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Schizophrenia is a chronic disabling disease affecting 1 % of the population. Current antipsychotics have limited efficacy in mitigating the severity of the symptoms of the disease. Therefore, searching for new therapeutic targets is essential. Previous studies have shown that α 2C -adrenoceptor antagonists may have antipsychotic and pro-cognitive effects. Therefore, the current study evaluates the behavioral and neurochemical effects of JP-1302, a selective α 2C -adrenoceptor antagonist, in a model of schizophrenia-like deficits induced by sub-chronic ketamine (KET) administration. Here, we administered ketamine (25 mg/kg, i.p.) to male and female Wistar rats for eight consecutive days. On the last two days of ketamine administration, rats were pretreated with either JP-1302 (1-3-10 μmol/kg, i.p.), chlorpromazine (0.1 mg/kg, i.p.), or saline, and the behavioral tests were performed. Behaviors related to positive (locomotor activity), negative (social interaction), and cognitive (novel object recognition) symptoms of schizophrenia were assessed. Glutamate, glutamine, GABA levels, and α 2C -adrenoceptor expression were measured in the frontal cortex and the hippocampus. Tyrosine hydroxylase immunocytochemical reactivity was also shown in the midbrain regions. Sub-chronic ketamine administration increased locomotor activity and produced robust social interaction and object recognition deficits, and JP-1302 significantly ameliorated ketamine-induced cognitive deficits. Ketamine induced a hyperdopaminergic activity in the striatum, which was reversed by the treatment with JP-1302. Also, the α 2C -adrenoceptor expression was higher in the frontal cortex and hippocampus in the ketamine-treated rats. Our findings confirm that α 2C -adrenoceptor antagonism may be a potential drug target for treating cognitive disorders related to schizophrenia., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose. Part of the data was presented as a poster at the British Pharmacology Society Meeting 2019 in Edinburg, Scotland., (Copyright © 2022. Published by Elsevier Inc.)