Behavioral, neurochemical and histopathological evaluation of ketamine-induced schizophrenia model

Objective: Schizophrenia is a common and complex neuropsychiatric disorder. The etiology of schizophrenia is still elusive and the available treatments remain insufficient. The preclinical studies are crucial for this purpose. There are methodological differences between the animal models of schizophrenia. The aim of this study is to validate the ketamine-induced schizophrenia model. The efficacy of selective α2C adrenoceptor antagonist was also evaluated. Material and methods: We first administered a sub-anesthetic dose of ketamine (25 mg/kg, i.p.) daily for eight consecutive days to adult male and female Wistar rats. The rats in the ketamine group received acute intraperitoneal injections of either JP-1302, chlorpromazine, or saline on test days. On the 7th and 8th days, the locomotor activity, social interaction, and novel object recognition tests were assessed. After the behavioral tests, the rats were sacrificed for analysis. Glutamate, glutamine, and GABA were measured by fluorometric HPLC analysis. The tyrosine hydroxylase immunoreactivity (TH-ir) in the striatum, nucleus accumbens (NAcc), ventral tegmental area (VTA), substantia nigra (SN) were measured by immunohistochemical method. Results: The locomotor activity and stereotypic behavior were increased and social interaction and the object recognition scores were decreased in the ketamine-induced psychosis (KIP) rats. Also, 10 μmol JP-1302 administration increased the social interaction time and object recognition scores. The TH-IR in the KIP rats was increased in the striatum, SN and VTA. The TH-IR was decreased after 3 and 10 μmol/kg JP-1302 treatments in the striatum and NAcc. Conclusion: The results of this study imply that the subchronic administration of ketamine can induce schizophrenia-like alterations in rats and therefore this animal model may be beneficial in the research of schizophrenia. Furthermore, the α2C-adrenoceptor may be a promising drug target for the treatment of schizophrenia.