On the Digital Psychopharmacology of Valproic Acid in Mice.
On the Digital Psychopharmacology of Valproic Acid in Mice.
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DOI：
10.3389/fnins.2020.594612
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发表时间：
2020
影响因子：
4.3
通讯作者：
Krishnan V
中科院分区：
文献类型：
--
作者：
Bass JS;Tuo AH;Ton LT;Jankovic MJ;Kapadia PK;Schirmer C;Krishnan V
抗癫痫药物（AED）需要每天摄入最大限度地预防癫痫发作。AED的不良精神后果表现为：（i）情绪、焦虑、愤怒和/或易怒的可逆性变化，通常需要停药，和（ii）胎儿暴露后的自闭症和/或认知/精神发育迟缓。量化自然啮齿动物行为的技术进步可能提供敏感的AED精神耐受性和神经精神致畸性的临床前评估。在这项研究中，我们应用仪器化的家庭笼监测，以评估丙戊酸（VPA，溶解在加糖的饮用水）如何改变成年C57 BL/6 J小鼠和VPA暴露的繁殖对的成年后代的家庭笼行为。通过幼鼠旷场试验，我们还研究了产前VPA暴露如何影响早期自发探索行为。在500-600 mg/kg/d剂量下，慢性VPA导致摄食过多，并增加了轮跑，但不影响睡眠、活动和风险规避措施。当在整个妊娠期间对小鼠的繁殖对应用VPA时，VPA延长了存活窝仔的潜伏期，而不影响窝仔数。暴露于VPA的两周龄幼仔表现出旷场活动减退，但趋触性没有改变。作为成年人，产前VPA暴露的小鼠表现出活跃状态的碎片化，食欲减退和车轮运行增加，以及微妙的变化，在家庭笼的二元行为。总之，这些数据说明了自发行为的自动化家庭笼舍评估如何捕获肠内给药VPA的以行为学为中心的心理药理学特征，该特征与人类临床经验一致。通过表征泛博VPA暴露的影响，我们发现了新的普遍神经发育的小鼠表达。对心理耐受性进行如此严格的评估，可能会为未来的AED设计提供信息，改善患者及其后代的神经精神安全性。
Antiepileptic drugs (AEDs) require daily ingestion for maximal seizure prophylaxis. Adverse psychiatric consequences of AEDs present as: (i) reversible changes in mood, anxiety, anger and/or irritability that often necessitate drug discontinuation, and (ii) autism and/or cognitive/psychomotor delays following fetal exposure. Technical advances in quantifying naturalistic rodent behaviors may provide sensitive preclinical estimates of AED psychiatric tolerability and neuropsychiatric teratogenicity. In this study, we applied instrumented home-cage monitoring to assess how valproic acid (VPA, dissolved in sweetened drinking water) alters home-cage behavior in adult C57BL/6J mice and in the adult offspring of VPA-exposed breeder pairs. Through a pup open field assay, we also examined how prenatal VPA exposure impacts early spontaneous exploratory behavior. At 500–600 mg/kg/d, chronic VPA produced hyperphagia and increased wheel-running without impacting sleep, activity and measures of risk aversion. When applied to breeder pairs of mice throughout gestation, VPA prolonged the latency to viable litters without affecting litter size. Two-weeks old VPA-exposed pups displayed open field hypoactivity without alterations in thigmotaxis. As adults, prenatal VPA-exposed mice displayed active state fragmentation, hypophagia and increased wheel running, together with subtle alterations in home-cage dyadic behavior. Together, these data illustrate how automated home-cage assessments of spontaneous behavior capture an ethologically centered psychopharmacological profile of enterally administered VPA that is aligned with human clinical experience. By characterizing the effects of pangestational VPA exposure, we discover novel murine expressions of pervasive neurodevelopment. Incorporating such rigorous assessments of psychological tolerability may inform the design of future AEDs with improved neuropsychiatric safety profiles, both for patients and their offspring.
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影响因子：
2.6
作者：
Chen, Baibing;Choi, Hyunmi;Detyniecki, Kamil
通讯作者：
Detyniecki, Kamil
影响因子：
3
作者：
Chen, Baibing;Choi, Hyunmi;Detyniecki, Kamil
通讯作者：
Detyniecki, Kamil
影响因子：
2.6
作者：
Cohen, Morris J.;Meador, Kimford J.;Zajdowicz, Thad
通讯作者：
Zajdowicz, Thad
影响因子：
2.6
作者：
Ghodke-Puranik Y;Thorn CF;Lamba JK;Leeder JS;Song W;Birnbaum AK;Altman RB;Klein TE
通讯作者：
Klein TE
DOI：
10.1111/gbb.12256
发表时间：
2016-01
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
Kazdoba TM;Leach PT;Crawley JN
通讯作者：
Crawley JN