circulating EGF in the early development substantially influences D2 receptor-dependent regulation of sensorimotor gating.
KeywordsEGF ErbB1 Dopamine Quinpirole D2-like receptor PPI ERK Striatum
analysis of variance
epidermal growth factor
extracellular signal-regulated kinase
cyclic adenosine monophosphate response element binding protein
transforming growth factor alpha
heparin-binding EGF-like growth factor
bovine serum albumin
- Berrahmoune H, Lamont JV, Herbeth B, FitzGerald PS, Visvikis-Siest S (2006) Biological determinants of and reference values for plasma interleukin-8, monocyte chemoattractant protein-1, epidermal growth factor, and vascular endothelial growth factor: results from the STANISLAS cohort. Clin Chem 52:504–510PubMedCrossRefGoogle Scholar
- Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D (1997) Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 94:2569–2574PubMedCrossRefGoogle Scholar
- Feldman RS, Meyer JS, Quenzer LE (1997) Principles of neuropsychopharmacology. Sinauer Associates Inc., Sunderland, MassachusettsGoogle Scholar
- Futamura T, Kakita A, Tohmi M, Sotoyama H, Takahashi H, Nawa H (2003) Neonatal perturbation of neurotrophic signaling results in abnormal sensorimotor gating and social interaction in adults: implication for epidermal growth factor in cognitive development. Mol Psychiatry 8:19–29PubMedCrossRefGoogle Scholar
- Kinney GG, Wilkinson LO, Saywell KL, Tricklebank MD (1999) Rat strain differences in the ability to disrupt sensorimotor gating are limited to the dopaminergic system, specific to prepulse inhibition, and unrelated to changes in startle amplitude or nucleus accumbens dopamine receptor sensitivity. J Neurosci 19:5644–5653PubMedGoogle Scholar