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The Journal of Neuroscience, September 19, 2007, 27(38):10116-10127; doi:10.1523/JNEUROSCI.2368-07.2007

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

Makoto Mizuno,^1,2 Hidekazu Sotoyama,² Eri Narita,² Hiroki Kawamura,² Hisaaki Namba,² Yingjun Zheng,² Takeyoshi Eda,² and Hiroyuki Nawa^1,2

¹Center for Transdisciplinary Research and ²Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan

Correspondence should be addressed to Hiroyuki Nawa, Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan. Email: hnawa{at}bri.niigata-u.ac.jp

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.

Key words: inflammation; cyclooxygenase; EGF; schizophrenia; dopamine; prostaglandin

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Received Jan. 18, 2007; revised July 9, 2007; accepted July 31, 2007.

Correspondence should be addressed to Hiroyuki Nawa, Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan. Email: hnawa{at}bri.niigata-u.ac.jp

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