Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
Neuroscience. 2013 Apr 16;236:298-312. doi: 10.1016/j.neuroscience.2013.01.040. Epub 2013 Jan 30.
Exposure to severe stress leads to development of neuropsychiatric disorders, including depression and Post-Traumatic Stress Disorder (PTSD) in at-risk individuals. Neuropeptide Y (NPY) is associated with resilience or improved recovery. Therefore exogenous administration to the brain has therapeutic potential although peripheral administration can trigger undesirable side effects. Here, we established conditions with intranasal (IN) NPY infusion to rats to obtain CSF concentrations in the proposed anxiolytic range without significant change in plasma NPY. Rats were pretreated with IN NPY or vehicle before exposure to single prolonged stress (SPS) animal model of PTSD and compared to untreated controls. The IN NPY appeared to lessen the perceived severity of stress, as these animals displayed less time immobile in forced swim part of the SPS. Thirty minutes after SPS the elevation of plasma adrenocorticotropic hormone (ACTH) and corticosterone was not as pronounced in NPY-infused rats and the induction of tyrosine hydroxylase (TH) in locus coeruleus (LC) was attenuated. Seven days after SPS, they displayed lower depressive-like behavior on Forced Swim Test and reduced anxiety-like behavior on Elevated Plus Maze. The prolonged effect of SPS on Acoustic Startle Response was also lower in NPY-infused rats. Plasma ACTH, corticosterone, and hippocampal glucocorticoid receptor levels were significantly above controls only in the vehicle - but not IN NPY-treated group 1week after SPS. Baseline TH mRNA levels in LC did not differ among groups, but increased with forced swim in the vehicle - but not NPY-pretreated animals. Administration of IN NPY after exposure to SPS led to similar, but not identical, reduction in development of anxiety, depressive-like behavior and hyperarousal. The results show that single IN NPY can alter stress-triggered dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and activation of central noradrenergic activity. These findings provide proof of concept for potential of IN NPY for non-invasive prophylactic treatment or early intervention in response to traumatic stress.
暴露于严重的压力会导致神经精神疾病的发展，包括易患个体的抑郁症和创伤后应激障碍（PTSD）。神经肽 Y（NPY）与韧性或改善恢复有关。因此，尽管外周给药会引发不良副作用，但脑内给药具有治疗潜力。在这里，我们通过鼻腔内（IN）NPY 输注建立了条件，以使 CSF 浓度达到拟用于抗焦虑的范围，而血浆 NPY 没有明显变化。在暴露于 PTSD 的单延长应激（SPS）动物模型之前，大鼠用 IN NPY 或载体预处理，并与未处理的对照组进行比较。IN NPY 似乎减轻了应激的严重程度，因为这些动物在 SPS 的强迫游泳部分中表现出更少的不动时间。在 SPS 后 30 分钟，NPY 输注大鼠的血浆促肾上腺皮质激素（ACTH）和皮质酮升高不那么明显，蓝斑核（LC）中的酪氨酸羟化酶（TH）诱导减弱。SPS 后 7 天，它们在强迫游泳试验中表现出较低的抑郁样行为，在高架十字迷宫上表现出较低的焦虑样行为。NPY 输注大鼠的声音惊吓反应的延长效应也较低。SPS 后 1 周，仅在载体组而非 IN NPY 处理组中，血浆 ACTH、皮质酮和海马糖皮质激素受体水平明显高于对照组。LC 中的基础 TH mRNA 水平在各组之间没有差异，但在载体组中，在强迫游泳后增加，但在 NPY 预处理动物中没有增加。在 SPS 暴露后给予 IN NPY 导致焦虑、抑郁样行为和过度觉醒的发展相似但不完全相同的减少。结果表明，单次 IN NPY 可以改变应激触发的下丘脑-垂体-肾上腺（HPA）轴失调和中枢去甲肾上腺素能活性的激活。这些发现为 IN NPY 用于创伤应激的非侵入性预防性治疗或早期干预提供了概念验证。
