Effects of Chronic Cannabis Use on the Neuroendocrine Stress Response

长期吸食大麻对神经内分泌应激反应的影响

基本信息

批准号：
10439578
负责人：
Ryan Joseph McLaughlin
金额：
$ 7.65万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439578
关键词：
Acute Address Adrenal Glands Agonist Amygdaloid structure Animal Model Anterior Pituitary Gland Anxiety Attenuated Biological Brain CNR1 gene Cannabis Cell Nucleus Chronic Coping Skills Corticosterone Corticotropin Corticotropin-Releasing Hormone Cross-Sectional Studies Cues Data Dose Drug Delivery Systems Electronic cigarette Emotional Event Exhibits Exposure to FOS gene Female Foundations Future Harvest Hormones Human Hypothalamic structure Immediate-Early Genes Immunohistochemistry Intake Intoxication Label Laboratories Link Lung Mental Depression Metabolic Methodology Modeling Neurons Neurosecretory Systems Pharmaceutical Preparations Physiological Pituitary Gland Plasma Population Positioning Attribute Post-Traumatic Stress Disorders Prevalence Property Psychological Stress Publishing Radioimmunoassay Rattus Reporting Research Risk Risk Factors Rodent Route Self Administration Sex Differences Stress Swimming Technology Testing Tetrahydrocannabinol Training Volition Work acute stress arm biological adaptation to stress cannabinoid receptor cell type emotional stimulus hypothalamic-pituitary-adrenal axis intraperitoneal male marijuana use marijuana user neuropsychiatry novel novel strategies paraventricular nucleus peptide hormone pre-clinical psychologic recruit response sex sobriety stress reactivity stress related disorder stressor synthetic cannabinoid vapor

项目摘要

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.

项目摘要使用习惯大麻的最常见原因是应对压力。虽然这可能会提供急性有益作用，长期使用的长期影响，尤其是在无药物的情况下条件，仍然未知。我们已经证明了清醒的慢性大麻用户表现出钝相对于非用户，对急性实验室压力源的心理和身体反应。但是，这个横截面方法无法在大麻使用与压力反应。临床前动物模型在这方面尤其有利，但目前的模型大麻使用的方法学问题困扰着这些数据的转换性人群。为了解决这些局限性，我们的实验室使用小说生成了重要的新数据，大麻蒸气自动给药的翻译相关模型，该模型使用响应递送的递送含有高浓度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利用自然暴露于天然大麻提取物（而不是强制递送合成大麻素通过肺部给予的受体激动剂或孤立的大麻构成）这在人类用户中最常见。我们将在当前建议中使用这种方法来确定是否大麻蒸气自我给药会导致下丘脑的基本和压力诱导的激活发生变化男性和雌性大鼠的垂体 - 肾上腺（HPA）应力轴。在AIM 1中，我们将使用免疫组织化学来量化阶室核内不同细胞类型中立即的早期基因C-FOS的激活雄性和雌性大鼠的下丘脑的（PVN）接受自我管理的大麻浓度不同或车辆蒸气。在AIM 2中，我们将对从大麻暴露的等离子体进行放射免疫测定在压力和无压力条件下的不暴露大鼠，以确定慢性自愿的程度大麻暴露改变了基础和压力诱导的肾上腺皮质激素（ACTH）和皮质酮（Cort）。此外，将提取大脑以评估促肾上腺素释放马酮（CRH）在压力下暴露于大麻和不暴露大鼠的杏仁核的中央核中的肽含量或无压力条件。我们预测，受过训练为自动大麻蒸气的大鼠将存在剂量 - 基本CORT，减弱应力诱导的CRH阳性PVN神经元激活的依赖升高，增加对被动应对策略的依赖，并招募ACTH，CORT和CRH内容相对于车辆暴露的大鼠。这些研究的结果将为理解长期的基础慢性大麻使用的后果，使我们能够确定大麻使用之间的因果关系压力反应性。此外，这项工作将支持未来研究的可行性，这将调查这些影响的基础机制，并确定压力反应中的改变是否是危险因素开发有问题的大麻使用。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A review of the effects of acute and chronic cannabinoid exposure on the stress response.

DOI：
10.1016/j.yfrne.2021.100945
发表时间：
2021-10
期刊：
Frontiers in neuroendocrinology
影响因子：
7.4
作者：
Glodosky NC;Cuttler C;McLaughlin RJ
通讯作者：
McLaughlin RJ

Cannabis vapor self-administration elicits sex- and dose-specific alterations in stress reactivity in rats.

大麻蒸气自我给药会引起大鼠应激反应性的性别和剂量特异性改变。

DOI：
10.1016/j.ynstr.2020.100260
发表时间：
2020-11
期刊：
Neurobiology of stress
影响因子：
5
作者：
Glodosky NC;Cuttler C;Freels TG;Wright HR;Rojas MJ;Baglot SL;Hill MN;McLaughlin RJ
通讯作者：
McLaughlin RJ