Antidepressant-like effects of the nociceptin/orphanin FQ receptor antagonist UP-101: new evidence from rats and mice
Antidepressant-like effects of the nociceptin/orphanin FQ receptor antagonist UP-101: new evidence from rats and mice
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DOI：
10.1007/s00210-004-0939-0
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发表时间：
2004-06-01
影响因子：
3.6
通讯作者：
Calo', G
中科院分区：
文献类型：
--
作者：
Gavioli, EC;Vaughan, CW;Calo', G
受体拮抗剂和敲除研究已经证明，阻断经由孤啡肽/孤啡肽FQ（N/OFQ）及其受体（NOP）的信号传导在进行强迫游泳试验（FST）的小鼠中具有抗抑郁样作用。本研究的目的是进一步探索NOP拮抗剂UFP-101在不同物种（小鼠和大鼠）中和使用不同测定[FST和悬尾试验（TST）]的抗抑郁样性质，并研究其作用所涉及的机制。将瑞士小鼠在TST中的不动时间（平均值+/- SEM）从179 +/- 11秒减少到111 +/- 10秒。N/OFQ（1 nmol i.c.v.）本身没有作用，但完全阻止了UFP-101的作用。TST中NOP-/-CD 1-C57 BL/6 J-129小鼠的自发不动时间远低于野生型（NOP+/+）同窝小鼠（75 +/- 11 vs. 144 +/- 17 s）或Swiss小鼠。UFP-101（10 nmol i.c.v.）在接受FST的大鼠中，减少不动时间（-65%）和增加攀爬时间（71%）。在大鼠脑片中，N/OFQ（100 nM）在蓝斑和中缝背核神经元中触发了强大的K+依赖性超极化电流。UFP-101（3 μ M）完全阻止N/OFQ诱导的电流，但本身无活性。氟西汀、地昔帕明（均为30 mg/kg i. p.）和UFP-101（10 nmol i.c.v.）减少小鼠在FST中的不动时间。5-羟色胺合成抑制剂对氯苯丙氨酸甲酯（PCPA，4x 100 mg/kg/天i. p.）阻止了氟西汀和UFP-101（但不是地昔帕明）的抗抑郁样作用，而N-（2-氯乙基）-N-乙基-2-溴苄胺（DSP-4，对去甲肾上腺素能神经元有神经毒性; 50 mg/kg i. p.，7天前），仅抑制地昔帕明的作用。因此，UFP-101在不同物种和动物模型中表现出明显的抗抑郁样作用，可能是通过阻止内源性N/OFQ对脑单胺能（特别是多巴胺能）神经传递的抑制作用。N/OFQ-NOP受体系统在情绪调节中的参与为抗抑郁药物的开发提供了新的潜在目标。
Receptor antagonist and knockout studies have demonstrated that blockade of signalling via nociceptin/ orphanin FQ (N/OFQ) and its receptor (NOP) has antidepressant-like effects in mice submitted to the forced swimming test (FST). The aim of the present study was to explore further the antidepressant-like properties of the NOP antagonist UFP-101 in different species (mouse and rat) and using different assays [FST and tail suspension test (TST)], and to investigate the mechanism(s) involved in its actions.UFP-101 (10nmol i.c.v.) reduced immobility time of Swiss mice in the TST (mean +/- SEM) from 179 +/- 11 to 111 +/- 10 s. N/OFQ (1 nmol i.c.v.) was without effect per se, but fully prevented the effect of UFP-101. The spontaneous immobility time of NOP-/- CD1-C57BL/6J-129 mice in the TST was much lower than that of wild-type (NOP+/+) littermates (75 +/- 11 vs. 144 +/- 17 s) or of Swiss mice. UFP-101 (10 nmol i.c.v.) decreased immobility time (-65%) and increased climbing time (71%) in rats submitted to the FST. In rat brain slices, N/OFQ (100 nM) triggered robust K+-dependent hyperpolarizing currents in locus coeruleus and dorsal raphe neurons. UFP-101 (3muM) fully prevented N/OFQ-induced currents, but was inactive per se. Flu-oxetine, desipramine (both 30mg/kg i.p.) and UFP-101 (10 nmol i.c.v.) reduced immobility time of mice in the FST. The serotonin synthesis inhibitor p-chlorophenylalanine methylester (PCPA, 4x100 mg/kg per day i.p.) prevented the antidepressant-like effects of fluoxetine and UFP-101 (but not desipramine), whereas N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, neurotoxic for noradrenergic neurons; 50 mg/kg i.p., 7 days beforehand), suppressed only the effect of desipramine. Neither pretreatment affected spontaneous immobility time per se.Thus, UFP-101 exhibits pronounced antidepressant-like effects in different species and animal models, possibly by preventing the inhibitory effects of endogenous N/OFQ on brain monoaminergic (in particular serotonergic) neurotransmission. Participation of the N/OFQ-NOP receptor system in mood modulation sets new potential targets for antidepressant drug development.