Antidepressant activity: contribution of brain microdialysis in knock-out mice to the understanding of BDNF/5-HT transporter/5-HT autoreceptor interactions

• Main Author: Alain M Gardier
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2013-08-01
• Series: Frontiers in Pharmacology
• Subjects: BDNF; knockout mice; serotonin transporter; mouse models; Antidepressants; monoamines
• Online Access: http://journal.frontiersin.org/Journal/10.3389/fphar.2013.00098/full

Why antidepressants vary in terms of efficacy is currently unclear. Despite the leadership of Selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression, the precise neurobiological mechanisms involved in their therapeutic action are poorly understood. A better knowledge of molecular interactions between monoaminergic system, pre- and post-synaptic partners, brain neuronal circuits and regions involved may help to overcome limitations of current treatments and to identify new therapeutic targets. Intracerebral in vivo microdialysis (ICM) already provided important information about the brain mechanism of action of antidepressants first in anesthetized rats in the early 90s, and since then in conscious wild-type or knockout mice. The principle of ICM is based on the balance between release of neurotransmitters (e.g., monoamines,) and re-uptake by selective transporters (e.g., SERT for serotonin 5-HT). Complementary to electrophysiology, this technique reflects presynaptic monoamines release and intrasynaptic events corresponding to ≈ 80% of whole brain tissue content. The inhibitory role of serotonergic autoreceptors infers that they limit somatodendritic and nerve terminal 5-HT release. It has been proposed that activation of 5-HT1A and 5-HT1B receptor sub-types limit the antidepressant-like activity of Selective Serotonin Reuptake Inhibitors (SSRI). This hypothesis is based partially on results obtained in ICM experiments performed in naïve, non-stressed Rodents. The present review will first remind the principle and methodology of ICM performed in mice. The crucial need of developing animal models that display anxiety and depression-like behaviors, neurochemical and brain morphological phenotypes reminiscent of these mood disorders in Human, will be underlined. Recently developed genetic mouse models have been generated to independently manipulate 5-HT1A auto and hetero-receptors and ICM helped to clarify the role of the presynaptic component