Sex differences in opioid regulation of the rat locus coeruleus in rats

描述(由申请人提供)：性别越来越被认为是神经精神疾病流行和严重程度的一个重要因素。值得注意的是，女性比男性更有可能患有抑郁症和焦虑症，而且有假设认为，这种性别差异是压力反应系统差异的结果。功能失调的应激反应与大量的神经精神疾病有关，如抑郁症和创伤后应激障碍(PTSD)。这些疾病的性别差异的基础可能存在于蓝斑(LC)-去甲肾上腺素(NE)系统，这是大脑中的一个主要的应激反应系统，被认为在应激相关的精神障碍中调节失调。在应激过程中，LC-NE系统被促肾上腺皮质激素释放因子(CRF)激活，CRF是应激反应的主要媒介。同时，内源性阿片神经肽对LC活性产生抑制作用，抑制CRF的激活，并在应激源终止时促进恢复到基线活性。CRF和阿片类药物对LC-NE系统的相反调节的任何不平衡都可能影响应激敏感性，并增强对应激的脆弱性。在LC水平上，性别差异可以通过对CRF或内源性阿片类药物敏感性的差异来表现。我们的实验室最近鉴定了LC中CRF受体功能的性别差异，这些差异使雌性大鼠对应激更敏感。值得注意的是，来自对人类和啮齿动物的止痛药研究的证据表明，雌性对鸦片类药物不那么敏感。如果这推广到LC-NE系统，它将是 另一个因素是女性的系统对压力的敏感度增加。基于这些观察结果和内源性阿片类物质在抑制应激相关LC神经元激活中的重要作用，本研究将检验以下假设：与雄性相比，女性对Lc的抑制作用减弱，这一特征增加了她们对应激的易感性。这项研究将结合电生理学、生化和行为学方法，据我所知，将是第一组专注于阿片类药物对雌性啮齿动物神经元影响的研究，以及它们对雄性啮齿动物影响的比较。目的1比较雌性和雄性大鼠对阿片激动剂Amgo的LC神经元反应。目的2将确定重复的社会应激是否像已在雄性大鼠中所记录的那样，在雌性大鼠的LC中参与内源性阿片类药物。目标3将使用生化方法来检查细胞机制，这些机制可能有助于LC阿片系统中不同的性别生理。

DESCRIPTION (provided by applicant): Sex is increasingly recognized as an important factor in the prevalence and severity of neuropsychiatric diseases. Notably, women are more likely than men to have depression and anxiety-related disorders, and it has been hypothesized that this sex difference results from differences in stress response systems. Dysfunctional stress responses are associated with a vast number of neuropsychiatric conditions, such as depression and post-traumatic stress disorder (PTSD). The basis for sex differences in these disorders may reside in the locus coeruleus (LC)-norepinephrine (NE) system, a major stress response system in the brain that is thought to be dysregulated in stress-related psychiatric disorders. During stress, the LC-NE system is activated by corticotropin releasing factor (CRF), a primary mediator of the stress response. At the same time endogenous opioid neuropeptides provide an inhibitory influence on LC activity that restrains CRF activation and facilitates a retun to baseline activity when the stressor is terminated. Any imbalance in the opposing regulation of the LC-NE system by CRF and opioids could influence stress-sensitivity and enhance vulnerability to stress. At the level of the LC, sex differences could be expressed through differences in sensitivity to either CRF or to endogenous opioids. Our laboratory recently characterized sex differences in CRF receptor function in the LC that render female rats more sensitive to stress. Notably, evidence from analgesic studies in both humans and rodents suggest that females are less sensitive to opiates. If this generalized to the LC-NE system, it be an additional factor contributing to increased sensitivity of the system in females to stress. Based on these observations and the important role of endogenous opioids in restraining stress-related activation of LC neurons, this research will test the hypothesis that MOR induced inhibition of the LC is attenuated in females as compared to males and this feature increases their vulnerability to stress. This research will integrate electrophysiological, biochemical and behavioral approaches and to my knowledge, will be the first set of studies focused on the neuronal effects of opiates in female rodents and the comparison to their effects in male rodents. Aim 1 will compare the LC neuronal responses to the opioid agonist, AMGO, between female and male rats. Aim 2 will determine whether repeated social stress engages endogenous opioids in the LC of female rats as has been documented in male rats. Aim 3 will use biochemical approaches to examine cellular mechanisms that could contribute to sexually distinct physiology in the LC opioid system.