CANNABINOIDS AND THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

大麻素与下丘脑-垂体-肾上腺轴

• 批准号: 6378648
• 负责人: Laura Murphy
• 金额: $ 13.71万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6378648
• 关键词: adrenalectomy; adrenocorticotropic hormone; brain metabolism; cannabinoid receptor; cannabinoids; catalepsy; corticotropin releasing factor; diet route /schedule; eating; female; gene expression; glucocorticoids; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; in situ hybridization; laboratory rat; luteinizing hormone; marijuana abuse; neuroendocrine system; nutrition related tag; ovariectomy; protein purification; radioimmunoassay; serotonin receptor; substance abuse related behavior

The long-term objectives of this proposal are to advance our knowledge of the physiological effects of marijuana abuse and to elucidate the neuroendocrine function of the endogenous cannabinoid system. This proposal will focus on the effects of cannabinoids on the hypothalamic-pituitary-adrenal (HPA) axis, a system which plays a critical role in coordinating the neuroendocrine response to stress. The specific aims of this proposal address the ability of cannabinoids to stimulate adrenocorticotropin hormone (ACTH) and corticosteroid release in the female and understanding the role of corticotropin-releasing hormone (CRH) in this response. Furthermore, the role of CRH in the ability of cannabinoids to decrease luteinizing hormone (LH) and induce catalepsy and alterations in feeding behavior will be investigated. Moreover, the site and mechanisms by which cannabinoids elicit their effects on CRH release and the modulation of the CNS responsiveness to cannabinoids by corticosteroids will be investigated. Initially, the role of cannabinoid receptors in the ability of marijuana to alter hormone secretion and feeding behavior will be determined by examining the effects of specific cannabinoid receptor agonists (levonantradol,methanandamide) and antagonists (SR141716A) on ACTH, corticosteroid and LH secretion and feeding behaviors in OVX rats. Secondly, the role of CRH in the ability of THC to alter hormone release, feeding behavior and catalepsy will be determined by measuring hypothalamic CRH gene expression following acute treatment with cannabinoid receptor agonists. The role of CRH as mediator of cannabinoid effects will also be determined utilizing a CRH receptor antagonist (D-PheCRH12-41) and studying its ability to block cannabinoid action. Thirdly, the site and mechanism of cannabinoid action in the stimulation of the HPA axis will be determined by addressing the role of serotonin in the ability of cannabinoids to affect the HPA axis and by examining the hypothalamus, hippocampus, amygdala, raphe nuclei) as potential sites of cannabinoid action. Lastly, the ability of glucocorticoids to modulate cannabinoid actions on the HPA axis will be investigated. Our findings using female rats will not only address the potential neuroendocrine role of endogenous cannabinoids, but will provide new information on how cannabinoids modulate the HPA system; activation of which may have significant consequences on the endocrine, reproductive and immune systems of the human marijuana user.

该提案的长期目标是提高我们对滥用大麻的生理影响的了解，并阐明内源性大麻素系统的神经内分泌功能。 该建议将集中于大麻素对下丘脑 - 垂体 - 肾上腺（HPA）轴的影响，该系统在协调神经内分泌对压力的反应方面起着至关重要的作用。 该提案的具体目的涉及大麻素在女性中刺激肾上腺皮质激素激素（ACTH）和皮质类固醇释放的能力，并了解皮质激素释放激素（CRH）在此反应中的作用。 此外，将研究CRH在大麻素降低黄体生成激素（LH）和诱导衰减和喂养行为改变的能力中的作用。 此外，将研究大麻素对CRH释放产生影响的部位和机制，并将研究CNS对大麻素对大麻素的反应性。 最初，大麻素受体在大麻改变激素分泌和喂养行为的能力中的作用将通过检查特定的大麻素受体激动剂（Levonantradol，甲烷酰胺）和拮抗剂（SR141716A）对ACTH，COTTH，Corticostroid and LHHSTICOCTORIT和LHHESTIRITION和FEEDICERION CARIDIS的影响来确定。 其次，CRH在THC改变激素释放的能力中的作用将通过测量大麻素受体激动剂急性治疗后测量下丘脑CRH基因表达来确定。 CRH作为大麻素作用的介体的作用也将利用CRH受体拮抗剂（D-PhecrH12-41）确定，并研究其阻断大麻素作用的能力。 第三，通过解决5-羟色胺在影响HPA轴的能力中的作用以及检查下丘脑，海马，海马，杏仁核，Raphe nuclei，作为大麻素的潜在部位，可以确定大麻素作用在刺激HPA轴上的位点和机制。 最后，将研究糖皮质激素在HPA轴上调节大麻素作用的能力。 我们使用雌性大鼠的发现不仅可以解决内源性大麻素的潜在神经内分泌作用，而且还将提供有关大麻素如何调节HPA系统的新信息。激活可能会对人类大麻使用者的内分泌，生殖和免疫系统产生重大影响。