Nahvi Roxanna J, Tanelian Arax, Nwokafor Chiso, Hollander Callie M, Peacock Lauren, Sabban Esther L
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, United States.
Front Behav Neurosci. 2021 Sep 8;15:705579. doi: 10.3389/fnbeh.2021.705579. eCollection 2021.
The susceptibility to stress-elicited disorders is markedly influenced by sex. Women are twice as likely as men to develop posttraumatic stress disorder (PTSD), depression, anxiety disorders, and social impairments following exposure to traumatic stress. However, most of the studies in animal models examining putative therapeutics for stress-triggered impairments, including single prolonged stress (SPS), were performed predominantly with males. Previous studies in males demonstrated that intranasal neuropeptide Y (NPY) can provide therapeutic relief of many SPS-triggered behaviors, but is ineffective in females at the same dose. Thus, females may need a higher dose of exogenous NPY to attain a therapeutically significant concentration since the overwhelming majority of studies found that NPY levels in females in many brain regions are lower than in male rodents. Here, we examined SPS as an appropriate model to elicit many PTSD-associated symptoms in females and whether intranasal NPY at higher doses than with males is able to alter the development of SPS-triggered behavioral impairments. Sprague-Dawley female rats were exposed to SPS only, or in a separate cohort after SPS stressors were immediately infused intranasally with one of several doses of NPY, starting with 600 μg/rat-four times the dose effective in males. In the third cohort of animals, females were infused intranasally with either 600 μg NPY, omarigliptin [a dipeptidyl peptidase IV (DPP4) inhibitor], or both right after the SPS stressors. After 19 days they were tested on several behavioral tests. SPS elicited significant depressive/despair like behavior on the forced swim test (FST), anxiety behavior on the elevated plus maze (EPM), as well as impaired social interaction. On the FST, there was a dose-response effect of intranasal NPY, with 1,200 μg, but not 600 μg, preventing the development of the SPS-elicited depressive-like behavior. The omarigliptin and 600 μg NPY combined treatment, but neither alone, was also sufficient at preventing depressive-like behavior on the FST. The results demonstrate that: (1) SPS elicits several behavioral manifestations of PTSD in females; (2) early intervention with a high dose of intranasal NPY has therapeutic potential also for females; and (3) NPY cleavage by DPP4 may play a role in the higher dose requirement for females.
应激引发的疾病易感性受性别影响显著。女性在遭受创伤性应激后患上创伤后应激障碍（PTSD）、抑郁症、焦虑症以及出现社交障碍的可能性是男性的两倍。然而，在动物模型中，大多数研究应激引发损伤的假定疗法（包括单次长时间应激，SPS）主要是在雄性动物身上进行的。先前对雄性动物的研究表明，鼻内注射神经肽Y（NPY）可以缓解许多由SPS引发的行为，但相同剂量对雌性无效。因此，由于绝大多数研究发现许多脑区雌性动物的NPY水平低于雄性啮齿动物，雌性可能需要更高剂量的外源性NPY才能达到具有治疗意义的浓度。在此，我们研究了SPS作为引发雌性动物许多PTSD相关症状的合适模型，以及鼻内注射比雄性更高剂量的NPY是否能够改变SPS引发的行为损伤的发展。将斯普拉格-道利雌性大鼠单独暴露于SPS，或者在另一组中，在SPS应激源后立即鼻内注射几种剂量的NPY之一，起始剂量为600μg/只（是对雄性有效的剂量的四倍）。在第三组动物中，雌性大鼠在SPS应激源后立即鼻内注射600μg NPY、奥格列汀（一种二肽基肽酶IV，DPP4抑制剂）或两者。19天后，对它们进行多项行为测试。SPS在强迫游泳试验（FST）中引发显著的抑郁/绝望样行为，在高架十字迷宫（EPM）中引发焦虑行为，以及损害社交互动。在FST中，鼻内注射NPY存在剂量反应效应，1200μg可预防SPS引发的抑郁样行为，而600μg则不能。奥格列汀和600μg NPY联合治疗（但单独使用均无效）也足以预防FST中的抑郁样行为。结果表明：（1）SPS在雌性动物中引发了PTSD的几种行为表现；（2）早期高剂量鼻内注射NPY对雌性也具有治疗潜力；（3）DPP4对NPY的切割可能在雌性对更高剂量的需求中起作用。
