A mechanism of antidepressant action is associated with decreasing levels of tumor necrosis factor (TNF) in the brain
Clonan, Ellyce Lauren
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Tumor necrosis factor-alpha (TNF), a pro-inflammatory cytokine, is involved in normal physiology of the body, as well as the pathophysiology of numerous diseases. A higher concentration of TNF has been noted to be involved in various neurological disorders including neuropathic pain, depression, Alzheimer's disease, stroke, and multiple sclerosis. Various therapeutic strategies aimed at decreasing TNF levels systemically have proven ineffective for these diseases. Therefore, targeting brain TNF to decrease local elevated levels may provide relief to patients suffering from these neurological disorders. Interestingly, antidepressants are used as a treatment method for these disorders. Following antidepressant treatment, it has been shown that TNF levels decrease, thereby supporting a role for TNF in the pathogenesis of these neurological disorders. A primary problem with antidepressants use for depression is that they fail to relieve depressive symptoms until approximately 14 days after their first administration, even though levels of monoamine neurotransmitters are increased within minutes to hours. Thus, there is a strong need for research into alternative antidepressant treatments that can work faster for a wider range of patients. Ketamine has been shown to rapidly improve depressive symptoms, but its mechanism of antidepressant action is relatively unknown. Omega-3 fatty- acids also decrease depressive symptoms, leading to speculation that its derivative, resolvin-D2, has antidepressant effects as well. The goal of this project was to assess ketamine and resolvin- D2 for antidepressant effectiveness and their influence on TNF levels in select brain regions, serum, and macrophages. Depressive-like behavior and TNF levels were assessed after acute drug administration in the forced swim test (FST) and after chronic drug administration in the novelty-induced hypophagia (NIH) test. Ketamine and resolvin-D2 were compared to the antidepressants desipramine, zimelidine, and wellbutrin to see if there was a common mechanism of action. In the FST, all drugs were shown to decrease depressive-like behavior. Ketamine and resolvin-D2 decreased serum and brain TNF levels specifically in the hippocampus and locus coeruleus, while desipramine and wellbutrin did not have an acute effect on brain TNF levels. Ketamine was the only agent to work in the NIH test after acute administration. All other antidepressant agents worked effectively in the NIH test after chronic administration by improving intake and latency to approach and consume graham crackers. After chronic administration of desipramine, zimelidine, wellbutrin, and resolvin-D2, TNF levels in the serum, hippocampus, and locus coeruleus showed a significant decrease. The decreasing brain TNF levels following antidepressant administration correlates with the alleviation of depressive-like symptoms within the behavioral tests. Therefore, these findings suggest that ketamine and resolvin-D2 may serve as effective antidepressant agents possibly by decreasing TNF levels in brain regions associated with antidepressant action.