Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York (P.C.C., B.S., A.W., S.D.C.); Department of Pharmacology Physiology and Neuroscience, University of South Carolina School of Medicine (S.K.W.) and Dorn VA Medical Center (S.K.W.), Columbia, South Carolina; and Research Triangle Institute, Center for Drug Discovery, Research Triangle Park, North Carolina (S.R.).
Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, New York (P.C.C., B.S., A.W., S.D.C.); Department of Pharmacology Physiology and Neuroscience, University of South Carolina School of Medicine (S.K.W.) and Dorn VA Medical Center (S.K.W.), Columbia, South Carolina; and Research Triangle Institute, Center for Drug Discovery, Research Triangle Park, North Carolina (S.R.)
J Pharmacol Exp Ther. 2024 Nov 19;391(3):460-471. doi: 10.1124/jpet.124.002415.
The neuropeptide S receptor (NPSR) has been identified as a potential therapeutic target for anxiety and post-traumatic stress disorder. Central administration of neuropeptide S (NPS) in male mice produces anxiolytic-like effects, hyperlocomotion, and memory enhancement. Currently, the literature is limited in the number of studies investigating the effects of NPS in female test subjects despite females facing a higher prevalence of anxiety-related pathology, as well as greater risk for adverse effects while taking psychoactive drugs. Moreover, no previous studies have considered the influence of estrous cycle on the effects of NPS. The present study investigates whether NPS-mediated behavioral phenotypes seen in males translate to females, and whether they are affected by estrous cycle stage. Female C57BL/6NCr mice were intracerebroventricularly cannulated and underwent behavioral paradigms to test locomotion, anxiety, and memory. Estrous cycle stage was determined through examination of vaginal cytology. Our results provide evidence that NPS-mediated behaviors are influenced by the estrous cycle. Administration of NPS decreased anxiety-like behaviors more robustly when the female mice were in high estrogen stages of the estrous cycle. Therefore, the desired anxiolytic-like effects of targeting the NPSR are intact in female mice. However, these effects may to be influenced by the stage of the estrous cycle. The NPSR remains a strong potential drug target for new anxiolytic compounds and based on our initial observations further studies exploring the interaction of estrous cycle and the NPS system are warranted. SIGNIFICANCE STATEMENT: The neuropeptide S (NPS) receptor has been identified as a potential target for treating anxiety, a condition that is most prevalent in females. Therefore, the potential interaction of estrous cycle with the NPS system described in the present study is an important first step in understanding the function of the NPS system in females.
神经肽 S 受体（NPSR）已被确定为治疗焦虑和创伤后应激障碍的潜在靶点。在雄性小鼠的中枢给予神经肽 S（NPS）会产生抗焦虑样作用、过度活跃和记忆增强。目前，尽管女性面临更高的焦虑相关病理发病率，以及在服用精神药物时出现不良反应的风险更高，但研究 NPS 对雌性受试动物影响的文献数量有限。此外，以前没有研究考虑过发情周期对 NPS 作用的影响。本研究调查了 NPS 在雄性中介导的行为表型是否转化为雌性，以及它们是否受到发情周期阶段的影响。雌性 C57BL/6NCr 小鼠接受脑室内套管植入，并进行行为范式测试，以测试运动、焦虑和记忆。通过检查阴道细胞学来确定发情周期阶段。我们的结果提供了证据，表明 NPS 介导的行为受发情周期的影响。当雌性小鼠处于发情周期的高雌激素阶段时，给予 NPS 会更显著地减少焦虑样行为。因此，靶向 NPSR 的抗焦虑样作用在雌性小鼠中仍然完整。然而，这些作用可能会受到发情周期阶段的影响。NPSR 仍然是新的抗焦虑化合物的强有力的潜在药物靶点，基于我们的初步观察，进一步研究探索发情周期和 NPS 系统的相互作用是必要的。
神经肽 S（NPS）受体已被确定为治疗焦虑的潜在靶点，焦虑是女性中最常见的疾病。因此，本研究中描述的发情周期与 NPS 系统的潜在相互作用是理解 NPS 系统在女性中的功能的重要第一步。
