Mechanisms Underlying Sex-Specific Effects of Creatine Supplementation on Depress

描述（由申请人提供）：越来越多的证据支持肌酸（肌肉和脑组织能量稳态的关键调节剂）以抗抑郁方式发挥作用的潜力。研究表明，肌酸补充剂可以显着改善治疗难治性抑郁症的情绪，并假设肌酸改变脑化学的方式，增加抗抑郁治疗的可能性。在过去的两年里，我们的实验室一直在积极研究慢性肌酸补充剂对抑郁样行为的影响，使用强迫游泳试验，一种对改变人类抑郁症状的药物选择性敏感的动物模型。重要的是，这些研究表明，长期补充肌酸可导致抑郁样行为发生可靠的性别特异性改变（艾伦et al，2009）。具体而言，肌酸在女性中产生抗抑郁样作用，在男性中产生促抑郁作用。这些发现支持Renshaw et al（2001）的报告，即抑郁症女性（而非男性）嘌呤水平的改变与治疗反应相关。深入了解这些影响的机制具有重要的临床意义，因为人类抑郁症的患病率和治疗存在性别差异。初步研究表明，女性肌酸的抗抑郁作用可能是由雌激素或雌激素代谢物对肌酸激酶的磷酸化作用解释的，肌酸激酶是一种刺激大脑能量储存消耗的酶。本研究的主要目的是确定肌酸补充剂对抑郁样行为的性别特异性影响是否归因于使用经典激素操作范例进行强迫游泳测试时性腺类固醇的作用。也就是说，这项工作将评估肌酸的影响是否可以在没有卵巢或睾丸激素的情况下持续。第二个目的是检查肌酸和神经营养相关的神经元活动之间是否存在关系。有证据表明，肌酸和脑源性神经营养因子（BDNF）之间有许多共同的品质，BDNF是突触可塑性的重要介质，与抑郁症密切相关。脑源性神经营养因子与性腺类固醇相互作用，可能是肌酸诱导抑郁行为改变的分子机制之一。如果性依赖的行为表型持续性腺类固醇操作后，研究计划评估组织的影响，性激素对抑郁反应的雄性和雌性大鼠补充肌酸。假设雌激素介导肌酸的抗抑郁作用，并且肌酸和BDNF在雄性和雌性大鼠中差异表达。肌酸和行为的激素和神经营养变量的检查是新颖的，这些研究的生化数据将是有价值的，在阐明肌酸的行为效应的潜在机制。这些研究将填补关于肌酸补充剂对抑郁行为的性二态性神经和行为后果的知识空白。 公共卫生相关性：由于肌酸在大脑中的功能和临床意义越来越大，因此必须更充分地描述这种药物在情绪障碍病理生理学中的作用。此外，研究肌酸治疗后大鼠抑郁样行为性别差异的机制将深刻影响我们对肌酸及其与抑郁行为关系的理解，并可能导致性别特异性治疗策略。这项研究与公共健康利益高度相关，因为肌酸是迄今为止使用最广泛的营养补充剂之一，肌酸改变情绪的潜力可能直接影响抑郁症的管理。

DESCRIPTION (provided by applicant): Growing evidence supports the potential for creatine, a critical regulator of energy homeostasis in muscle and brain tissue, to function in an antidepressant manner. Studies indicate that creatine supplementation can significantly improve mood in treatment resistant depression, and it is hypothesized that creatine alters brain chemistry in a manner that increases the likelihood of response to antidepressant treatment. Over the last two years, our lab has been actively studying the effects of chronic creatine supplementation on depression-like behavior in rats using the forced swim test, an animal model that is selectively sensitive to agents that alter depressive symptoms in humans. Importantly, these studies show that long-term supplementation with creatine results in reliable sex-specific alterations in depression-like behavior (Allen et al, 2009). Specifically, creatine produces antidepressant-like effects in females and pro-depressant effects in males. These findings are supportive of the report by Renshaw et al (2001) that altered purine levels in depressed women, but not men, are associated with treatment response. Insight into the mechanisms underlying these effects is of great clinical importance as sex differences in the prevalence and treatment of depression in humans are widely reported. Preliminary research suggests the antidepressant-like effect of creatine in females may be explained by the phosphorylating action of estrogens or estrogenic metabolites upon creatine kinase, an enzyme that stimulates the consumption of brain energy stores. The primary aim of the present research is to determine whether the sex-specific effects of creatine supplementation on depression-like behavior are attributable to the actions of gonadal steroids at the time of forced swim testing using classic hormone manipulation paradigms. That is, this work will assess whether the effects of creatine can endure in the absence of ovarian or testicular hormones. A secondary aim is to examine whether there is a relationship between creatine and neurotrophic- related neuronal activity. Evidence points to a number of shared qualities among creatine and brain-derived neurotrophic factor (BDNF), an essential mediator of synaptic plasticity that is robustly linked with depression. BDNF diversely interacts with gonadal steroids and may be one molecular mechanism involved in the creatine- induced alterations in depressive behavior. If sex-dependent behavioral phenotypes persist after gonadal steroid manipulation, studies are planned to assess the organizational effects of sex hormones on depressive responsivity in male and female rats supplemented with creatine. It is hypothesized that estrogens mediate the antidepressant effects of creatine, and that creatine and BDNF are differentially expressed in male and female rats. The examination of hormonal and neurotrophic variables with creatine and behavior is novel, and the biochemical data from these studies will be valuable in elucidating the underlying mechanism of creatine's behavioral effects. Together these studies will fill critical gaps in knowledge regarding the sexually dimorphic neural and behavioral consequences of creatine supplementation on depressive behavior. PUBLIC HEALTH RELEVANCE: Given the mounting functional and clinical significance of creatine in the brain, it is essential to more fully characterize the role of this agent in the pathophysiology of mood disorders. Moreover, examining mechanisms underlying sex differences in depression-like behavior in rats in response to creatine treatment will profoundly affect our understanding of creatine, its relationship with depressive behavior, and may lead to sex-specific therapeutic strategies. This research is highly relevant to public health interests, as creatine is among the most extensively used nutritional supplements to date and the potential for creatine to alter mood may directly impact management of depression.