Most preclinical studies investigating the effects and the mechanism of action of
antidepressants have been performed in naive rodents. This is inappropriate because
antidepressants act on specific symptoms of the pathological condition, such as distress and anxiety. We have developed a mouse model of anxiety/depression based on addition of
corticosterone to
drinking water. This model is highly reproducible and easy to set up compared with unpredictable chronic mild stress. The
serotonin 1A (5-HT(1A))
autoreceptor is known to play a role in
mood disorders and their treatments. An increase in somatodendritic 5-HT(1A)
autoreceptor density in the dorsal raphe (DR) attenuates the therapeutic activity of
selective serotonin-reuptake inhibitors (
SSRIs), whereas their functional desensitization promotes activation of brain serotonergic transmission, thereby representing an adaptive change relevant to their
therapeutic effect. Here we assessed the effects of sustained administration of the SSRI
fluoxetine on 5-HT(1A)
autoreceptor sensitivity in mice administered with
corticosterone.
Fluoxetine attenuated
hypothermia induced by the
5-HT(1A) receptor agonist
8-hydroxy-2-(di-n-propylamino)tetralin, decreased DR
5-HT neuronal activity, and decreased
5-HT release in both vehicle- and
corticosterone-pretreated mice. However, such desensitization was more pronounced in
corticosterone-pretreated mice. This change had an overall effect on serotonergic tone because we found a greater firing rate of
5-HT neurons associated with an enhancement of
5-HT outflow in the DR of
corticosterone-pretreated mice in response to
fluoxetine compared with the corresponding group of vehicle-pretreated mice. These results provide cellular explanations for the
antidepressant effects produced by
SSRIs in subjects with pathological conditions but not in naive animals or healthy volunteers.