Endocrine Abstracts (2006) 11 OC34

Transgenic mice overexpressing Urocortin 3 show increased anxiety- and depressive-like behaviours but a hyporesponsive ACTH response to stress

PM Jamieson, A Chen & W Vale

The Salk Insititute for Biological Studies, La Jolla, CA, 92037, United States.

Urocortin 3 is a CRF-related ligand highly specific for the Corticotropin-Releasing Factor Receptor Type 2 (CRFR2). CRFR2 is implicated in the regulation of stress-related behaviours and the neuroendocrine response to stressors. Close anatomical association between major Urocortin 3 terminal fields and CRFR2 in the limbic system and hypothalamus indicate this system is well placed to be involved in modulating of the physiological stress response. Transgenic mice ubiquitously overexpressing Urocortin 3 under the control of the ROSA26 promoter were generated as a model of chronic CRFR2 activation. Urocortin 3 peptide was expressed in brain by 40 times wildtype levels as measured by specific radioimmunoassay. Studies were carried out on group-housed adult male mice between 12 and 14 weeks old. Urocortin 3 transgenic mice showed increased anxiety-like behaviour in the elevated plus maze with decreased open arm entries, decreased time spent on the open arms and increased time spent on the closed arms of the maze compared to wildtype littermates. No differences in indices of anxiety were observed in the open field or light dark box apparatus. There were no differences in activity levels between genotypes in behavioural tests. Urocortin 3 overexpressing mice also showed increased immobility in the tail suspension test indicative of increased depressive-like behaviour. ACTH and corticosterone levels under non-stressed conditions were not significantly different between genotypes in the AM or PM. However Urocortin 3 transgenic mice showed an attenuated ACTH response to restraint stress, with ACTH peaking earlier and at lower levels. This incongruity between the behavioural and neuroendocrine response to stress has been reported with repeated stressors or maternal separation in rodents and posttraumatic stress disorder in humans due to desensitisation of CRF receptors and the HPA axis. These data suggest a potential role of the CRFR2/ Urocortin 3 system in regulation of the chronic stress response.

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