Nurdan Tekin , Tuğba Eryiğit Karamahmutoğlu , Aslı Aykaç , Dilek Akakın , Mehmet Zafer Gören
{"title":"α 2c肾上腺素能受体拮抗剂JP-1302在氯胺酮诱导的精神分裂症样缺陷大鼠模型中控制行为参数、酪氨酸羟化酶活性和受体表达","authors":"Nurdan Tekin , Tuğba Eryiğit Karamahmutoğlu , Aslı Aykaç , Dilek Akakın , Mehmet Zafer Gören","doi":"10.1016/j.pbb.2022.173490","DOIUrl":null,"url":null,"abstract":"<div><p><span><span>Schizophrenia is a chronic disabling disease affecting 1 % of the population. Current </span>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</span><sub>2C</sub>-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<sub>2C</sub><span>-adrenoceptor antagonist, in a model of schizophrenia-like deficits induced by sub-chronic ketamine (KET) administration.</span></p><p><span><span>Here, we administered ketamine (25 mg/kg, i.p.) to male and female Wistar rats<span> 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. </span></span>Glutamate, glutamine, GABA levels, and α</span><sub>2C</sub><span><span>-adrenoceptor expression were measured in the frontal cortex and the hippocampus. </span>Tyrosine hydroxylase immunocytochemical reactivity was also shown in the midbrain regions.</span></p><p><span><span>Sub-chronic ketamine administration increased locomotor activity and produced robust social interaction and object recognition deficits, and JP-1302 significantly ameliorated ketamine-induced </span>cognitive deficits. Ketamine induced a hyperdopaminergic activity in the striatum, which was reversed by the treatment with JP-1302. Also, the α</span><sub>2C</sub>-adrenoceptor expression was higher in the frontal cortex and hippocampus in the ketamine-treated rats.</p><p>Our findings confirm that α<sub>2C</sub>-adrenoceptor antagonism may be a potential drug target for treating cognitive disorders related to schizophrenia.</p></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"221 ","pages":"Article 173490"},"PeriodicalIF":3.3000,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":"{\"title\":\"The α2C-adrenoceptor antagonist JP-1302 controls behavioral parameters, tyrosine hydroxylase activity and receptor expression in a rat model of ketamine-induced schizophrenia-like deficits\",\"authors\":\"Nurdan Tekin , Tuğba Eryiğit Karamahmutoğlu , Aslı Aykaç , Dilek Akakın , Mehmet Zafer Gören\",\"doi\":\"10.1016/j.pbb.2022.173490\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p><span><span>Schizophrenia is a chronic disabling disease affecting 1 % of the population. Current </span>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</span><sub>2C</sub>-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<sub>2C</sub><span>-adrenoceptor antagonist, in a model of schizophrenia-like deficits induced by sub-chronic ketamine (KET) administration.</span></p><p><span><span>Here, we administered ketamine (25 mg/kg, i.p.) to male and female Wistar rats<span> 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. </span></span>Glutamate, glutamine, GABA levels, and α</span><sub>2C</sub><span><span>-adrenoceptor expression were measured in the frontal cortex and the hippocampus. </span>Tyrosine hydroxylase immunocytochemical reactivity was also shown in the midbrain regions.</span></p><p><span><span>Sub-chronic ketamine administration increased locomotor activity and produced robust social interaction and object recognition deficits, and JP-1302 significantly ameliorated ketamine-induced </span>cognitive deficits. Ketamine induced a hyperdopaminergic activity in the striatum, which was reversed by the treatment with JP-1302. Also, the α</span><sub>2C</sub>-adrenoceptor expression was higher in the frontal cortex and hippocampus in the ketamine-treated rats.</p><p>Our findings confirm that α<sub>2C</sub>-adrenoceptor antagonism may be a potential drug target for treating cognitive disorders related to schizophrenia.</p></div>\",\"PeriodicalId\":19893,\"journal\":{\"name\":\"Pharmacology Biochemistry and Behavior\",\"volume\":\"221 \",\"pages\":\"Article 173490\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2022-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"2\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pharmacology Biochemistry and Behavior\",\"FirstCategoryId\":\"102\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0091305722001691\",\"RegionNum\":3,\"RegionCategory\":\"心理学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BEHAVIORAL SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacology Biochemistry and Behavior","FirstCategoryId":"102","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0091305722001691","RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BEHAVIORAL SCIENCES","Score":null,"Total":0}
The α2C-adrenoceptor antagonist JP-1302 controls behavioral parameters, tyrosine hydroxylase activity and receptor expression in a rat model of ketamine-induced schizophrenia-like deficits
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 α2C-adrenoceptor antagonists may have antipsychotic and pro-cognitive effects. Therefore, the current study evaluates the behavioral and neurochemical effects of JP-1302, a selective α2C-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 α2C-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 α2C-adrenoceptor expression was higher in the frontal cortex and hippocampus in the ketamine-treated rats.
Our findings confirm that α2C-adrenoceptor antagonism may be a potential drug target for treating cognitive disorders related to schizophrenia.
期刊介绍：
Pharmacology Biochemistry & Behavior publishes original reports in the areas of pharmacology and biochemistry in which the primary emphasis and theoretical context are behavioral. Contributions may involve clinical, preclinical, or basic research. Purely biochemical or toxicology studies will not be published. Papers describing the behavioral effects of novel drugs in models of psychiatric, neurological and cognitive disorders, and central pain must include a positive control unless the paper is on a disease where such a drug is not available yet. Papers focusing on physiological processes (e.g., peripheral pain mechanisms, body temperature regulation, seizure activity) are not accepted as we would like to retain the focus of Pharmacology Biochemistry & Behavior on behavior and its interaction with the biochemistry and neurochemistry of the central nervous system. Papers describing the effects of plant materials are generally not considered, unless the active ingredients are studied, the extraction method is well described, the doses tested are known, and clear and definite experimental evidence on the mechanism of action of the active ingredients is provided.
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