Pregnane steroidogenesis is altered by HIV-1 Tat and morphine: Physiological allopregnanolone is protective against neurotoxic and psychomotor effects
Year: 2020
Type: article
Abstract: , 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.
Source: Neurobiology of Stress
Language: English
Subfield: Behavioral Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,350
Awards: Opiate abuse and sex steroids influence neuroAIDS pathology, Selective vulnerability of discrete neural circuits in the striatum to HIV-opiate comorbidity, Glial Progenitors as Targets of HIV/Opiate Interactions, Mechanisms of opiate drug-HIV-induced neurodegeneration, COBRE Phase III Transitional Center, MOR and CCR5 interactive signaling mediates opiate and HIV-driven synaptodendritic injury, Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences, Regulation of HIV and opiate-directed synaptodendritic injury/death in striatum, Neuron-Glia Mechanisms & Interactions Underlying Opioid Abuse-HIV-1 Comorbidity, Glial CCR5 mediates HIV-Tat and opiate neurotoxicity, G9000176233
OpenAlex ID: W3003960853