Use of a mouse model of anxious depression to assess the safety of pediatric anti

描述(由申请人提供)： 本申请涉及广泛的挑战领域(15)翻译科学和特定挑战主题15-MH-101，精神药物对动物模型中神经发育和行为的影响“。抗抑郁药和抗焦虑药越来越多地被开给年龄越来越小的儿科患者，而且往往是延长了时间。这些药物作用于神经生物底物，从胚胎发育到儿童和青春期，这些底物经历了深刻的结构和功能变化，这引发了人们对药物对大脑发育有害影响的担忧。特别是，使用氟西汀等抗抑郁药物治疗儿童和青少年可能会导致自杀行为和致命性增加。此外，在小鼠身上的实验表明，在与人类发育的最后三个月对应的出生后发育阶段服用氟西汀会导致成年后焦虑和情绪化加剧的行为。这些效应让人想起用地西潘治疗幼鼠时观察到的有害行为影响，地西潘是一种通过GABA-A受体增强GABA功能的苯二氮卓类原型药物。事实上，越来越多的证据表明，氟西汀等抗抑郁剂可能部分通过调节GABA能传递而发挥作用。因此，氟西汀和安定可能最终会通过需要进行直接比较的共同机制来影响发育中的神经系统。出生后的大脑发育涉及GABA能神经回路的渐进性、神经活动依赖性和功能特异性的成熟，这在细胞水平上包括从GABA-A受体的主要去极化功能到主要超极化效应的转换。这种发育机制被提出用来定义依赖活动的功能成熟的关键时期的时间边界，这一点普遍适用于大多数大脑功能，如果不是所有的话。这种机制可能适用于焦虑和情绪障碍的神经生物学底物的证据可以从GABA-A受体Gamma2亚单位杂合小鼠(Gamma2小鼠)中获得，这些小鼠被建立为焦虑抑郁的动物模型，包括与患者焦虑和情绪障碍相关的认知、行为、细胞和内分泌特征。重要的是，对条件性Gamma2小鼠的分析表明，这些小鼠的行为和其他异常是由发育中的GABA-A受体缺陷介导的。有趣的是，虽然给幼鼠服用安定对野生型(WT)小鼠的成年行为有类似焦虑症的影响，但对幼年Gamma 2小鼠进行类似的治疗是中性的或具有类似焦虑症的效果。这些发现表明，在与焦虑和抑郁样行为相关的神经回路中，Gamma2小鼠在神经可塑性的关键时期表现出GABA能缺陷。相反，药物诱导增强正常发育的大脑的GABA能传递，对相同回路的正常成熟产生负面影响。鉴于给年轻的WT小鼠服用氟西汀和安定对成年后的行为具有类似的焦虑性作用，我们假设这两种药物对与焦虑和抑郁相关的行为相关的GABA能回路的成熟具有类似的干扰作用。为了进一步阐明氟西汀和安定潜在有害发育影响的机制，我们建议：1)确定和比较这两种药物在成年后影响WT和GABAAR Gamma2亚单位杂合小鼠行为的出生后发育窗口。此外，我们将分析和比较这些药物对不同分子和细胞标记物的发育影响，这些标记物在伽马2小鼠中发生变化，并与焦虑和抑郁相关的行为有关。这些研究将提醒人们注意抗抑郁剂和抗焦虑药物对出生后大脑发育的潜在有害影响，并将有助于区分中性或可能有益的药物对大脑发育的有害影响。此外，它们还可以提高专门针对儿童和青少年患者的抗抑郁和抗焦虑疗法的设计和安全性。 公共卫生相关性：抗抑郁药、抗焦虑药和其他精神药物越来越多地被开给年龄越来越小的儿科患者，而且往往是较长时间的。这些药物作用于神经生物底物，在儿童和青少年时期经历了深刻的结构和功能变化，但它们在发育中的神经系统中的作用机制在很大程度上是未知的。在这里，我们利用焦虑抑郁的小鼠模型来评估抗抑郁药物治疗在代表儿科患者的年轻动物中的分子、细胞、内分泌和行为后果。这些研究将提醒人们注意抗抑郁剂和抗焦虑药物对出生后大脑发育的潜在有害影响，并将有助于区分中性或可能有益的药物对大脑发育的有害影响。此外，它们还可以提高专门针对儿童和青少年患者的抗抑郁和抗焦虑疗法的设计和安全性。

DESCRIPTION (provided by applicant): This application addresses broad challenge area (15) Translational Science and specific challenge topic 15-MH-101, Effects of Psychotropic Medications on Neurodevelopment and Behavior in Animal Models". Antidepressants and anxiolytics are increasingly prescribed to pediatric patients at progressively younger ages and often for extended periods of time. These drugs act upon neurobiological substrates that undergo profound structural and functional changes from embryogenesis to childhood and adolescence, raising concerns for detrimental drug effects on brain development. In particular, treatment of children and adolescents with antidepressant drugs such as fluoxetine may result in increased suicidal behavior and lethality. Moreover, experiments in mice indicate that administration of fluoxetine during postnatal developmental stages corresponding to the last trimester of human development leads to behavior indicative of heightened anxiety and emotionality in adulthood. These effects are reminiscent of detrimental behavioral effects observed upon treatment of young mice with diazepam, a prototype benzodiazepine that potentiates the function of GABA via GABA-A receptors. Indeed, accumulating evidence suggests that antidepressants such as fluoxetine may exert their effect in part by modulation of GABAergic transmission. Fluoxetine and diazepam therefore might ultimately affect the developing nervous system through common mechanisms that call for a direct comparison. Postnatal brain development involves progressive, neural activity-dependent and function-specific maturation of GABAergic circuits, which at the cellular level includes a switch from mostly depolarizing function of GABA-A receptors to mostly hyperpolarizing effects. This developmental mechanism has been proposed to define temporal boundaries for critical periods of activity-dependent functional maturation that applies universally to most if not all brain functions. Evidence that such mechanisms might apply to the neurobiological substrate of anxiety and mood disorders is available from GABA-A receptor gamma2 subunit heterozygous mice (gamma2 mice), which have been established as an animal model of anxious depression that includes cognitive, behavioral, cellular, and endocrine characteristics associated with anxiety and mood disorders in patients. Importantly, analyses of conditional gamma2 mice suggest that the behavioral and other abnormalities in these mice are mediated by a developmental GABA-A receptor deficit. Interestingly, while diazepam administered to young mice has anxiogenic-like effects on adult behavior in wildtype (WT) mice, similar treatment of young gamma 2 mice is neutral or has anxiolytic like effects. These findings suggest that gamma2 mice exhibit GABAergic deficits in a critical period of neural plasticity in neural circuits relevant for anxiety and depressive- like behavior. Conversely, drug induced potentiation of GABAergic transmission of an otherwise normally developing brain negatively affects proper maturation of the same circuits. Given that fluoxetine and diazepam administered to young WT mice have similar anxiogenic-like effects on behavior in adulthood, we hypothesize that the two drugs interfere similarly with maturation of GABAergic circuits that are relevant for anxiety and depression-related behavior. To further address the mechanism of potentially detrimental developmental effects of fluoxetine and diazepam we here propose to i) determine and compare the postnatal developmental windows during which these two drugs affect behavior of WT and GABAAR gamma2 subunit heterozygous mice in adulthood. In addition, we will analyze and compare the developmental effects of these drugs on diverse molecular and cellular markers that are altered in gamma 2 mice and are implicated in anxiety and depression-related behavior. These studies will alert to potentially detrimental effects of antidepressant and anxiolytic drug on the developing postnatal brain and will help to delineate detrimental from neutral or possibly beneficial drug effects on brain development. In addition, they may advance the design and safety of antidepressant and anxiolytic therapies directed specifically at pediatric and adolescent patients. PUBLIC HEALTH RELEVANCE: Antidepressants, anxiolytics and other psychotropic medications are increasingly prescribed to pediatric patients at progressively younger age and often for extended periods of time. These drugs act upon neurobiological substrates that undergo profound structural and functional changes during childhood and adolescence, yet their mechanisms of action in the developing nervous system are largely unknown. We here take advantage of a mouse model of anxious depression to assess molecular, cellular, endocrine and behavioral consequences of antidepressant drug treatment in young animals representative of pedriatic patients. These studies will alert to potentially detrimental effects of antidepressant and anxiolytic drug on the developing postnatal brain and will help to delineate detrimental from neutral or possibly beneficial drug effects on brain development. In addition, they may advance the design and safety of antidepressant and anxiolytic therapies directed specifically at pediatric and adolescent patients.