Effects of Chronic Stress or Psychostimulants on CNS and ANS

描述(申请人提供)：在我们的社会中，行为压力是不可避免的。不幸的是，有些人对压力环境没有做出适当的反应。其中一些人通过使用非法的精神刺激剂寻求缓解。在许多方面，这些药物对身体的影响与行为压力的急性暴露非常相似。因此，许多使个人产生压力的因素很可能也会被非法药物的使用所激活。这项建议旨在确定压力和精神刺激剂使用之间的长期影响和相互作用。在一些清醒的Spraogue-Dawley大鼠中，可卡因或惊厥引起全身血管阻力(SVR)和肾交感神经活动的显著增加，同时心输出量(CO)减少。我们已经指定这些动物为血管反应者。相反，我们识别为混合反应者的大鼠SVR增加较小，相反，可卡因或惊吓引起的CO增加。与混合反应者相比，血管反应者更容易患上可卡因引起的心肌病和高血压。我们的数据表明，这些组之间的主要区别是血管反应者对应激或精神刺激剂有更大的中枢神经系统介导的交感兴奋。我们建议使用居民-入侵者范式，或使用可卡因的慢性精神刺激剂，研究慢性行为应激对惊吓和可卡因的急性反应的影响。我们假设，与混合反应者相比，血管反应者反复暴露于应激或精神刺激剂会首先增强然后减弱自主神经和下丘脑-垂体轴(HPA)对急性应激或精神刺激剂的反应。此外，我们认为，反应性的差异将反映在下丘脑和边缘神经肽受体或多肽表达的变化和心脏细胞凋亡上。最后，我们提出，与反复应激相关的中枢神经系统变化将类似于反复给予精神刺激剂所引起的变化。我们将比较慢性应激和/或精神刺激剂的影响，并确定对这些刺激的自主神经、神经内分泌和神经化学反应是否存在交叉耐受。此外，我们还鉴定了两个近交系大鼠的亚系，它们类似于血管反应和混合反应。我们建议以类似于杂交的Spraogue-Dawley大鼠的方式来研究它们。换句话说，我们认为神经递质表达的更大变化将在血管反应器子品系中明显。这些研究将结合研究血流动力学和自主神经反应性、神经内分泌指数和中枢神经回路的研究人员的专业知识，以确定在已知对心血管疾病敏感或抵抗的模型中使用应激或精神刺激剂的长期影响。这一结果将阐明中枢自主神经和神经内分泌对压力和精神刺激剂反应的异同。

DESCRIPTION (provided by applicant): Behavioral stress is unavoidable in our society. Unfortunately, some individuals do not respond appropriately to stressful situations. A number of those seek relief by using illegal psychostimulants. In many regards, these drugs have very similar effects on the body as acute exposure to behavioral stress. Therefore, it is likely that many of the factors that condition individuals to stress may also be activated by the use of illicit drugs. This proposal is designed to determine the long-term effects and interactions between stress and psychostimulant use. In some conscious Sprague-Dawley rats, cocaine or startle evoke substantial increases in systemic vascular resistance (SVR) and renal sympathetic nerve activity concurrent with reductions in cardiac output (CO). We have designated these animals vascular responders. In contrast, rats we identify to be mixed responders have smaller increases in SVR and, instead, an increase in CO in response to cocaine or startle. Vascular responders are more susceptible to cocaine induced cardiomyopathies and hypertension compared to mixed responders. Our data suggest that the primary difference between these groups is that vascular responders have greater CNS-mediated sympathoexcitation in response to stress or psychostimulants. We propose to study the effects of chronic behavioral stress, using the resident-intruder paradigm, or chronic psychostimulants, using cocaine, on acute responses to startle and to cocaine. We hypothesize that repeated exposure to stress or psychostimulants will initially enhance then attenuate autonomic and hypothalamic-pituitary axis (HPA) responsiveness to acute stress or psychostimulants to a greater extent in vascular responders than mixed responders. Moreover, we propose that the differences in responsiveness will be reflected in changes in hypothalamic and limbic neuropeptide receptor or peptide expression and cardiac apoptosis. Finally, we propose that the CNS changes associated with repeated stress will resemble those elicited by repeated psychostimulant administration. We will compare the effects of chronic stress and/or psychostimulants and determine whether there is cross-tolerance regarding the autonomic, neuroendocrine and neurochemical responses to these stimuli. In addition, we have identified two inbred sub-strains of rats that resemble vascular and mixed responders. We propose to study them in a similar manner as the outbred Sprague-Dawley rats. In other words, we propose that greater alterations in neurotransmitter expression will be apparent in the vascular responder sub-strain. These studies will combine the expertise of investigators studying hemodynamic and autonomic responsivity, neuroendocrine indices and central neuronal circuitry to determine the long-term effects of stress or psychostimulant use in models known to be sensitive or resistant to cardiovascular disease. The results will illuminate the similarities and differences in central autonomic and neuroendocrine responsiveness to stress and psychostimulants.