BACKGROUND: The prevalence of major depression in those with HIV/AIDS is substantially higher than in the general population. Mechanisms underlying this comorbidity are poorly understood. HIV-transactivator of transcription (Tat) protein, produced and excreted by HIV, could be involved. We determined whether conditional Tat protein expression in mice is sufficient to induce depression-like behaviors and oxidative stress. Further, as oxidative stress is associated with depression, we determined whether decreasing or increasing oxidative stress by administering methylsulfonylmethane (MSM) or diethylmaleate (DEM), respectively, altered depression-like behavior. METHODS: GT-tg bigenic mice received intraperitoneal saline or doxycycline (Dox, 25-100 mg/kg/day) to induce Tat expression. G-tg mice, which do not express Tat protein, also received Dox. Depression-like behavior was assessed with the tail suspension test (TST) and the two-bottle saccharin/water consumption task. Reactive oxygen/nitrogen species (ROS/RNS) were assessed ex vivo. Medial frontal cortex (MFC) oxidative stress and temperature were measured in vivo with 9.4-Tesla proton magnetic resonance spectroscopy (MRS). RESULTS: Tat expression increased TST immobility time in an exposure-dependent manner and reduced saccharin consumption. MSM decreased immobility time while DEM increased it in saline-treated GT-tg mice. Tat and MSM behavioral effects persisted for 28 days. Tat and DEM increased while MSM decreased ROS/RNS levels. Tat expression increased MFC glutathione levels and temperature. CONCLUSIONS: Tat expression induced rapid and enduring depression-like behaviors and oxidative stress. Increasing/decreasing oxidative stress increased/decreased, respectively, depression-like behavior. Thus, Tat produced by HIV may contribute to the high depression prevalence among those with HIV. Further, mitigation of oxidative stress could reduce depression severity.
BACKGROUND: The prevalence of major depression in those with HIV/AIDS is substantially higher than in the general population. Mechanisms underlying this comorbidity are poorly understood. HIV-transactivator of transcription (Tat) protein, produced and excreted by HIV, could be involved. We determined whether conditional Tat protein expression in mice is sufficient to induce depression-like behaviors and oxidative stress. Further, as oxidative stress is associated with depression, we determined whether decreasing or increasing oxidative stress by administering methylsulfonylmethane (MSM) or diethylmaleate (DEM), respectively, altered depression-like behavior. METHODS: GT-tg bigenic mice received intraperitoneal saline or doxycycline (Dox, 25-100 mg/kg/day) to induce Tat expression. G-tg mice, which do not express Tat protein, also received Dox. Depression-like behavior was assessed with the tail suspension test (TST) and the two-bottle saccharin/water consumption task. Reactive oxygen/nitrogen species (ROS/RNS) were assessed ex vivo. Medial frontal cortex (MFC) oxidative stress and temperature were measured in vivo with 9.4-Tesla proton magnetic resonance spectroscopy (MRS). RESULTS: Tat expression increased TST immobility time in an exposure-dependent manner and reduced saccharin consumption. MSM decreased immobility time while DEM increased it in saline-treated GT-tg mice. Tat and MSM behavioral effects persisted for 28 days. Tat and DEM increased while MSM decreased ROS/RNS levels. Tat expression increased MFC glutathione levels and temperature. CONCLUSIONS: Tat expression induced rapid and enduring depression-like behaviors and oxidative stress. Increasing/decreasing oxidative stress increased/decreased, respectively, depression-like behavior. Thus, Tat produced by HIV may contribute to the high depression prevalence among those with HIV. Further, mitigation of oxidative stress could reduce depression severity.
Entities:
Keywords:
HIV; Tat; glutathione; magnetic resonance spectroscopy; major depression; oxidative stress; transgenic mice
Authors: Karim S Echtay; Damien Roussel; Julie St-Pierre; Mika B Jekabsons; Susana Cadenas; Jeff A Stuart; James A Harper; Stephen J Roebuck; Alastair Morrison; Susan Pickering; John C Clapham; Martin D Brand Journal: Nature Date: 2002-01-03 Impact factor: 49.962
Authors: Amanda N Carey; Elizabeth I Sypek; Harminder D Singh; Marc J Kaufman; Jay P McLaughlin Journal: Behav Brain Res Date: 2011-12-20 Impact factor: 3.332
Authors: Iandra Holzmann; Luísa Mota da Silva; José Afonso Corrêa da Silva; Viviane Miranda Bispo Steimbach; Márcia Maria de Souza Journal: Pharmacol Biochem Behav Date: 2015-07-18 Impact factor: 3.533
Authors: Tao Song; Xiaopeng Song; Chenyawen Zhu; Regan Patrick; Miranda Skurla; Isabella Santangelo; Morgan Green; David Harper; Boyu Ren; Brent P Forester; Dost Öngür; Fei Du Journal: Ageing Res Rev Date: 2021-10-29 Impact factor: 10.895
Authors: Gordana D Vitaliano; Jae K Kim; Marc J Kaufman; Christopher W Adam; Gonzalo Zeballos; Abinaya Shanmugavadivu; Sivan Subburaju; Jay P McLaughlin; Scott E Lukas; Franco Vitaliano Journal: Commun Biol Date: 2022-03-17
Authors: Mohammed F Salahuddin; Alaa N Qrareya; Fakhri Mahdi; Dejun Jackson; Matthew Foster; Tamara Vujanovic; J Gaston Box; Jason J Paris Journal: Horm Behav Date: 2019-12-13 Impact factor: 3.587
Authors: Jason J Paris; Xi Chen; Joseph Anderson; Alaa N Qrareya; Fakhri Mahdi; Fei Du; Jay P McLaughlin; Marc J Kaufman Journal: Geroscience Date: 2021-04-05 Impact factor: 7.713
Authors: Mohammed F Salahuddin; Alaa N Qrareya; Fakhri Mahdi; Emaya Moss; Nicholas S Akins; Jing Li; Hoang V Le; Jason J Paris Journal: J Neuroendocrinol Date: 2021-10-14 Impact factor: 3.870
Authors: Sara R Nass; Arianna R S Lark; Yun K Hahn; Virginia D McLane; Therese M Ihrig; Liangru Contois; T Celeste Napier; Pamela E Knapp; Kurt F Hauser Journal: Horm Behav Date: 2021-06-23 Impact factor: 3.492
Authors: Thomas J Cirino; Amy R Alleyne; Vinicius Duarte; Ariana Figueroa; Chloe A Simons; Emet M Anceaume; Justin Kendrick; Olivia Wallman; Shainnel O Eans; Heather M Stacy; Jessica M Medina; Jay P McLaughlin Journal: J Neuroimmune Pharmacol Date: 2021-02-22 Impact factor: 7.285