Sex differences in both the endocannabinoid system and stress responses have been established for decades. While there is ample evidence that the sexes respond differently to stress and that the endocannabinoid system is involved in this response, what is less clear is whether the endocannabinoid system mediates this response to stress differently in both sexes. Also, do the sexes respond similarly to exogenous cannabinoids (CBs) following stress? Can the administration of exogenous CBs normalize the effects of stress and if so, does this happen similarly in male and female subjects? This review will attempt to delineate the stress induced neurochemical alterations in the endocannabinoid system and the resulting behavioral changes across periods of development: prenatal, early neonatal or adolescent in males and females. Within this frame work, we will then examine the neurochemical and behavioral effects of exogenous CBs and illustrate that the response to CBs is determined by the stress history of the animal. The theoretical framework for this endeavor relates to the established effects of adverse childhood experiences (ACE) in increasing substance abuse, depression and anxiety and the possibility that individuals with high ACE scores may consume cannabinoids to "self-medicate". Overall, we see that while there are instances where exogenous cannabinoids "normalize" the adverse effects produced by early stress, this normalization does not occur in all animal models with any sort of consistency. The most compelling report where CB administration appears to normalize behaviors altered by early stress, shows minimal differences between the sexes (Alteba et al., 2016). This is in stark contrast to the majority of studies on early stress and the endocannabinoid system where both sexes are included and show quite divergent, in fact opposite, effects in males and females. Frequently there is a disconnect between neurochemical changes and behavioral changes and often, exogenous CBs have greater effects in stressed animals compared to non-stressed controls. This report as well as others reviewed here do support the concept that the effects of exogenous CBs are different in individuals experiencing early stress and that these differences are not equal in males and females. However, due to the wide variety of stressors used and the range of ages when the stress is applied, additional careful studies are warranted to fully understand the interactive effects of stress and the endocannabinoid system in males and females. In general, the findings do not support the statement that CB self-administration is an effective treatment for the adverse behavioral effects of early maltreatment in either males or females. Certainly this review should draw the attention of clinicians working with children, adolescents and adults exposed to early trauma and provide some perspective on the dysregulation of the endocannabinoid system in the response to trauma, the complex actions of exogenous CBs based on stress history and the unique effects of these factors in men and women.

中文翻译：

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早期生活压力和内源性大麻素系统相互作用的性别差异。

几十年来，内源性大麻素系统和压力反应的性别差异已经确立。虽然有充分的证据表明两性对压力的反应不同，并且内源性大麻素系统参与了这种反应，但不太清楚的是内源性大麻素系统是否在两性中以不同的方式介导了这种对压力的反应。此外，在压力后，两性对外源性大麻素 (CBs) 的反应是否相似？外源性 CB 的给药能否使压力的影响正常化，如果是这样，这在男性和女性受试者中是否会发生类似的情况？本综述将试图描述内源性大麻素系统中压力引起的神经化学变化以及由此产生的跨发育时期的行为变化：男性和女性的产前、新生儿早期或青春期。在这个框架内，然后，我们将检查外源性 CBs 的神经化学和行为影响，并说明对 CBs 的反应是由动物的应激历史决定的。这项努力的理论框架涉及不良童年经历 (ACE) 在增加药物滥用、抑郁和焦虑方面的既定影响，以及 ACE 评分高的人可能会消耗大麻素来“自我治疗”。总体而言，我们看到，虽然在某些情况下，外源性大麻素使早期压力产生的不利影响“正常化”，但这种正常化并非在所有具有任何一致性的动物模型中都发生。CB 管理似乎使早期压力改变的行为正常化的最引人注目的报告显示，两性之间的差异很小（Alteba 等，2016）。这与大多数关于早期压力和内源性大麻素系统的研究形成鲜明对比，其中包括两性，并且在男性和女性中显示出相当不同，实际上相反的影响。神经化学变化和行为变化之间经常存在脱节，而且与非应激对照相比，外源性 CB 对应激动物的影响通常更大。本报告以及此处审查的其他报告确实支持这样一个概念，即外源性 CB 的影响在经历早期压力的个体中是不同的，并且这些差异在男性和女性中并不相等。然而，由于使用的压力源种类繁多，施加压力的年龄范围也不同，因此需要进行额外的仔细研究，以充分了解压力与男性和女性内源性大麻素系统的相互作用。总的来说，研究结果不支持CB自我给药是对男性或女性早期虐待的不良行为影响的有效治疗的说法。当然，这篇综述应该引起与暴露于早期创伤的儿童、青少年和成人一起工作的临床医生的注意，并提供一些关于内源性大麻素系统在应对创伤时的失调、基于压力史的外源性 CB 的复杂行为和独特的这些因素对男性和女性的影响。