Abstract
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.
Footnotes
This work was supported by fellowships from the French Ministry for Research (to Q.R. and G.Q.) and a fellowship from the French Embassy in Vietnam. The Department of Neuropharmacology is an Equipe d'Accueil (EA 3544) from the Ministère de la Jeunesse, de l'Education Nationale et de la Recherche (MJENR-France). This work was also supported by the technical assistance of Valerie Dupont-Domergue and staff from the animal care facility of the Institut Féderatif de Recherche-IFR141 of the Paris XI University.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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ABBREVIATIONS:
- UCMS
- unpredictable chronic mild stress
- DR
- dorsal raphe
- 5-HT
- serotonin
- SSRI
- selective serotonin-reuptake inhibitor
- 8-OH-DPAT
- 8-hydroxy-2-(di-n-propylamino)tetralin
- WAY100635
- (N-{2-[4 (2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide tri-hydrochloride
- ANOVA
- analysis of variance
- AUC
- area under the curve.
- Received September 20, 2011.
- Accepted October 26, 2011.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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