RT Journal Article
SR Electronic
T1 Functional Status of Somatodendritic Serotonin 1A Autoreceptor after Long-Term 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 106
OP 112
DO 10.1124/mol.111.075796
VO 81
IS 2
A1 Quentin Rainer
A1 Hai T. Nguyen
A1 Gaël Quesseveur
A1 Alain M. Gardier
A1 Denis J. David
A1 Bruno P. Guiard
YR 2012
UL http://molpharm.aspetjournals.org/content/81/2/106.abstract
AB 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-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 hypothermia induced by the 5-HT1A 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.