RT Journal Article
SR Electronic
T1 Functional Status of Somatodendritic 5-HT1A Autoreceptor after Chronic Treatment with Fluoxetine in a Mouse Model of Anxiety/depression Based on Repeated Corticosterone Administration
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.111.075796
DO 10.1124/mol.111.075796
A1 Quentin Rainer
A1 Thanh Hai Nguyen
A1 Gael Quesseveur
A1 Alain M Gardier
A1 Denis J David
A1 Bruno P Guiard
YR 2011
UL http://molpharm.aspetjournals.org/content/early/2011/10/26/mol.111.075796.abstract
AB 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.