title: Emergence of anxiety-like behaviours in depressive-like Cpe(fat/fat) mice.
abstract: 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.
authors: Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC, USA.
authors: Ramona M
authors: RM
authors: Rodriguiz
authors: John J
authors: JJ
authors: Wilkins
authors: Thomas K
authors: TK
authors: Creson
authors: Reeta
authors: R
authors: Biswas
authors: Iryna
authors: I
authors: Berezniuk
authors: Arun D
authors: AD
authors: Fricker
authors: Lloyd D
authors: LD
authors: Fricker
authors: William C
authors: WC
authors: Wetsel
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics; D043423:Carboxypeptidase H / Q000235:genetics*; D003863:Depression / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics; D003975:Diazepam / Q000627:therapeutic use; D005106:Exploratory Behavior / Q000187:drug effects; D019417:Hindlimb Suspension / Q000379:methods; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects; D009765:Obesity / Q000150:complications* / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D000077593:Reboxetine; D013550:Swimming / Q000523:psychology
chemical_list: D000928:Antidepressive Agents; D009025:Morpholines; D000077593:Reboxetine; D043423:Carboxypeptidase H; D003975:Diazepam