Grant: Operating Grant

Depression is a heavy burden for individuals and society. The brain neurotransmitter serotonin (5-HT) is incriminated in this disease, and drugs that block its re-entry into 5-HT nerve cells, so-called SSRIs, are commonly used as antidepressants. Yet, little is known of the neurobiological bases of the depressed state, and especially of the molecular mechanisms underlying the efficacy of SSRI antidepressants. We will therefore investigate, in rat models of depression, the subcellular localization of two proteins which determine the activity of 5-HT neurons: the 5-HT1A receptor regulating their firing and release, and SERT, the 5-HT transporter on their plama membrane and primary target of SSRIs. Both proteins will be visualized by immuno-electron microscopy, before and during a chronic treatment with the prototypic SSRI, fluoxetine (Prozac®, and after its cessation. In each condition, the functional state of 5-HT1A receptors will be assessed by examining their capacity to translocate from the surface (membrane) to the inside (cytoplasm) of 5-HT neurons (internalize) when activated with a selective agonist (8-OH-DPAT), and that of SERT by measuring its relative amount on the membrane versus the cytoplasm of 5-HT neurons. Behavioral tests performed in the same animals will allow to correlate observed changes in the functional localization of 5-HT1A receptors and SERT with the behavioral responsiveness to the treatment. Signalling molecules presumably involved in the internalization of 5-HT1A receptors will also be investigated. Such novel information on key parameters of 5-HT function in depression as well as under and after SSRI treatment should help to develop better antidepressant treatments, and also prompt further brain imaging studies eventually applicable to the early diagnosis and therapeutic management of the depressed state in human.