Antidepressant action of ketamine in two genetic models of impaired glutamate and melatonin function

Abstract

Major depression is a mental disorder characterized by extreme low mood and anhedonia. Facing major depression is an urgent social and medical need since it involves a lot of suffering in patients and their families or friends as well as an important socio-economic cost worldwide. Depression has been studied for many years the different hypothesis have important limitations including the latency time needed for antidepressants to start working, the great number of resistant patients and the enduring vulnerability of many patients to relapse. Those limitations drive the need to develop new strategies to treat this mental disorder. In recent years, one of the molecules that have opened this field is the NMDA antagonist ketamine that increases glutamate transmission in the PFC and trigger antidepressant effects within a few hours. At the preclinical level, most studies focused on identification of molecular mechanisms mediating the rapid antidepressant response of ketamine have been carried out in healthy mice. Here we have studied the effect of ketamine, comparatively to the classic antidepressant reboxetine, in two genetic models of impaired glutamate and melatonin function. The specific endophenotype of the VGLUT1+/- depression model has provided a better comprehension of the molecular mechanisms involved in antidepressant response or resistance to treatment. Specifically this model was resistant to the rapid antidepressant action of ketamine and it is suggested that the phosphorylation of the intracellular mediator eukaryote elongation factor 2 (p-eEF2) could be responsible for this resistance. Further stimulation of PFC VGLUT1 expression using the priming effect of a classic antidepressant or by recombinant adeno-associated virus (AAV) technology rescued the antidepressant action of ketamine. On the other hand, the melatonin receptor 2 deficient model (MT2-/- knock-out mice) showed impaired reward reactivity associated to circadian rhythm disruption and interestingly, both classic and the rapid-acting antidepressant ketamine were effective.