Pregnane steroidogenesis is altered by HIV-1 Tat and morphine: Physiological allopregnanolone is protective against neurotoxic and psychomotor effects

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 Hauser

doi:10.1016/j.ynstr.2020.100211

Abstract

Pregnane 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, promoting 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 progesterone, deoxycorticosterone, corticosterone, and their metabolites) likely via activation of the hypothalamic-pituitary-adrenal stress axis. Tat, but not morphine, caused glucocorticoid resistance in primary splenocytes. In neurons, Tat depolarized mitochondrial membrane potential and increased cell death. Physiological concentrations of AlloP (0.1, 1, or 10 nM) reversed these effects. High-concentration AlloP (100 nM) was neurotoxic in combination with morphine. Tat induction in transgenic mice potentiated the psychomotor effects of acute morphine, while exogenous AlloP (1.0 mg/kg, but not 0.5 mg/kg) was ameliorative. Data demonstrate that steroidogenesis is altered by HIV-1 Tat or morphine and that physiological AlloP attenuates resulting neurotoxic and psychomotor effects.

Highlights

Drugs of abuse interact with human immunodeficiency virus type 1 (HIV-1) proteins to promote central nervous system (CNS) dysfunction and/or toxicity in cultured neural cells or animal models (Cai et al, 2016; Mediouni et al, 2015a, 2015b; Nath et al, 2002; Silverstein et al, 2012; Soontornniyomkij et al, 2016)
To first assess whether HIV-1 Tat influences pregnane steroidogenesis, central and circulating steroid levels were measured in Tat(−) and Tat(+) male mice
These findings support the notion that central steroidogenesis is influenced by HIV-1 Tat or morphine and exogenous AlloP may exert several therapeutic benefits that are of interest for present and future work

Summary

Introduction

Drugs of abuse interact with human immunodeficiency virus type 1 (HIV-1) proteins to promote central nervous system (CNS) dysfunction and/or toxicity in cultured neural cells or animal models (Cai et al, 2016; Mediouni et al, 2015a, 2015b; Nath et al, 2002; Silverstein et al, 2012; Soontornniyomkij et al, 2016). The HIV-1 regulatory protein, trans-activator of transcription (Tat), promotes neuroinflammation via the activation of infected and uninfected microglia and astrocytes, indirectly contributing to neurotoxicity (Hauser et al, 2006; Nath et al, 2002). Opioids such as morphine, heroin, methadone, and buprenorphine can exacerbate Tat-mediated cytokine production (Festa and Meucci, 2012; Fitting et al, 2014a; Hauser et al, 2012; Nath et al, 2002).

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