| Abstract |
Anxiety and depressive disorders are serious illnesses that affect a large percentage of the population. Despite the development of anxiolytic and antidepressant drugs over the past half century, 50% of all depressed patients remain unresponsive to any kind of antidepressant treatment. Therefore there is still an immense medical need to develop pharmacotherapies that are more effective, faster acting and with fewer side-effects than current medications. Stress is one of the leading predisposing factors for anxiety and depression. Although studied broadly, the brain regions and molecular mechanisms underlying pathophysiology of depression have not yet been fully identified. Basic and clinical studies brought to surface several signaling components, significantly dysregulated in depressed patients, and the list is growing further. Accumulating evidence suggests that among the brain regions implicated in the disorder is the prefrontal cortex (PFC), associated with cognition and the nucleus accumbens (NAc), traditionally associated with reward and increased motivation. Members of the regulators of G protein signaling (RGS) are implicated in addiction and NAc-associated actions, while it is known that anxiety, addiction and depression often comorbid. Previous studies from our laboratory have established the involvement of RGS9-2 and RGS4 in the mechanisms of addiction. Here, by using Mus musculus model organism for behavioral and biochemical assays we report a role of those two proteins in stress and depression. Specifically, we show that exposure to immobilization stress upregulates RGS4 protein levels in the PFC, while administration of the non-monoamine targeting drugs, which possess antidepressant action, SNC80 and Ketamine, result in its downregulation. On the contrary, we have recently shown that administration of the tricyclic desipramine, upregulates RGS4 in the other brain region examined, NAc. Here we found that the molecular mechanism underlying desipramine’s action involves changes in the phosphorylation status of the kinase Akt and the transcription factor CREB, which remain unaffected in RGS4 KO mice. Furthermore, we show that ablation of the other RGS protein examined, RGS9-2, produces a depression-like phenotype, while RGS9-2 seems to be important for the action of the monoamine targeting desipramine. Together, the present data shed light on the actions of these two proteins, which convey clinical significance as future direct targets of novel antidepressant drugs or as molecules intervening causally with treatment of depression.
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A Role of murine RGS4 and RGS9-2 in Stress and Depression
