Abstract
Human immunodeficiency virus (HIV) is associated with co-morbid affective and stress-sensitive neuropsychiatric disorders that may be related to dysfunction of the hypothalamic-pituitary-adrenal (HPA) stress axis. The HPA axis is perturbed in up to 46% of HIV patients, but the mechanisms are not known. The neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat), may contribute. We hypothesized that HPA dysregulation may contribute to Tat-mediated interactions with oxycodone, a clinically-used opioid often prescribed to HIV patients. In transgenic male mice, Tat expression produced significantly higher basal corticosterone levels with adrenal insufficiency in response to a natural stressor or pharmacological blockade of HPA feedback, recapitulating the clinical phenotype. On acute exposure, HIV-1 Tat interacted with oxycodone to potentiate psychomotor and anxiety like-behavior in an open field and light-dark transition tasks, whereas repeated exposure sensitized stress-related psychomotor behavior and the HPA stress response. Pharmacological blockade of glucocorticoid receptors (GR) partially-restored the stress response and decreased oxycodone-mediated psychomotor behavior in Tat-expressing mice, implicating GR in these effects. Blocking corticotrophin-releasing factor (CRF) receptors reduced anxiety-like behavior in mice that were exposed to oxycodone. Together, these effects support the notion that Tat exposure can dysregulate the HPA axis, potentially raising vulnerability to stress-related substance use and affective disorders.
Highlights
Human immunodeficiency virus type 1 (HIV-1) continues to be a serious health concern with over 1 million infected individuals in the U.S [1]
Combined antiretroviral drugs have greatly increased the life expectancy of people living with HIV and have reduced the incidence of HIV-associated dementias [2]
Patients still contend with a constellation of neurological symptoms, likely due to poor retention of Combined antiretroviral drugs (cART) within the central nervous system (CNS) and its inability to target neurotoxic HIV-1 proteins and latent viral reservoirs [3]
Summary
Human immunodeficiency virus type 1 (HIV-1) continues to be a serious health concern with over 1 million infected individuals in the U.S [1]. Circulating ACTH stimulates adrenal release of glucocorticoids (primarily cortisol in humans and corticosterone in rats and mice) which act at CNS targets, including glucocorticoid receptors (GR), to attenuate the HPA axis response and restore the sympathetic/parasympathetic tone within the CNS. We have recently observed that transgenic expression of Tat is sufficient to elevate circulating glucocorticoids and central CRF in mice [13] These effects were augmented by exposure to the clinically-prescribed opioid, oxycodone consistent with preclinical demonstrations of Tat/opioid synergy [13,14,15]. We hypothesized that HIV-1 Tat and/or oxycodone would interact to promote HPA axis dysregulation, potentiating oxycodone-mediated effects including psychomotor stimulation and affective dysfunction in a conditionally-inducible Tat transgenic mouse model. We further expected pharmacological blockade of GR and/or CRF receptors to restore HPA function and to ameliorate behavioral deficits
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