Emergence of anxiety-like behaviours in depressive-like Cpe mice

Cpe 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. Cpemice develop obesity, diabetes and infertility in adulthood. We examined whether anxietyand/or depressive-like behaviours are also present. Anxiety-like responses are not evident in young Cpe mice (y60 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 mice display depressive-like responses agedy60 d, whereas anxiety-like behaviours emergey1 month later. In tail suspension, the reboxetine findings show that noradrenergic actions of antidepressants are intact in Cpe 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 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. Received 24 November 2012 ; Reviewed 24 December 2012 ; Revised 30 December 2012 ; Accepted 11 January 2013 ; First published online 27 February 2013