Chronic Stress or Psychostimulants on Central and Autonomic Nervous Systems

描述（由申请人提供）：行为压力在我们的社会中是不可避免的。 不幸的是，有些人对压力情况没有做出适当的反应。 其中一些人通过使用非法的精神兴奋剂寻求缓解。 在许多方面，这些药物对身体的影响与急性暴露于行为压力非常相似。 因此，使用非法药物可能也会激活许多使个人处于紧张状态的因素。 该提案旨在确定压力和精神兴奋剂使用之间的长期影响和相互作用。 在一些清醒的Sprague-Dawley大鼠中，可卡因或惊吓引起全身血管阻力（SVR）和肾交感神经活动的显著增加，同时心输出量（CO）减少。 我们将这些动物指定为血管反应者。 相比之下，我们确定为混合反应者的大鼠SVR增加较小，相反，对可卡因或惊吓的CO增加。 与混合反应者相比，血管反应者对可卡因诱导的心肌病和高血压更敏感。 我们的数据表明，这些群体之间的主要差异是血管反应者在应对压力或精神兴奋剂时具有更大的中枢神经系统介导的交感神经兴奋。 我们建议研究慢性行为应激的影响，使用居民-入侵者范式，或慢性精神兴奋剂，使用可卡因，对惊吓和可卡因的急性反应。 我们假设，反复暴露于压力或精神兴奋剂将最初增强，然后减弱自主神经和下丘脑-垂体轴（HPA）的反应，急性压力或精神兴奋剂在更大程度上在血管反应比混合反应。 此外，我们提出，反应性的差异将反映在下丘脑和边缘系统的神经肽受体或肽的表达和心脏细胞凋亡的变化。 最后，我们提出，中枢神经系统的变化与反复的压力将类似于那些引起的反复精神兴奋剂管理。 我们将比较慢性应激和/或精神兴奋剂的影响，并确定是否有交叉耐受性的自主神经，神经内分泌和神经化学反应，这些刺激。 此外，我们已经确定了两个近交系的大鼠，类似于血管和混合反应。 我们建议以与远交Sprague-Dawley大鼠相似的方式对其进行研究。 换句话说，我们建议，更大的神经递质表达的变化将是明显的血管反应亚株。 这些研究将结合联合收割机研究人员的专业知识，研究血流动力学和自主反应性、神经内分泌指数和中枢神经元回路，以确定在已知对心血管疾病敏感或耐药的模型中使用应激或精神兴奋剂的长期影响。 这些结果将阐明中枢自主神经和神经内分泌对压力和精神兴奋剂反应的相似性和差异。

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.