CANNABINOIDS AND THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

本提案的长期目标是提高我们对大麻滥用的生理效应的认识，并阐明内源性大麻素系统的神经内分泌功能。该提案将重点关注大麻素对下丘脑-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中起关键作用。本提案的具体目的是解决大麻素刺激女性促肾上腺皮质激素（ACTH）和皮质类固醇释放的能力，并了解促肾上腺皮质激素释放激素（CRH）在这一反应中的作用。此外，CRH在大麻素降低黄体生成素（LH）、诱导猝睡和摄食行为改变中的作用将被研究。此外，大麻素对CRH释放的影响以及皮质类固醇调节CNS对大麻素的反应性的位点和机制将被研究。首先，大麻素受体在大麻改变激素分泌和摄食行为能力中的作用将通过检测特定大麻素受体激动剂（左旋antradol、甲胺）和拮抗剂（SR141716A）对OVX大鼠ACTH、皮质类固醇和LH分泌和摄食行为的影响来确定。其次，在使用大麻素受体激动剂急性治疗后，通过测量下丘脑CRH基因表达来确定CRH在四氢大麻酚改变激素释放、摄食行为和猝睡能力中的作用。CRH作为大麻素作用中介的作用也将利用CRH受体拮抗剂（D-PheCRH12-41）来确定，并研究其阻断大麻素作用的能力。第三，通过研究5 -羟色胺在大麻素影响HPA轴中的作用，以及下丘脑、海马、杏仁核、中叶核等大麻素可能作用的部位，确定大麻素刺激HPA轴的部位和机制。最后，糖皮质激素调节大麻素在HPA轴上的作用的能力将被研究。我们使用雌性大鼠的研究结果不仅将解决内源性大麻素的潜在神经内分泌作用，而且将提供大麻素如何调节HPA系统的新信息；它的激活可能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。

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.