ABSTRACT
We investigated the mechanisms underlying the effects of the antidepressant fluoxetine on behavior and adult hippocampal neurogenesis (AHN). After confirming our earlier report that the signaling molecule ß-arrestin-2 (ß-Arr2) is required for the antidepressant-like effects of fluoxetine, we found that the effects of fluoxetine on proliferation of neural progenitors and survival of adult-born granule cells are absent in the ß-Arr2 knockout (KO) mice. To our surprise, fluoxetine induced a dramatic upregulation of the number of doublecortin (DCX)-expressing cells in the ß-Arr2 KO mice, indicating that this marker can be increased even though AHN is not. We discovered two other conditions where a complex relationship occurs between the number of DCX-expressing cells compared to levels of AHN: a chronic antidepressant model where DCX is upregulated and an inflammation model where DCX is downregulated. We concluded that assessing the number of DCX-expressing cells alone to quantify levels of AHN can be complex and that caution should be applied when label retention techniques are unavailable.
Subject(s)
Doublecortin Protein , Fluoxetine , Animals , Mice , Antidepressive Agents/pharmacology , Fluoxetine/pharmacology , Hippocampus/physiology , Neurogenesis/physiology , NeuronsABSTRACT
Vortioxetine (Brintellix(®), 1-[2-(2,4-dimethylphenyl-sulfanyl)-phenyl]-piperazine) is a multimodal antidepressant targeting the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT3, 5-HT7 receptors and the serotonin (5-HT) transporter (5-HTT). Vortioxetine administration induces antidepressant- and anxiolytic-like effects, and can enhance cognitive performance in rodents. Several clinical trials have reported the efficiency and a satisfactory tolerability of vortioxetine treatment in depressed patients. Remarkably, vortioxetine has a specific positive impact on cognitive symptoms in depressed patients. Overall, vortioxetine is an efficacious antidepressant drug for the treatment of patients with a major depressive episode and has a unique mechanism of action offering a new therapeutic option.
Subject(s)
Antidepressive Agents/therapeutic use , Depressive Disorder, Major/drug therapy , Piperazines/therapeutic use , Sulfides/therapeutic use , Animals , Anti-Anxiety Agents/adverse effects , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/therapeutic use , Antidepressive Agents/adverse effects , Antidepressive Agents/pharmacology , Cognition/drug effects , Depressive Disorder, Major/physiopathology , Humans , Piperazines/adverse effects , Piperazines/pharmacology , Selective Serotonin Reuptake Inhibitors/adverse effects , Selective Serotonin Reuptake Inhibitors/pharmacology , Selective Serotonin Reuptake Inhibitors/therapeutic use , Sulfides/adverse effects , Sulfides/pharmacology , VortioxetineABSTRACT
Depression is a polygenic and highly complex psychiatric disorder that is currently a major burden on society. Depression is highly heterogeneous in presentation and frequently exhibits high comorbidity with other psychiatric and somatic disorders. Commonly used treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal since only a subset of patients achieve remission. In addition, the reason why some individuals respond to SSRIs while others don't are unknown. Here we begin to ask what the basis of treatment resistance is, and propose new strategies to model this phenomenon in animals. We focus specifically on animal models that offer the appropriate framework to study treatment resistance with face, construct and predictive validity.
