A Cyclooxygenase-2 Inhibitor Ameliorates Behavioral Impairments Induced by Striatal Administration of Epidermal Growth Factor

Abstract

Consistent with the hypothesis that neuroinflammatory processes contribute to the neuropathology of schizophrenia, the protein levels of epidermal growth factor (EGF) and its receptor ErbB1 are abnormal in patients with schizophrenia. To evaluate neuropathological significance of this abnormality, we established an animal model for behavioral deficits by administering EGF into the striatum and evaluated the effects of cyclooxygenase-2 (Cox-2) inhibitor celecoxib. Intracranial infusion of EGF into the striatum of adult male rats activated ErbB1 and induced neurobehavioral impairments observed in several schizophrenia models. Unilateral EGF infusion to the striatum lowered prepulse inhibition (PPI) in a dose-dependent manner and impaired latent learning of active shock avoidance without affecting basal learning ability. Bilateral EGF infusion similarly affected PPI. In contrast, EGF infusion to the nucleus accumbens did not induce a behavioral deficit. Intrastriatal EGF infusion also increased Cox-2 expression, elevated tyrosine hydroxylase activity, and upregulated the levels of dopamine and its metabolites. Subchronic administration of celecoxib (10 mg/kg, p.o.) ameliorated the abnormalities in PPI and latent learning as well as normalized dopamine metabolism. We conclude that this EGF-triggered neuroinflammatory process is mediated in part by Cox-2 activity and perturbs dopamine metabolism to generate neurobehavioral abnormalities.

An Attempt of Non-human Primate Modeling of Schizophrenia with Neonatal Challenges of Epidermal Growth Factor

“…These findings indicate that EGF/ ErbB1signals are indeed altered in both acute and chronic phases of schizophrenia. In agreement with the postmortem results, peripheral administration of EGF to neonatal rats or mice results in displays of post-pubertal abnormality in cognitive and behavioral traits such as acoustic startle response, prepulse inhibition, hyperlocomotion, social interaction, latent inhibition of learning and sensitivity to methamphetamine [13][14][15][16]. Since EGF signaling can be induced by…”

“…Neonatal administration of EGF to rodents has been reported to induce several schizophrenia-associated behavioral endophenotypes [13][14][15][16]. Most of the behavioral impairments are sensitive to antipsychotics [13,26].…”

Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia

“…39 Contents of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and L-DOPA were determined by HPLC using a C18 column (model CA-5ODS, 4.6 Â 150 mm, Eicom). 39 Dialysis samples were directly applied onto the HPLC system equipped with BDS Hypersil C18 column (1.0 Â 100 mm, Keystone Scientific, Bellefonte, PA, USA). For details, see Supplementary Materials and Methods.…”

Antipsychotic Potential of Quinazoline ErbB1 Inhibitors in a Schizophrenia Model Established With Neonatal Hippocampal Lesioning

“…The procedure for drug infusion into the rat brain has been described previously (34). After confirming deep anesthesia with sodium pentobarbital (50 mg/kg, i.p.…”