Roles of MT1 and MT2 Receptors in Mediating the Effects of Luzindole on Depression-like and Anxiety-like Behaviors and Hippocampal Neurogenesis
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Mood disorders, particularly major depressive disorder, are a leading cause of morbidity and mortality in the world. The current antidepressant treatments are limited in term of efficacy and safety, opening a venue to develop novel antidepressants. Melatonin is a neuro-hormone primarily synthesized by the pineal gland following a circadian rhythm with a high level during the night and a low level during the day. Disturbance in the synthesis and secretion of melatonin has been reported in various mood disorders, including major depressive disorder. However, the role of endogenous melatonin in the pathophysiology of depressive disorder is unclear. Melatonin primarily acts through two G protein-coupled receptors, the MT 1 and MT 2 . Previously, we demonstrated that luzindole, an MT 1 /MT 2 competitive melatonin receptor antagonist, exerts antidepressant-like activity in a rodent test of behavioral despair via action on the MT 2 receptor in C3H/HeN mice. The current thesis study further investigated the antidepressant-like properties of luzindole in modulating hippocampal neurogenesis and in rescuing depressive-like behaviors in a model of depression. In addition, the thesis study investigated the role of the MT 1 and MT 2 receptor in regulating the basal level depressive- and anxiety-like behaviors and the effect of luzindole. Antidepressants increase hippocampal neurogenesis to exert antidepressant-like effect in rodent and nonhuman primate model of depression. We assessed the effect of chronic luzindole treatment on antidepressant-like activity and hippocampal neurogenesis. Luzindole induced antidepressant-like activity and increased hippocampal neurogenesis. The melatonin receptor type mediating effect of luzindole was determined using mice with genetic deletion of the MT 1 and/or MT 2 receptors. The MT 1 receptor knockout (MT 1 KO) blocked effect of luzindole on hippocampal cell proliferation while the MT 2 knockout (MT¬2KO) blocked the antidepressant-like effect of luzindole. To further characterize the antidepressant-like properties of luzindole, its effects were investigated in a chronic unpredictable mild stress model of depression in the C3H/HeN mice. The stress group received 4 weeks of unpredictable mild stress while the control was left undisturbed. Then control and stress groups were treated with chronic vehicle, luzindole or fluoxetine. The stress protocol significantly increased the level of anhedonia, behavioral despair, and social avoidance in mice. Post-stress treatment with luzindole rescued behavioral despair but had no effect on social avoidance behavior in the stressed mice. In addition, luzindole treatment may have increased anxiety-like behavior in the control mice. To determine the role of the melatonin receptors in depression and anxiety, the effect of genetic deletion of the MT 1 and/or MT 2 receptors on depression-like and anxiety-like behaviors was studied in C3H/HeN mice. Deletion of the MT 1 and/or MT 2 receptors caused anhedonic and social avoidance behavior, and anxiety-like behavior. In conclusion, luzindole treatment increased hippocampal neurogenesis and exerted antidepressant-like effect through distinct actions at the MT 1 and MT 2 receptors indicating that the antidepressant-like effect of luzindole does not require an increase in hippocampal cell proliferation and neurogenesis. Luzindole, through blocking the MT 2 receptor, may have therapeutic potential in depression. However, luzindole blocking the MT 1 and MT 2 melatonin may increase the risk of anxiety-related symptoms. Furthermore, down-regulation of the MT 1 and MT 2 receptors may be involved in the development of depression and anxiety.