Efficacy of the MCHR1 antagonist N-[3-(1-{[4-(3,4-difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847) in mouse models of anxiety and depression following acute and chronic administration is independent of hippocampal neurogenesis
Efficacy of the MCHR1 antagonist N-[3-(1-{[4-(3,4-difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847) in mouse models of anxiety and depression following acute and chronic administration is independent of hippocampal neurogenesis
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DOI：
10.1124/jpet.106.109678
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发表时间：
2007-04-01
影响因子：
3.5
通讯作者：
Hen, R.
中科院分区：
文献类型：
--
作者：
David, D. J.;Klemenhagen, K. C.;Hen, R.
黑色素浓集激素（MCH）是一种下丘脑神经肽，在调节食物摄入和情绪中发挥作用。在啮齿类动物中，MCH的作用是通过MCHR 1受体介导的。本研究的目的是研究急性（1小时）和慢性（28天）p.o.在预测抗抑郁/抗焦虑样活性的三种小鼠模型中给予新的MCHR 1拮抗剂N-[3-（1-{[4-（3，4-二氟苯氧基）苯基]甲基}（4-哌啶基））-4-甲基苯基]-2-甲基丙酰胺（SNAP 94847）：129 S6/SvEvTac小鼠中的新奇性抑制进食（NSF）和BALB/cJ小鼠中的亮/暗范例（L/D）和强迫游泳试验（FST）。观察到响应于用SNAP 94847的急性和慢性处理，在L/D盒的光室中花费的时间显著增加。急性和慢性治疗后，在NSF试验中发现了抗焦虑/抗抑郁样作用，而在FST中未观察到任何作用。由于在NSF测试中，齿状回中的神经发生已被证明是抗抑郁药作用的必要条件，因此我们研究了SNAP 94847的作用是否需要神经发生。我们发现，用SNAP 94847长期处理刺激齿状回中祖细胞的增殖。然而，SNAP 94847在NSF测试中的功效在神经发生被X射线照射抑制的小鼠中没有改变。这些结果表明，SNAP 94847在急性和慢性给药后具有独特的抗焦虑样特征，其作用机制与选择性5-羟色胺再摄取抑制剂和三环类抗抑郁药不同。
Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that plays a role in the modulation of food intake and mood. In rodents, the actions of MCH are mediated via the MCHR1 receptor. The goal of this study was to investigate the effects of acute (1 h) and chronic (28 days) p.o. dosing of a novel MCHR1 antagonist, N-[3-(1-{[4-(3,4-difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP94847), in three mouse models predictive of antidepressant/anxiolytic-like activity: novelty suppressed feeding (NSF) in 129S6/SvEvTac mice and light/dark paradigm (L/D) and forced swim test (FST) in BALB/cJ mice. A significant increase in the time spent in the light compartment of the L/D box was observed in response to acute and chronic treatment with SNAP 94847. An anxiolytic/antidepressant-like effect was found in the NSF test after acute and chronic treatment, whereas no effect was observed in the FST. Because neurogenesis in the dentate gyrus has been shown to be a requirement for the effects of antidepressants in the NSF test, we investigated whether neurogenesis was required for the effect of SNAP 94847. We showed that chronic treatment with SNAP 94847 stimulated proliferation of progenitors in the dentate gyrus. The efficacy of SNAP 94847 in the NSF test, however, was unaltered in mice in which neurogenesis was suppressed by X-irradiation. These results indicate that SNAP 94847 has a unique anxiolytic-like profile after both acute and chronic administration and that its mechanism of action is distinct from that of selective serotonin reuptake inhibitors and tricyclic antidepressants.