Effects of Chronic Cannabis Use on the Neuroendocrine Stress Response

项目摘要 习惯性使用大麻的最常见原因是科普压力。虽然这可能会提供 长期使用大麻的长期后果，特别是在无毒品的情况下， 条件，仍然未知。我们已经证明，清醒的慢性大麻使用者表现出迟钝， 相对于非使用者，对急性实验室应激源的心理和生理反应。但这 跨部门方法排除了在大麻使用和吸毒之间建立因果关系的能力， 应激反应在这方面，临床前动物模型是特别有利的，然而，目前的动物模型在这方面是非常有利的。 大麻使用一直受到方法问题的困扰，这些问题限制了这些数据对人类的可翻译性。 人口。为了解决这些局限性，我们的实验室使用一种新的， 大麻蒸汽自我给药的预防相关模型，其使用响应-视情况递送 含有高浓度Δ9四氢大麻酚的汽化大麻提取物。这种方法是独一无二的 因为它使用自愿暴露于天然大麻提取物（而不是强制递送合成大麻素 受体激动剂或分离的大麻成分）通过肺部给药途径递送 这在人类用户中最为常见。我们将在目前的建议中采用这种方法，以确定是否 大麻蒸汽自我给药引起下丘脑的基础和应激诱导的激活的改变， 垂体-肾上腺（HPA）应激轴。在目标1中，我们将使用免疫组织化学来 定量室旁核内不同类型细胞中即刻早期基因c-fos的激活 (PVN)训练雄性和雌性大鼠自我服用不同浓度的大麻， 或车辆蒸汽。在目标2中，我们将对从暴露于大麻的患者中收集的血浆进行放射免疫测定。 和非暴露大鼠在应激和无应激条件下，以确定慢性意志性 大麻暴露改变了基础和应激诱导的促肾上腺皮质激素（ACTH）的募集， 皮质酮（CORT）。此外，将提取大脑以评估促肾上腺皮质激素释放激素（CRH） 应激状态下大麻染毒与非染毒大鼠杏仁中央核内肽含量的变化 或无压力条件下。我们预测接受过自我注射大麻蒸汽训练的老鼠会表现出剂量- 依赖性升高基础CORT，减弱应激诱导的CRH阳性PVN神经元激活， 增加对被动应对策略的依赖，抑制ACTH、CORT和CRH含量的募集 相对于接触溶剂的大鼠。这些研究的结果将为理解长期的 慢性大麻使用的后果，并使我们能够确定大麻使用和 应激反应性。此外，这项工作将支持未来研究的可行性， 这些影响的潜在机制，并确定压力反应的改变是否是一个危险因素， 滥用大麻的问题

PROJECT SUMMARY The most commonly cited reason for habitual cannabis use is to cope with stress. Although this may provide acute beneficial effects, the long-term ramifications of chronic cannabis use, particularly under drug-free conditions, remain unknown. We have demonstrated that sober chronic cannabis users display blunted psychological and physiological responses to an acute laboratory stressor relative to non-users. However, this cross-sectional approach precludes the ability to establish causal relationships between cannabis use and the stress response. Preclinical animal models are particularly advantageous in this respect, yet current models of cannabis use have been plagued by methodological concerns that limit the translatability of these data to human populations. To address these limitations, our laboratory has generated important new data using a novel, translationally relevant model of cannabis vapor self-administration that uses response-contingent delivery of vaporized cannabis extracts containing high concentrations of Δ9 tetrahydrocannabinol. This approach is unique in that it uses volitional exposure to natural cannabis extracts (rather than forced delivery of synthetic cannabinoid receptor agonists or isolated cannabis constituents) that are delivered via the pulmonary route of administration that is most common in human users. We will use this approach in the current proposal to determine whether cannabis vapor self-administration causes alterations in basal and stress-induced activation of the hypothalamic- pituitary-adrenal (HPA) stress axis in male and female rats. In Aim 1, we will use immunohistochemistry to quantify activation of the immediate early gene c-fos in different cell types within the paraventricular nucleus (PVN) of the hypothalamus of male and female rats trained to self-administer varying concentrations of cannabis or vehicle vapor. In Aim 2, we will perform radioimmunoassays on plasma harvested from cannabis-exposed and non-exposed rats in stress and no-stress conditions to determine the extent to which chronic volitional cannabis exposure alters basal and stress-induced recruitment of adrenocorticotropic hormone (ACTH) and corticosterone (CORT). Additionally, brains will be extracted to assess corticotropin-releasing hormone (CRH) peptide content in the central nucleus of the amygdala of cannabis-exposed and non-exposed rats under stress or non-stress conditions. We predict that rats trained to self-administer cannabis vapor will exhibit dose- dependent elevations in basal CORT, attenuated stress-induced activation of CRH-positive PVN neurons, increased reliance on passive coping strategies, and dampened recruitment of ACTH, CORT and CRH content relative to vehicle-exposed rats. Results from these studies will provide a foundation for understanding long-term consequences of chronic cannabis use and allow us to identify causal relationships between cannabis use and stress reactivity. Moreover, this work will support the feasibility of future studies that will investigate the mechanisms underlying these effects and identify whether alterations in the stress response are a risk factor for developing problematic cannabis use.