Influence of the dose of ketamine used on schizophrenia-like symptoms in mice: A correlation study with TH, GAD67, and PPAR-γ

IF 3.3 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior Pub Date : 2023-10-05 DOI:10.1016/j.pbb.2023.173658

Talita Rodrigues , Getulio Nicola Bressan , Bárbara Nunes Krum , Félix Alexandre Antunes Soares , Roselei Fachinetto

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引用次数: 0

Abstract

Schizophrenia is a chronic, debilitating mental illness that has not yet been completely understood. In this study, we aimed to investigate the effects of different doses of ketamine, a non-competitive NMDA receptor antagonist, on the positive- and negative-like symptoms of schizophrenia. We also explored whether these effects are related to changes in the immunoreactivity of GAD₆₇, TH, and PPAR-γ in brain structures. To conduct the study, male mice received ketamine (20–40 mg/kg) or its vehicle (0.9 % NaCl) intraperitoneally for 14 consecutive days. We quantified stereotyped behavior, the time of immobility in the forced swimming test (FST), and locomotor activity after 7 or 14 days. In addition, we performed ex vivo analysis of the immunoreactivity of GAD, TH, and PPAR-γ, in brain tissues after 14 days. The results showed that ketamine administration for 14 days increased the grooming time in the nose region at all tested doses. It also increased immobility in the FST at 30 mg/kg doses and decreased the number of rearing cycles during stereotyped behavior at 40 mg/kg. These behavioral effects were not associated with changes in locomotor activity. We did not observe any significant alterations regarding the immunoreactivity of brain proteins. However, we found that GAD and TH were positively correlated with the number of rearing during the stereotyped behavior at doses of 20 and 30 mg/kg ketamine, respectively. GAD was positively correlated with the number of rearing in the open field test at a dose of 20 mg/kg. TH was inversely correlated with immobility time in the FST at a dose of 30 mg/kg. PPAR-γ was inversely correlated with the number of bouts of stereotyped behavior at a dose of 40 mg/kg of ketamine. In conclusion, the behavioral alterations induced by ketamine in positive-like symptoms were reproduced with all doses tested and appear to depend on the modulatory effects of TH, GAD, and PPAR-γ. Conversely, negative-like symptoms were associated with a specific dose of ketamine.

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氯胺酮剂量对小鼠精神分裂症样症状的影响:与TH、GAD67和PPAR-γ的相关性研究

精神分裂症是一种慢性的、使人衰弱的精神疾病，至今尚未完全被人们所了解。在本研究中，我们旨在研究不同剂量的氯胺酮（一种非竞争性NMDA受体拮抗剂）对精神分裂症阳性和阴性样症状的影响。我们还探讨了这些作用是否与大脑结构中GAD67、TH和PPAR-γ免疫反应性的变化有关。为了进行这项研究，雄性小鼠连续14天腹膜内接受氯胺酮（20-40 mg/kg）或其载体（0.9%NaCl）。我们量化了刻板行为、强迫游泳测试（FST）中的不动时间以及7或14天后的运动活动。此外，我们对14天后脑组织中GAD、TH和PPAR-γ的免疫反应性进行了离体分析。结果显示，在所有测试剂量下，氯胺酮给药14天增加了鼻子区域的梳理时间。它还增加了30 mg/kg剂量下FST的不动性，并减少了40 mg/kg剂量下定型行为期间的饲养周期数。这些行为影响与运动活动的变化无关。我们没有观察到大脑蛋白质免疫反应性的任何显著变化。然而，我们发现，在20和30 mg/kg氯胺酮剂量下，GAD和TH分别与刻板行为期间的养育次数呈正相关。在20 mg/kg的剂量下，GAD与露地试验中的饲养次数呈正相关。在30 mg/kg的剂量下，TH与FST中的不动时间呈负相关。PPAR-γ与40 mg/kg氯胺酮剂量下刻板行为发作次数呈负相关。总之，氯胺酮在阳性样症状中诱导的行为改变在所有剂量的测试中都得到了再现，并且似乎取决于TH、GAD和PPAR-γ的调节作用。相反，阴性样症状与特定剂量的氯胺酮有关。

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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.