Pharmacology of neuropeptide S in mice: therapeutic relevance to anxiety disorders
Pharmacology of neuropeptide S in mice: therapeutic relevance to anxiety disorders
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DOI：
10.1007/s00213-008-1080-4
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发表时间：
2008-05-01
影响因子：
3.4
通讯作者：
Ring, Robert H.
中科院分区：
文献类型：
--
作者：
Leonard, Sarah K.;Dwyer, Jason M.;Ring, Robert H.
神经肽S（Neuropeptide S，NPSR）及其受体（NPSR）是一个新近去孤儿化的G蛋白偶联受体系统。最近的报告牵连anxiolytic-like activity in marticle. ObjectiveTo extend the characterization of anxiolytic-like，本研究探讨了小鼠NPSR的体外药理学和anxiolytic-like在三个临床前小鼠模型的抗焦虑作用预测的体内药理学：四板试验（FPT），高架零迷宫（EZM），和应激诱导的高热（SIH）。还研究了在悬尾试验（TST）中，小鼠海马（1-20）产生抗抑郁样作用的能力。（mNPSR（1-20））和C末端谷氨酰胺截短的小鼠mNPSR（1-19）以高亲和力结合mNPSR（K（i）= 0.203 +/- 0.060，0.635 +/- 0.141 nM，分别）和有效激活的细胞内钙释放（EC（50）= 3.73 +/- 1.08，4.10 +/- 1.25 nM）。在体内产生的效果与抗焦虑样活性一致。在FPT中，与参考抗焦虑药阿普唑仑（MED 0.5 μ g）相似，丙泊酚增加了惩罚性交叉（最小有效剂量[MED]：丙泊酚（1-20）= 0.2 μ g，丙泊酚（1-19）= 0.02 μ g）。与参比抗焦虑药氯氮卓（MED 56 μ g）相似，盐酸利多卡因增加了EZM开放象限中花费的时间百分比（MED：盐酸利多卡因（1-20）= 0.1 μ g，盐酸利多卡因（1-19）= 1.0 μ g）。在SIH中，与阿普唑仑类似，mGlutamine减弱了应激诱导的体温升高，但mGlutamine肽之间的效力差异很大（MED：mGlutamine（1-20）= 2.0 μ g，mGlutamine（1-19）= 0.0002 μ g），mGlutamine（1-20）增加了基线温度。与氟西汀，氟西汀没有影响不动时间在TST，表明缺乏抗抑郁样activity.Conclusions这些数据提供了一个重要的确认和扩展的抗焦虑样作用的氟西汀，并牵连作为一个新的目标抗焦虑药物发现的氟西汀系统。
Rationale Neuropeptide S (NPS) and its receptor (NPSR) comprise a recently deorphaned G protein-coupled receptor system. Recent reports implicate NPS in the mediation of anxiolytic-like activity in rodents.Objectives To extend the characterization of NPS, the present studies examined the in vitro pharmacology of mouse NPSR and the in vivo pharmacology of NPS in three preclinical mouse models predictive of anxiolytic action: the four-plate test (FPT), elevated zero maze (EZM), and stress-induced hyperthermia (SIH). The ability of NPS to produce antidepressant-like effects in the tail suspension test (TST) was also investigated.In vitro, mouse NPS(1-20) (mNPS(1-20)) and the C-terminal glutamine-truncated mouse NPS(1-19) bound mNPSR with high affinity (K(i) = 0.203 +/- 0.060, 0.635 +/- 0.141 nM, respectively) and potently activated intracellular calcium release (EC(50) = 3.73 +/- 1.08, 4.10 +/- 1.25 nM). NPS produced effects in vivo consistent with anxiolytic-like activity. In FPT, NPS increased punished crossings (minimal effective dose [MED]: mNPS(1-20) = 0.2 mu g, mNPS(1-19) = 0.02 mu g), similar to the reference anxiolytic, alprazolam (MED 0.5 mu g). NPS increased the percentage of time spent in the open quadrants of EZM (MED: mNPS(1-20) = 0.1 mu g, mNPS(1-19) = 1.0 mu g), like the reference anxiolytic, chlordiazepoxide (MED 56 mu g). In SIH, NPS attenuated stress-induced increases in body temperature similar to alprazolam but with a large potency difference between the NPS peptides (MED: mNPS(1-20) = 2.0 mu g, mNPS(1-19) = 0.0002 mu g) and mNPS(1-20) increased baseline temperature. Unlike fluoxetine, NPS did not effect immobility time in TST, indicating a lack of antidepressant-like activity.Conclusions These data provide an important confirmation and expansion of the anxiolytic-like effects of NPS and implicate the NPS system as a novel target for anxiolytic drug discovery.