Understanding the physiopathology of affective disorders and their treatment relies
on the availability of experimental models that accurately mimic aspects of the disease.
Here we describe a mouse model of an anxiety/depressive-like state induced by chronic
corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the
behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by
corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis
is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some, but
not all, behavioral paradigms, suggesting both neurogenesis-dependent and -independent
mechanisms of antidepressant action. Finally, we identified a number of candidate
genes, the expression of which is decreased by chronic corticosterone and normalized
by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice
deficient in one of these genes, beta-arrestin 2, displayed a reduced response to
fluoxetine in multiple tasks, suggesting that beta-arrestin signaling is necessary
for the antidepressant effects of fluoxetine.