Abstract
Most of preclinical studies investigating the effects and the mechanism of action of antidepressants have been performed in naïve rodents. This is inappropriate since antidepressants act on specific symptoms of the pathology such as distress and anxiety. Recently, we have developed a mouse model of anxiety/depression based on corticosterone addition in the drinking water. This model is highly reproducible and easy to set up compared to the unpredictable chronic mild stress. 5-HT1A autoreceptor is known to play a role in mood disorders and their treatments. An increase in somatodendritic 5-HT1A 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-HT1A autoreceptor sensitivity in mice administered with corticosterone. Fluoxetine attenuated the 5-HT1A receptor agonist 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT)-induced hypothermia, decrease in DR 5-HT neuronal activity and 5-HT release in both vehicle- and corticosterone-pre-treated mice. However, such desensitization was more pronounced in corticosterone pre-treated mice. This change had an overall effect on serotonergic tone since we found a greater firing rate of 5-HT neurons associated with an enhancement of 5-HT outflow in the DR of corticosterone-pre-treated mice in response to fluoxetine compared to the corresponding group of vehicle-pre-treated mice. These results provide cellular explanations on the reasons why SSRIs produce antidepressant effects in pathological conditions but not in naïve animals or healthy volunteers.
- Received September 20, 2011.
- Revision received October 26, 2011.
- Accepted October 26, 2011.
- The American Society for Pharmacology and Experimental Therapeutics