HYPOTHALAMIC PITUITARY ADRENAL AXIS AND NEUROBEHAVIORAL EFFECTS OF COCAINE

最近的研究表明，下丘脑-垂体-肾上腺 (HPA)轴在可卡因的行为效应中。可卡因诱导 糖皮质激素释放(如皮质酮、ACTH)可能是由于 促肾上腺皮质激素释放因子。一般说来，增加的治疗 这些荷尔蒙水平会增强可卡因的一些行为效应， 而降低这些荷尔蒙水平的治疗会减弱一些 这些影响。这包括激活HPA轴的应激源暴露。 并放大了可卡因的行为影响。而且，更大的行为 对可卡因的反应性与固有的高HPA轴有关 荷尔蒙水平。HPA轴功能存在固有差异 两个近交系，Lewis和Fischer 344(F344)大鼠，它们在 他们对精神活性药物的行为和生化反应。刘易斯 与F344大鼠相比，大鼠表现出更高的敏感度和偏好 为了可卡因。这些菌株在几个生化方面也有所不同。 中脑边缘多巴胺系统的特征--一个相关的神经区 与药物反应有关。矛盾的是，Lewis大鼠削弱了HPA荷尔蒙 活动和受损的自身免疫反应。HPA轴激素 与免疫系统相互作用(例如，ACTH诱导释放一些 细胞因子)可能对细胞因子的关系有重要意义 免疫疾病，如艾滋病毒感染和可卡因滥用。这 Grant将比较HPA轴的各种操作(例如， 糖皮质激素应用肾上腺切除术、CRF抗血清和拮抗剂 管理、压力暴露)会影响神经行为反应 Lewis和F344大鼠中的可卡因；这些菌株提供了研究的模型 神经内分泌和免疫系统的相互作用及其研究 对药物滥用的脆弱性。行为测量将包括运动 活动、场所调节、药物歧视和自我管理。 生化措施将包括许多信号转导蛋白(例如， 酪氨酸羟化酶，蛋白激酶A)在VTA/NAcc中被特异性调节 通过慢性药物或压力暴露。此外，与ACTH相关的水平 将对细胞因子进行评估。这些研究可能会提供对 可卡因滥用可能有不同的病因和治疗方法。

Recent research suggests a role for the hypothalamic-pituitary-adrenal (HPA) axis in the behavioral effects of cocaine. Cocaine induces glucocorticoid release (e.g., corticosterone, ACTH) probably due to corticotropin releasing factor (CRF). In general, treatments that increase levels of these hormones enhance some behavioral effects of cocaine, whereas treatments that decrease levels of these hormones attenuate some of these effects. This includes stressor exposure that activates the HPA axis and amplifies the behavioral effects of cocaine. And, greater behavioral responsivity to cocaine has been related to inherently high HPA axis hormone levels. Inherent differences in HPA axis function exist between two inbred strains, lewis and Fischer 344 (F344) rats, which also differ in their behavioral and biochemical responses to psychoactive drugs. Lewis rats, compared to F344 rats, exhibit enhanced sensitivity to and preference for cocaine. These strains also differ in several biochemical characteristics of the mesolimbic dopamine system, a neural area associated with drug responses. Paradoxically, Lewis rats have blunted HPA hormonal activity and impaired autoimmune responses. That HPA axis hormones interact with the immune system (e.g., ACTH induces release of some cytokines) may have important implications for the relationship of immunological diseases, such as HIV infection, and cocaine abuse. This grant will compare how various manipulations of the HPA axis (e.g., glucocorticoid administration adrenalectomy, CRF antiserum and antagonist administration, stress exposures) affect the neurobehavioral responses to cocaine in Lewis and F344 rats; these strains provide models both to study interactions of the neuroendocrine and immune systems and to study vulnerability to drug abuse. Behavioral measures will include locomotor activity, place conditioning, drug discrimination, and self-administration. Biochemical measures will include many signal transduction proteins (e.g, tyrosine hydroxylase, protein kinase A) regulated specifically in VTA/NAcc by chronic drug or stress exposure. In addition, levels of ACTH-related cytokines will be assessed. These studies may provide insight into possible differing etiologies and treatment approaches for cocaine abuse.