Golub Mari S, Hackett Edward P, Hogrefe Casey E, Leranth Csaba, Elsworth John D, Roth Robert H
Department of Environmental Toxicology, University of California, Davis, CA, USA.
California National Primate Research Center, University of California, Davis, CA, USA.
Dev Cogn Neurosci. 2017 Aug;26:52-61. doi: 10.1016/j.dcn.2017.04.008. Epub 2017 May 1.
Potential long term effects on brain development are a concern when drugs are used to treat depression and anxiety in childhood. In this study, male juvenile rhesus monkeys (three-four years of age) were dosed with fluoxetine or vehicle (N=16/group) for two years. Histomorphometric examination of cortical dendritic spines conducted after euthanasia at one year postdosing (N=8/group) suggested a trend toward greater dendritic spine synapse density in prefrontal cortex of the fluoxetine-treated monkeys. During dosing, subjects were trained for automated cognitive testing, and evaluated with a test of sustained attention. After dosing was discontinued, sustained attention, recognition memory and cognitive flexibility were evaluated. Sustained attention was affected by fluoxetine, both during and after dosing, as indexed by omission errors. Response accuracy was not affected by fluoxetine in post-dosing recognition memory and cognitive flexibility tests, but formerly fluoxetine-treated monkeys compared to vehicle controls had more missed trial initiations and choices during testing. Drug treatment also interacted with genetic and environmental variables: MAOA genotype (high- and low transcription rate polymorphisms) and testing location (upper or lower tier of cages). Altered development of top-down cortical regulation of effortful attention may be relevant to this pattern of cognitive test performance after juvenile fluoxetine treatment.
在使用药物治疗儿童抑郁症和焦虑症时，对大脑发育的潜在长期影响令人担忧。在这项研究中，雄性幼年恒河猴（3至4岁）被给予氟西汀或赋形剂（每组N = 16只），持续两年。给药后一年安乐死时进行的皮质树突棘组织形态计量学检查（每组N = 8只）表明，氟西汀治疗组猴子前额叶皮质中树突棘突触密度有增加的趋势。给药期间，对实验对象进行自动认知测试训练，并通过持续注意力测试进行评估。停药后，对持续注意力、识别记忆和认知灵活性进行评估。以遗漏错误为指标，氟西汀在给药期间和给药后均对持续注意力有影响。在给药后的识别记忆和认知灵活性测试中，氟西汀对反应准确性没有影响，但与赋形剂对照组相比，曾接受氟西汀治疗的猴子在测试过程中更多地错过试验启动和选择。药物治疗还与遗传和环境变量相互作用：MAOA基因型（高转录率和低转录率多态性）和测试位置（笼子的上层或下层）。幼年氟西汀治疗后，自上而下的皮质对努力注意力的调节发育改变可能与这种认知测试表现模式有关。
