Cannabinoids reverse the effects of early stress on neurocognitive performance in adulthood.
Cannabinoids reverse the effects of early stress on neurocognitive performance in adulthood.
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DOI：
10.1101/lm.041608.116
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发表时间：
2016-07
期刊：
影响因子：
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通讯作者：
Akirav I
中科院分区：
文献类型：
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作者：
Alteba S;Korem N;Akirav I
早期生活压力（ES）显着增加精神病理学的倾向。大麻素可能会导致认知缺陷并加剧 ES 的影响。尽管如此，内源性大麻素系统已被建议作为治疗压力和焦虑相关疾病的治疗靶点。在这里，我们研究了在“青春期晚期”（18-25 岁的人类广泛使用大麻）期间服用大麻素是否可以逆转 ES 对成年期神经认知功能的长期不利影响。雄性和雌性大鼠在出生后第 7-14 天 (P) 暴露于 ES，在青春期后期 (P45-60) 注射大麻素 CB1/2 受体激动剂 WIN55,212-2 (WIN; 1.2 mg/kg, i.p.) 2 周，并在成年期 (P90) 测试工作记忆、焦虑和 CB1 受体 (CB1r) 的变化，以及压力回路中的糖皮质激素受体 (GR) [海马、前额皮质 (PFC) 和基底外侧杏仁核 (BLA)]。 ES男性和女性成年后在空间位置和社会识别任务中的短期记忆表现受损；男性在新物体识别任务中也受到损害。在青春期后期进行的 WIN 预防了这些压力引起的损伤并降低了焦虑水平。 WIN 使 ES 诱导的女性 PFC-GR 和 CA1-CB1r 上调正常化。在男性中，WIN 使 ES 诱导的 PFC-GR 上调和 BLA-CB1r 下调正常化。内源性大麻素系统在早期生活压力对成年行为的影响中发挥着至关重要的作用。认知记忆以及恐惧回路中 GR 和 CB1r 表达的差异表明应对压力的机制存在性别差异。
Early life stress (ES) significantly increases predisposition to psychopathologies. Cannabinoids may cause cognitive deficits and exacerbate the effects of ES. Nevertheless, the endocannabinoid system has been suggested as a therapeutic target for the treatment of stress- and anxiety-related disorders. Here we examined whether cannabinoids administered during “late adolescence” (extensive cannabis use in humans at the ages 18–25) could reverse the long-term adverse effects of ES on neurocognitive function in adulthood. Male and female rats were exposed to ES during post-natal days (P) 7–14, injected with the cannabinoid CB1/2 receptor agonist WIN55,212-2 (WIN; 1.2 mg/kg, i.p.) for 2 wk during late adolescence (P45–60) and tested in adulthood (P90) for working memory, anxiety, and alterations in CB1 receptors (CB1r), and glucocorticoid receptors (GRs) in the stress circuit [hippocampus, prefrontal cortex (PFC), and basolateral amygdala (BLA)]. ES males and females exhibited impaired performance in short-term memory in adulthood in the spatial location and social recognition tasks; males were also impaired in the novel object recognition task. WIN administered during late adolescence prevented these stress-induced impairments and reduced anxiety levels. WIN normalized the ES-induced up-regulation in PFC-GRs and CA1–CB1r in females. In males, WIN normalized the ES-induced up-regulation in PFC-GR and down-regulation in BLA-CB1r. There is a crucial role of the endocannabinoid system in the effects of early life stress on behavior at adulthood. Differences in recognition memory and in the expression of GRs and CB1r in the fear circuit suggest sex differences in the mechanism underlying coping with stress.