Becker C, Zeau B, Rivat C, Blugeot A, Hamon M, Benoliel J-J
Faculté de Médecine Pierre et Marie Curie, UMR 713 INSERM/UPMC, Douleurs et Stress, Paris Cedex, France.
Mol Psychiatry. 2008 Dec;13(12):1079-92. doi: 10.1038/sj.mp.4002097. Epub 2007 Sep 25.
Cholecystokinin (CCK) involvement in depression-like disorders is poorly documented. Here, we investigated whether CCKergic neurotransmission is relevant to depressive-like symptoms and antidepressant therapy using a novel preclinical model based on repeated social defeat over 4 weeks in rats. Repeated social defeat triggers changes that could be considered as behavioral and biological correlates of depressive symptoms in humans, such as a hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis (increase of serum corticosterone levels and of adrenal gland weight), increased immobility time in the forced swimming test (FST), decrease of body weight and of sweet water consumption and reduction of hippocampal volume associated with a decreased cell proliferation in the dentate gyrus. In addition, in vivo microdialysis showed that cortical CCK release was tonically increased in defeated rats. Chronic imipramine treatment (16 mg kg(-1) per day for 25 days) prevented both the repeated social defeat-induced alterations of biological and behavioral parameters and the associated increase of cortical CCK release. Chronic blockade of CCK2 receptors by the specific antagonist CI-988 (1 mg kg(-1) per day for 25 days) also normalized immobility time in the FST and prevented HPA axis hyperactivity, reduction of hippocampal volume and cell proliferation and decreased sweet water intake normally evoked by repeated social defeat. These data showed that the repeated social-defeat paradigm can be considered as a suitable model of 'depression' in rats. The causal link between social defeat-evoked (1) increase in cortical CCKergic neurotransmission and (2) depression-like symptoms that we highlighted here strongly suggests that CCKergic systems may be a relevant target for novel antidepressant therapy.
胆囊收缩素（CCK）与抑郁样障碍的关系鲜有文献记载。在此，我们使用一种基于大鼠连续4周遭受社会挫败的新型临床前模型，研究CCK能神经传递是否与抑郁样症状及抗抑郁治疗相关。连续的社会挫败会引发一些变化，这些变化可被视为人类抑郁症状的行为和生物学相关因素，如下丘脑 - 垂体 - 肾上腺（HPA）轴功能亢进（血清皮质酮水平和肾上腺重量增加）、强迫游泳试验（FST）中不动时间增加、体重减轻、糖水消耗量减少以及海马体积减小，同时齿状回细胞增殖减少。此外，体内微透析显示，遭受挫败的大鼠皮质CCK释放持续增加。慢性丙咪嗪治疗（每天16 mg·kg⁻¹，持续25天）可预防连续社会挫败诱导的生物学和行为参数改变以及皮质CCK释放的相关增加。特异性拮抗剂CI - 988对CCK2受体的慢性阻断（每天1 mg·kg⁻¹，持续25天）也可使FST中的不动时间恢复正常，并预防HPA轴功能亢进、海马体积减小、细胞增殖以及连续社会挫败通常引起的糖水摄入量减少。这些数据表明，连续社会挫败范式可被视为大鼠“抑郁”的合适模型。我们在此强调的社会挫败诱发的（1）皮质CCK能神经传递增加与（2）抑郁样症状之间的因果联系强烈表明，CCK能系统可能是新型抗抑郁治疗的相关靶点。
