Adolescence is a developmental stage in which the incidence of psychiatric disorders, such as anxiety disorders, peaks. Selective serotonin reuptake inhibitors (SSRIs) are the main class of agents used to treat anxiety disorders. However, the impact of SSRIs on the developing brain during adolescence remains unknown. The authors assessed the impact of developmentally timed SSRI administration in a genetic mouse model displaying elevated anxiety-like behaviors.

Knock-in mice containing a common human single-nucleotide polymorphism (Val66Met; rs6265) in brain-derived neurotrophic factor (BDNF), a growth factor implicated in the mechanism of action of SSRIs, were studied based on their established phenotype of increased anxiety-like behavior. Timed administration of fluoxetine was delivered during one of three developmental periods (postnatal days 21–42, 40–61, or 60–81), spanning the transition from childhood to adulthood. Neurochemical and anxiety-like behavioral analyses were performed.

We identified a “sensitive period” during periadolescence (postnatal days 21–42) in which developmentally timed fluoxetine administration rescued anxiety-like phenotypes in BDNF Val66Met mice in adulthood. Compared with littermate controls, BDNF^Met/Met mice exhibited diminished maturation of serotonergic fibers projecting particularly to the prefrontal cortex, as well as decreased expression of the serotonergic trophic factor S100B in the dorsal raphe. Interestingly, deficient serotonergic innervation, as well as S100B levels, were rescued with fluoxetine administration during periadolescence.

These findings suggest that SSRI administration during a “sensitive period” during periadolescence leads to long-lasting anxiolytic effects in a genetic mouse model of elevated anxiety-like behaviors. These persistent effects highlight the role of BDNF in the maturation of the serotonin system and the capacity to enhance its development through a pharmacological intervention.

青春期是一个发展阶段，其中精神疾病（例如焦虑症）的发生率达到顶峰。选择性5-羟色胺再摄取抑制剂（SSRIs）是用于治疗焦虑症的主要药物。然而，SSRIs在青春期对发育中的大脑的影响仍然未知。作者评估了发育中定时SSRI给药对表现出焦虑样行为增加的遗传小鼠模型的影响。

基于已确定的焦虑-情绪增加表型，研究了在脑源性神经营养因子（BDNF）中含有常见人类单核苷酸多态性（Val66Met; rs6265）的敲入小鼠。喜欢的行为。在从儿童期到成年期的三个发育阶段之一（出生后21-42、40-61或60-81天）中，定时给予氟西汀治疗。进行了神经化学和焦虑样行为分析。

我们在青春期（出生后21-42天）期间确定了一个“敏感时期”，在该时期中发育定时的氟西汀给药挽救了成年BDNF Val66Met小鼠的焦虑样表型。与同窝对照相比，BDNF ^{Met / Met}小鼠的浆膜神经营养纤维的成熟减少，特别是投射到额叶前额叶，以及浆膜中浆膜神经营养因子S100B的表达降低。有趣的是，在青春期期间通过氟西汀给药可以挽救缺乏的血清素能神经支配以及S100B水平。

这些发现表明，在青春期“敏感期”内使用SSRI可以在焦虑样行为增加的遗传小鼠模型中产生长期的抗焦虑作用。这些持续的作用突出了BDNF在5-羟色胺系统成熟中的作用以及通过药理学干预促进其发展的能力。