Despite several decades of research, no unifying hypothesis for a molecular/cellular basis of action for antidepressant drugs (or depressive disorders) has emerged. Over the last several years, we have suggested that, in addition to pre-synaptic targets (uptake sites), a number of antidepressant drugs have a post-synaptic mechanism of action. Toward this end, we have observed that chronic treatment (3-5 days) of C6 glioma cells with a number of chemically diverse antidepressant compounds translocates the heterotrimeric G protein Gs1 out of lipid rafts and into a closer association with adenylyl cyclase. Post-mortem tissue from depressed- suicides shows just the opposite, with an increased proportion of Gsa ensconsed in lipid rafts. This study will examine the antidepressant-induced movement of Gs1 out of lipid rafts and the consequences of this for G protein signaling systems. The cells to be examined are lymphoblasts generated from depressed subjects who responded, or did not respond to citalopram (many from the STAR*D study). While these cells are routinely used for genetic studies, we suggest that their use in a cell biological approach to depression and antidepressant action is both novel and with great potential. The extent of Gs1 in lipid rafts will be correlated with both depression ratings and clinical response to antidepressants. Cells will treated directly with antidepressant and will then be analyzed for the amount of Gsa in raft and non-raft membrane compartments both before and during drug treatment. This will be correlated with degree of depression and extent of therapeutic response. Cells will also be examined for downstream consequences of increased cAMP signaling, including activated pCREB and BDNF. Gsa translocation will also be confirmed in living cells expressing a fluorescent Gsa fusion protein. The ratio between raft:non-raft Gsa may prove to be a peripheral tissue biological marker for depression and an early (< 1 week) indicator of successful antidepressant treatment that can be developed into a clinically useful, inexpensive and readily-available biomarker for clinical use.
The burden of depression, both from a societal and economic standpoint, ranks second only to ischemic heart disease. By the year 2020, the World Health Organization projects that depression will be the leading cause of disability worldwide. Depression and suicide are particularly prevalent in military returning from deployment and the population of Veterans they become. We have observed in studies with cultured cells and examination of brains taken from suicide victims with documented depression, that a protein involved in the action of neurotransmitters, such as serotonin, becomes less soluble in the presence of a detergent. We will examine this in blood cells from depressed patients who responded to antidepressants as well as those who didn't. We suggest that the solubility of this protein, known as Gsa, is an easily identified marker for depression as well as therapeutic response, which is available in blood cells. Knowledge gained from this study should help to develop a rapid and inexpensive screen for antidepressant responsiveness, allowing changes in therapy long before the current 4-6 week lag time.
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