Bergamini Giorgio, Massinet Helene, Hart Aaron, Durkin Sean, Pierlot Gabin, Steiner Michel Alexander
CNS Pharmacology and Drug Discovery, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland.
Scientific Computing Drug Discovery, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland.
Front Psychiatry. 2023 Feb 21;14:1054163. doi: 10.3389/fpsyt.2023.1054163. eCollection 2023.
People with dementia (PwD) often present with neuropsychiatric symptoms (NPS). NPS are of substantial burden to the patients, and current treatment options are unsatisfactory. Investigators searching for novel medications need animal models that present disease-relevant phenotypes and can be used for drug screening. The Senescence Accelerated Mouse-Prone 8 (SAMP8) strain shows an accelerated aging phenotype associated with neurodegeneration and cognitive decline. Its behavioural phenotype in relation to NPS has not yet been thoroughly investigated. Physical and verbal aggression in reaction to the external environment (e.g., interaction with the caregiver) is one of the most prevalent and debilitating NPS occurring in PwD. Reactive aggression can be studied in male mice using the Resident-Intruder (R-I) test. SAMP8 mice are known to be more aggressive than the Senescence Accelerated Mouse-Resistant 1 (SAMR1) control strain at specific ages, but the development of the aggressive phenotype over time, is still unknown.
In our study, we performed a longitudinal, within-subject, assessment of aggressive behaviour of male SAMP8 and SAMR1 mice at 4, 5, 6 and 7 months of age. Aggressive behaviour from video recordings of the R-I sessions was analysed using an in-house developed behaviour recognition software.
SAMP8 mice were more aggressive relative to SAMR1 mice starting at 5 months of age, and the phenotype was still present at 7 months of age. Treatment with risperidone (an antipsychotic frequently used to treat agitation in clinical practice) reduced aggression in both strains. In a three-chamber social interaction test, SAMP8 mice also interacted more fervently with male mice than SAMR1, possibly because of their aggression-seeking phenotype. They did not show any social withdrawal.
Our data support the notion that SAMP8 mice might be a useful preclinical tool to identify novel treatment options for CNS disorders associated with raised levels of reactive aggression such as dementia.
痴呆症患者（PwD）常伴有神经精神症状（NPS）。NPS给患者带来沉重负担，而目前的治疗选择并不令人满意。寻找新型药物的研究人员需要能够呈现与疾病相关表型且可用于药物筛选的动物模型。衰老加速易患8型（SAMP8）小鼠品系表现出与神经退行性变和认知衰退相关的加速衰老表型。其与NPS相关的行为表型尚未得到充分研究。对外部环境（如与照料者互动）做出反应的身体攻击和言语攻击是PwD中最常见且最具致残性的NPS之一。可使用定居者-入侵者（R-I）测试在雄性小鼠中研究反应性攻击行为。已知SAMP8小鼠在特定年龄比衰老加速抗性1型（SAMR1）对照品系更具攻击性，但攻击性表型随时间的发展仍不清楚。
在我们的研究中，我们对4、5、6和7月龄的雄性SAMP8和SAMR1小鼠的攻击行为进行了纵向的、个体内评估。使用自行开发的行为识别软件分析R-I实验视频记录中的攻击行为。
从5月龄开始，SAMP8小鼠相对于SAMR1小鼠更具攻击性，且该表型在7月龄时仍然存在。使用利培酮（临床实践中常用于治疗激越的一种抗精神病药物）治疗可降低两个品系的攻击性。在三室社交互动测试中，SAMP8小鼠与雄性小鼠的互动也比SAMR1小鼠更热烈，这可能是因为它们具有寻求攻击的表型。它们没有表现出任何社交退缩。
我们的数据支持这样一种观点，即SAMP8小鼠可能是一种有用的临床前工具，可用于识别针对与反应性攻击水平升高相关的中枢神经系统疾病（如痴呆症）的新型治疗选择。
