The α 2C -adrenoceptor antagonist JP-1302 controls behavioral parameters, tyrosine hydroxylase activity and receptor expression in a rat model of ketamine-induced schizophrenia-like deficits

• Published in: Pharmacology, biochemistry and behavior Vol. 221; p. 173490
• Main Authors: Tekin, Nurdan, Karamahmutoğlu, Tuğba Eryiğit, Aykaç, Aslı, Akakın, Dilek, Gören, Mehmet Zafer
• Format: Journal Article
• Language: English
• Published: United States 01-11-2022
• Subjects: Animals; Antipsychotic Agents - therapeutic use; Disease Models, Animal; Female; Ketamine - therapeutic use; Male; Rats; Rats, Wistar; Schizophrenia - chemically induced; Schizophrenia - drug therapy; Tyrosine 3-Monooxygenase; Western-blotting; Schizophrenia; Novel object recognition; HPLC
• ISSN: 1873-5177

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
-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
-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
-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
-adrenoceptor expression was higher in the frontal cortex and hippocampus in the ketamine-treated rats. Our findings confirm that α
-adrenoceptor antagonism may be a potential drug target for treating cognitive disorders related to schizophrenia.