Emergence of anxiety-like behaviours in depressive-like Cpe ^fat/fat mice

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 (∼60Â d), but appear in older animals (>90Â 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 ∼60Â 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 2Â wk, but not acute, treatment with fluoxetine or bupropion, these mice may serve as a useful model that resembles human depression.