HIV-1 Tat Protein and Oxycodone Dysregulate Hypothalamic Pituitary Adrenal axis and Promote Affective and Cognitive Dysfunction in Mice

Human immunodeficiency virus (HIV) is associated with co-morbid affective and neurocognitive disorders that afflict ~50% of infected individuals. One factor that may contribute to neuropathology is the HIV regulatory protein, trans-activator of transcription (Tat), which promotes neuroinflammation and neurotoxicity that can be exacerbated by opioids. We and others have observed steroid hormones, such as estradiol and/or progesterone, to attenuate Tat-mediated neurotoxicity in cell culture; however, their interactions with opioids and their protective effects in a whole-animal model are unknown.

Mohammed NJbC

We hypothesized that doxycycline-inducible expression of Tat in transgenic mice would interact with the opioid, oxycodone, to induce psychomotor, anxiety-like, and depression-like behavior and to dysregulate hypothalamic pituitary adrenal (HPA) axis. When administered acutely, oxycodone (3 mg/kg) increased psychomotor behavior in an open field and induction of HIV-1 Tat protein significantly potentiated these effects. Tat expression also potentiated the anxiolytic-like effects of oxycodone, increasing entries into the center of the open field, but only among females in the diestrous phase of the estrous cycle. Tat increased depression-like behavior among proestrous, but not diestrous, females. When administered oxycodone (3 mg/kg, QD for 5d) repeatedly expression of Tat protein interacted with estrous cycle of mice to decrease cognitive performance in a novel object recognition test in proestrous mice.

These data suggest that induction of Tat potentiates psychomotor and anxiety-like effects of acute oxycodone and either Tat induction or repeated oxycodone perturb cognitive performance. Manipulations also influenced HPA axis. Tat or oxycodone increased circulating corticosterone in all mice acutely and repeated administration produced greater elevations. Tat-neurotoxicity in differentiated SH-SY5Y cell cultures is ameliorated by estradiol or progesterone and does not interact with oxycodone. Thus, neuroendocrine function may be an important target for HIV-1 Tat/opioid interactions.

Salahuddin Mohammed

Department of Biomolecular Sciences

University of Mississippi

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