Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA.
Int J Neuropsychopharmacol. 2013 Aug;16(7):1623-34. doi: 10.1017/S1461145713000059. Epub 2013 Feb 27.
Cpe(fat/fat) mice have a point mutation in carboxypeptidase E (Cpe), an exopeptidase that removes C-terminal basic amino acids from intermediates to produce bioactive peptides. The mutation renders the enzyme inactive and unstable. The absence of Cpe activity in these mutants leads to abnormal processing of many peptides, with elevated levels of intermediates and greatly reduced levels of the mature peptides. Cpe(fat/fat) mice develop obesity, diabetes and infertility in adulthood. We examined whether anxiety- and/or depressive-like behaviours are also present. Anxiety-like responses are not evident in young Cpe(fat/fat) mice (∼60 d), but appear in older animals (>90 d). These behaviours are reversed by acute treatment with diazepam or fluoxetine. In contrast, increased immobilities in forced swim and tail suspension are evident in all age groups examined. These behaviours are reversed by acute administration of reboxetine. In comparison acute treatments with fluoxetine or bupropion are ineffective; however, immobility times are normalized with 2 wk treatment. These data demonstrate that Cpe(fat/fat) mice display depressive-like responses aged ∼60 d, whereas anxiety-like behaviours emerge ∼1 month later. In tail suspension, the reboxetine findings show that noradrenergic actions of antidepressants are intact in Cpe(fat/fat) mice. The ability of acute fluoxetine treatment to rescue anxiety-like while leaving depressive-like responses unaffected suggests that serotonin mechanisms underlying these behaviours are different. Since depressive-like responses in the Cpe(fat/fat) mice are rescued by 2 wk, but not acute, treatment with fluoxetine or bupropion, these mice may serve as a useful model that resembles human depression.
Cpe（fat/fat）小鼠的羧肽酶 E（Cpe）发生点突变，这是一种外肽酶，可从中间产物中去除 C 末端碱性氨基酸，从而产生生物活性肽。该突变使酶失活且不稳定。这些突变体中 Cpe 活性的缺失导致许多肽的异常加工，中间产物水平升高，成熟肽水平大大降低。Cpe（fat/fat）小鼠在成年后会出现肥胖、糖尿病和不育。我们研究了它们是否也存在焦虑和/或抑郁样行为。年轻的 Cpe（fat/fat）小鼠（约 60 天）没有明显的焦虑样反应，但在老年动物（>90 天）中出现。这些行为可被地西泮或氟西汀的急性治疗逆转。相比之下，所有检查的年龄组中均出现强迫游泳和悬尾的不动性增加。这些行为可被瑞波西汀的急性给药逆转。相比之下，氟西汀或安非他酮的急性治疗无效；然而，经过 2 周的治疗后，不动时间恢复正常。这些数据表明，Cpe（fat/fat）小鼠在约 60 天龄时表现出抑郁样反应，而焦虑样行为则在 1 个月后出现。在悬尾试验中，瑞波西汀的结果表明，Cpe（fat/fat）小鼠的抗抑郁药的去甲肾上腺素能作用是完整的。急性氟西汀治疗可挽救焦虑样行为而不影响抑郁样行为，这表明这些行为的 5-羟色胺机制不同。由于 Cpe（fat/fat）小鼠的抑郁样反应可通过 2 周而不是急性治疗用氟西汀或安非他酮来挽救，因此这些小鼠可能成为一种有用的模型，类似于人类抑郁症。
