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）转化科学和特定的挑战主题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用于越来越年轻的儿科患者，并且通常持续很长一段时间。这些药物作用于从胚胎发育到儿童和青春期经历深刻结构和功能变化的神经生物学底物，引起了对大脑发育有害药物影响的担忧。特别是，使用抗抑郁药物（如氟西汀）治疗儿童和青少年可能会导致自杀行为和致死率增加。此外，在小鼠中的实验表明，在对应于人类发育的最后三个月的出生后发育阶段期间给予氟西汀导致指示成年期焦虑和情绪性升高的行为。这些作用使人联想到在用地西泮（一种通过GABA-A受体增强GABA的功能的原型苯二氮卓类）处理年幼小鼠时观察到的有害行为作用。事实上，越来越多的证据表明，抗抑郁药，如氟西汀，可能发挥其作用的一部分，通过调制GABA能传输。因此，氟西汀和地西泮可能最终通过共同的机制影响发育中的神经系统，需要进行直接比较。 出生后的大脑发育涉及GABA能回路的进行性、神经活动依赖性和功能特异性成熟，其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作用的转变。这种发育机制已被提出来定义活动依赖性功能成熟的关键时期的时间边界，这普遍适用于大多数（如果不是所有的话）大脑功能。这些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从GABA-A受体γ 2亚基杂合小鼠（γ 2小鼠）获得，其已被建立为焦虑抑郁症的动物模型，包括与患者中的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γ 2小鼠的分析表明，这些小鼠的行为和其他异常是由发育性GABA-A受体缺陷介导的。有趣的是，虽然给予幼龄小鼠地西泮对野生型（WT）小鼠的成年行为具有致焦虑样作用，但对幼龄γ 2小鼠的类似治疗是中性的或具有抗焦虑样作用。这些发现表明，γ 2小鼠在与焦虑和抑郁样行为相关的神经回路中的神经可塑性的关键时期表现出GABA能缺陷。相反，药物诱导的GABA能传递的增强对正常发育的大脑产生负面影响，影响相同回路的适当成熟。鉴于氟西汀和地西泮对幼年WT小鼠成年后的行为具有相似的致焦虑样作用，我们假设这两种药物对与焦虑和抑郁相关行为相关的GABA能回路的成熟具有相似的干扰作用。为了进一步阐明氟西汀和地西泮潜在有害发育作用的机制，我们在此提出i）确定并比较这两种药物影响WT和GABAAR γ 2亚基杂合子小鼠成年期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γ 2小鼠中发生改变，并与焦虑和抑郁相关行为有关。这些研究将提醒抗抑郁药和抗焦虑药对发育中的出生后大脑的潜在有害影响，并将有助于描述对大脑发育的中性或可能有益的药物影响。此外，他们可能会推进专门针对儿童和青少年患者的抗抑郁和抗焦虑治疗的设计和安全性。 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越来越年轻的儿科患者，并且通常持续很长一段时间。这些药物作用于在儿童和青春期经历深刻的结构和功能变化的神经生物学底物，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，我们利用小鼠模型的焦虑抑郁症，以评估分子，细胞，内分泌和行为的后果，抗抑郁药物治疗的年轻动物的儿科患者的代表。这些研究将提醒抗抑郁药和抗焦虑药对发育中的出生后大脑的潜在有害影响，并将有助于描述有害的中性或可能有益的药物对大脑发育的影响。此外，他们可能会推进专门针对儿童和青少年患者的抗抑郁和抗焦虑治疗的设计和安全性。

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.