Pregnane Steroidogenesis is Altered by HIV-1 Tat and Morphine: Physiological Allopregnanolone is Protective against Neurotoxic and Psychomotor Effects

Publication date: Available online 29 January 2020Source: Neurobiology of StressAuthor(s): Jason J. Paris, Philippe Liere, Sarah Kim, Fakhri Mahdi, Meagan E. Buchanan, Sara R. Nass, Alaa N. Qrareya, Mohammed F. Salahuddin, Antoine Pianos, Neïké Fernandez, Zia Shariat-Madar, Pamela E. Knapp, Michael Schumacher, Kurt F. HauserAbstractPregnane steroids, particularly allopregnanolone (AlloP), are neuroprotective in response to central insult. While unexplored in vivo, AlloP may confer protection against the neurological dysfunction associated with human immunodeficiency virus type 1 (HIV-1). The HIV-1 regulatory protein, trans-activator of transcription (Tat), is neurotoxic and its expression in mice increases anxiety-like behavior; an effect that can be ameliorated by progesterone, but not when 5α-reduction is blocked. Given that Tat’s neurotoxic effects involve mitochondrial dysfunction and can be worsened with opioid exposure, we hypothesized that Tat and/or combined morphine would perturb steroidogenesis in mice, promote neuronal death, and that exogenous AlloP would rescue these effects. Like other models of neural injury, conditionally inducing HIV-1 Tat in transgenic mice significantly increased the central synthesis of pregnenolone and progesterone’s 5α-reduced metabolites, including AlloP, while decreasing central deoxycorticosterone (independent of changes in plasma). Morphine significantly increased brain and plasma concentrations of several steroids (including...
Source: Neurobiology of Stress - Category: Neuroscience Source Type: research