Glutamatergic Changes Induced by Stress in the Brain and Effects of Rapid-Acting Antidepressants

Stress is a renowned risk factor for psychiatric disorders, including depression. Although being a physiological response, the inadequate activation of coping strategies or the overwhelming exposure to stress may induce maladaptive changes that favor a condition of vulnerability toward physical and mental diseases. Accordingly, animal models based on stress exposure have been used to study the etiopathology of depression and the mechanisms of antidepressant drugs. Importantly, functional and imaging studies on the brain of depressed patients as well as preclinical evidence in stress-based animal models have shown morpho-functional alterations in glutamatergic brain areas involved in the control of mood and cognitive function, such as the prefrontal cortex, the hippocampus, and the amygdala. Dysfunctions of glutamatergic signaling in these areas have been associated with depressive-like phenotypes in animal models and are thought to be involved in the etiopathogenesis of mental disorders. Therefore, glutamatergic agents have gained increasing attention as therapeutic strategies for the treatment of depression and stress-related disorders. Among them, the NMDA receptor antagonist ketamine has been the first drug to show rapid and sustained antidepressant activity. Ketamine action has been associated with the ability to rescue glutamatergic neuroplastic alterations, and other glutamatergic drugs are under evaluation for their therapeutic potential. This chapter will focus on changes of brain glutamatergic transmission under stress exposure and modulation by rapid-acting glutamatergic antidepressants.