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

IF 3.3 3区心理学 Q1 BEHAVIORAL SCIENCES Pharmacology Biochemistry and Behavior Pub Date : 2022-11-01 DOI:10.1016/j.pbb.2022.173490

Nurdan Tekin , Tuğba Eryiğit Karamahmutoğlu , Aslı Aykaç , Dilek Akakın , Mehmet Zafer Gören

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引用次数: 2

Abstract

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.

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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

精神分裂症是一种影响1%人口的慢性致残疾病。目前的抗精神病药物在减轻疾病症状的严重程度方面疗效有限。因此，寻找新的治疗靶点至关重要。先前的研究表明α - 2c肾上腺素受体拮抗剂可能具有抗精神病和促进认知的作用。因此，本研究评估了选择性α 2c肾上腺素能受体拮抗剂JP-1302在亚慢性氯胺酮(KET)诱导的精神分裂症样缺陷模型中的行为和神经化学作用。在这里，我们给雄性和雌性Wistar大鼠服用氯胺酮(25 mg/kg, i.p)，连续8天。在氯胺酮给药的最后2天，分别用JP-1302 (1-3-10 μmol/kg, i.p.)、氯丙嗪(0.1 mg/kg, i.p.)或生理盐水预处理大鼠，并进行行为学测试。评估与精神分裂症阳性(运动活动)、阴性(社会互动)和认知(新物体识别)症状相关的行为。测定大鼠额叶皮质和海马中谷氨酸、谷氨酰胺、GABA水平和α 2c -肾上腺素能受体表达。酪氨酸羟化酶免疫细胞化学反应也显示在中脑区域。亚慢性氯胺酮服用增加运动活动，产生强大的社会互动和物体识别缺陷，JP-1302显著改善氯胺酮诱导的认知缺陷。氯胺酮诱导纹状体的高多巴胺能活性，用JP-1302治疗可以逆转这种活性。氯胺酮处理大鼠额叶皮质和海马α 2c -肾上腺素能受体表达升高。我们的研究结果证实，α 2c -肾上腺素能受体拮抗剂可能是治疗精神分裂症相关认知障碍的潜在药物靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pharmacology Biochemistry and Behavior 医学-行为科学

CiteScore

6.40

自引率

2.80%

发文量

122

审稿时长

38 days

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.