Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
Neuropsychopharmacology. 2010 Feb;35(3):752-63. doi: 10.1038/npp.2009.183. Epub 2009 Nov 18.
The Wistar Kyoto (WKY) rat strain is a putative genetic model of comorbid depression and anxiety. Previous research showing increased kappa-opioid receptor (KOR) gene expression in the brains of WKY rats, combined with studies implicating the KOR in animal models of depression and anxiety, suggests that alterations in the KOR system could have a role in the WKY behavioral phenotype. Here, the effects of KOR antagonists in the forced swim test (FST) were compared with the WKY and the Sprague-Dawley (SD) rat strains. As previously reported, WKY rats showed more immobility behavior than SD rats. The KOR antagonists selectively produced antidepressant-like effects in the WKY rats. By contrast, the antidepressant desipramine reduced immobility in both strains. Brain regions potentially underlying the strain-specific effects of KOR antagonists in the FST were identified using c-fos expression as a marker of neuronal activity. The KOR antagonist nor-binaltorphimine produced differential effects on the number of c-fos-positive profiles in the piriform cortex and nucleus accumbens shell between SD and WKY rats. The piriform cortex and nucleus accumbens also contained higher levels of KOR protein and dynorphin A peptide, respectively, in the WKY strain. In addition, local administration of nor-binaltorphimine directly into the piriform cortex produced antidepressant-like effects in WKY rats further implicating this region in the antidepressant-like response to KOR antagonists. These results support the use of the WKY rat as a model of affective disorders potentially involving KOR overactivity and provide more evidence that KOR antagonists could potentially be used as novel antidepressants.
Wistar Kyoto（WKY）大鼠品系是一种潜在的抑郁和焦虑共病的遗传模型。先前的研究表明，WKY 大鼠大脑中的κ-阿片受体（KOR）基因表达增加，结合 KOR 在抑郁和焦虑动物模型中的研究，表明 KOR 系统的改变可能在 WKY 行为表型中起作用。在这里，比较了 KOR 拮抗剂在强迫游泳试验（FST）中的作用与 WKY 和 Sprague-Dawley（SD）大鼠品系。如前所述，WKY 大鼠比 SD 大鼠表现出更多的不动行为。KOR 拮抗剂选择性地对 WKY 大鼠产生抗抑郁样作用。相比之下，抗抑郁药去甲丙咪嗪减少了两种品系的不动行为。使用 c-fos 表达作为神经元活性的标志物，鉴定了 KOR 拮抗剂在 FST 中对特定于品系的作用的潜在脑区。KOR 拮抗剂 nor-binaltorphimine 在 SD 和 WKY 大鼠的梨状皮层和伏隔核壳中产生了 c-fos 阳性谱的差异效应。梨状皮层和伏隔核也分别在 WKY 品系中含有更高水平的 KOR 蛋白和强啡肽 A 肽。此外，nor-binaltorphimine 直接向梨状皮层局部给药对 WKY 大鼠产生抗抑郁样作用，进一步表明该区域与 KOR 拮抗剂的抗抑郁样反应有关。这些结果支持将 WKY 大鼠用作潜在涉及 KOR 过度活跃的情感障碍模型，并提供更多证据表明 KOR 拮抗剂可能可作为新型抗抑郁药。
