Altered serotonergic activity in hippocampus and neocortex of urocortin over-expressing mice

Paul AT Kelly, Youjia Zhong, Kylie Conroy, Louise J. Valentine, Neil Dawson, Pauline M Jamieson. University of Edinburgh, Edinburgh, Scotland, United Kingdom.

Corticotropin-releasing factor (CRF) is the principal neuropeptide involved in regulating the stress response. Affective disorders are associated with CRF hyperactivity and CRF is known to affect the neurotransmitter systems currently targeted by antidepressants, in particular 5-HT. Urocortins are the endogenous ligands for the CRF type 2 receptor and transgenic mice over-expressing urocortin 3 (UCN3+) provide a useful model with which to explore CRF/5-HT interactions in the brain.

A total of 14 male UCN3+ mice and 14 wild-type (wt) littermates were used in this study. Equal numbers from each genotype were injected (i.p.) with either saline (0.1ml) or 10mg.kg-1 8-OH-DPAT in saline. Local cerebral glucose utilization (LCMRglc) was measured in neocortex and hippocampus ten minutes later using the semi-quantitative autoradiographic imaging method described by us previously (Dawson et al., 2008). Data were analysed by two-way analysis of variance and post hoc t-test with appropriate Bonferroni correction applied. Acceptable levels of significance were set at P<0.05.

There was no significant main effect of genotype. There was however a significant main effect of treatment, and in 8-OH-DPAT-treated wt mice, LCMRglc was significantly decreased in all brain areas examined. The most marked effects were found in prefrontal cortex where LCMRglc was decreased by 53%, and in hippocampal CA3 (-52%). A significant genotype x treatment interaction was detected and further analysis revealed that the response to 8-OH-DPAT in UCN3+ mice was significantly attenuated. This was most marked in parietal cortex where a 35% decrease induced by 8-OH-DPAT in wt mice was reduced to 10% (n.s.) in UCN3+ mice.

These results suggest that while a life-long increase in urocortin 3 expression does not alter constitutive brain function, it does result in changes to endogenous serotonin systems. In particular, a decrease in 5-HT1A functional activity is suggested by the attenuation of responses to 8-OH-DPAT, in urocortin 3 over-expressing mice.

Dawson, N. et al. (2008) J. Neurosci. Meth. 175, 25-35.

This work was funded by EC Grant LSHM-CT-2004-503474.