Redrobe John P, Dumont Yvan, Fournier Alain, Baker Glen B, Quirion Rémi
Douglas Hospital Resarch Centre, McGill University, Department of Psychiatry, 6875 Blvd. LaSalle, Montréal (Verdun), Que., Canada H4H 1R3.
Peptides. 2005 Aug;26(8):1394-400. doi: 10.1016/j.peptides.2005.03.029. Epub 2005 Apr 25.
Neuropeptide Y (NPY) is thought to be implicated in depressive disorders. The mouse forced swim test (FST) is an animal model widely used as a predictor of the efficacy of antidepressant drugs. The present study was undertaken to explore the possible contribution of endogenous serotonin (5-HT) systems in the behavioral effects elicited by NPY in this model. The selective serotonin re-uptake inhibitor (SSRI), fluoxetine, was also tested for comparison. 5-HT was depleted prior to testing by the administration of the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA; 300 mg/kg, i.p., each day for 3 days; control mice received saline-vehicle over the same period). On the fourth day, mice received NPY (3 nmol, I.C.V.), fluoxetine (16 mg/kg, i.p.) or saline injections before testing in the FST. Both NPY and fluoxetine significantly reduced immobility time in saline-treated control animals. Pre-treatment with PCPA significantly blocked the effects of fluoxetine in the FST, confirming the role of endogenous 5-HT. Similarly, pre-treatment with PCPA also significantly attenuated the anti-immobility effects of NPY, thus suggesting a role for 5-HT in the effects of NPY in the FST. Quantitative receptor autoradiography revealed increases in specific [125I][Leu31, Pro34]PYY sites that were sensitive to BIBP3226 (Y1-like sites) in various brain regions. Specific [125I]GR231118 and [125I]PYY(3-36) binding levels were not changed following PCPA treatment, suggesting that depletion of endogenous 5-HT resulted in an apparent increase in the level of Y1 sites in their high-affinity state. Taken together, these results suggest a role for 5-HT-related systems in the antidepressant-like properties of NPY.
神经肽Y（NPY）被认为与抑郁症有关。小鼠强迫游泳试验（FST）是一种广泛用作抗抑郁药物疗效预测指标的动物模型。本研究旨在探讨内源性5-羟色胺（5-HT）系统在该模型中NPY引发的行为效应中的可能作用。还测试了选择性5-羟色胺再摄取抑制剂（SSRI）氟西汀作为对照。在测试前，通过给予色氨酸羟化酶抑制剂对氯苯丙氨酸（PCPA；300mg/kg，腹腔注射，每天一次，共3天；同期对照小鼠接受生理盐水载体）来耗尽5-HT。在第4天，小鼠在FST测试前接受NPY（3nmol，脑室内注射）、氟西汀（16mg/kg，腹腔注射）或生理盐水注射。NPY和氟西汀均显著减少了生理盐水处理的对照动物的不动时间。PCPA预处理显著阻断了氟西汀在FST中的作用，证实了内源性5-HT的作用。同样，PCPA预处理也显著减弱了NPY的抗不动作用，因此表明5-HT在FST中NPY的作用中发挥作用。定量受体放射自显影显示，在各个脑区中，对BIBP3226敏感的特异性[125I][Leu31, Pro34]PYY位点（Y1样位点）增加。PCPA处理后，特异性[125I]GR231118和[125I]PYY(3-36)结合水平未发生变化，表明内源性5-HT的耗尽导致其高亲和力状态下Y1位点水平明显增加。综上所述，这些结果表明5-HT相关系统在NPY的抗抑郁样特性中发挥作用。
