HIV-1 Tat Protein Promotes Neuroendocrine Dysfunction Concurrent with the Potentiation of Oxycodone's Psychomotor Effects in Female Mice.
Human immunodeficiency virus (HIV) is associated with neuroendocrine dysfunction which may contribute to co-morbid stress-sensitive disorders. The hypothalamic-pituitary-adrenal (HPA) or -gonadal (HPG) axes are perturbed in up to 50% of HIV patients. The mechanisms are not known, but we have found the HIV-1 trans-activator of transcription (Tat) protein to recapitulate the clinical phenotype in male mice. We hypothesized that HPA and/or HPG dysregulation contributes to Tat-mediated interactions with oxycodone, an opioid often prescribed to HIV patients, in females. Female mice that conditionally-expressed the Tat1-86 protein [Tat(+) mice] or their counterparts that did not [Tat(-) control mice] were exposed to forced swim stress (or not) and behaviorally-assessed for motor and anxiety-like behavior. Some mice had glucocorticoid receptors (GR) or corticotropin-releasing factor receptors (CRF-R) pharmacologically inhibited. Some mice were ovariectomized (OVX). As seen previously in males, Tat elevated basal corticosterone levels and potentiated oxycodone's psychomotor activity in females. Unlike males, females did not demonstrate adrenal insufficiency and oxycodone potentiation was not regulated by GRs or CRF-Rs. Rather OVX attenuated Tat/oxycodone interactions. Either Tat or oxycodone increased anxiety-like behavior and their combination increased hypothalamic allopregnanolone. OVX increased basal hypothalamic allopregnanolone and obviated Tat or oxycodone-mediated fluctuations. Together, these data provide further evidence for Tat-mediated dysregulation of the HPA axis and reveal the importance of HPG axis regulation in females. HPA/HPG disruption may contribute vulnerability to affective and substance use disorders.
['Salahuddin|Mohammed F|MF|0000-0001-7306-5989', 'Mahdi|Fakhri|F|', 'Sulochana|Suresh P|SP|0000-0003-0665-9757', 'Paris|Jason J|JJ|0000-0002-5628-1134']
D000818:Animals D001522:Behavior, Animal D004195:Disease Models, Animal D030762:Estrous Cycle D005260:Female D015658:HIV Infections D015497:HIV-1 D006801:Humans D007030:Hypothalamo-Hypophyseal System D051379:Mice D009043:Motor Activity D009490:Neurosecretory Systems D010098:Oxycodone D010913:Pituitary-Adrenal System D011280:Pregnanolone D011597:Psychomotor Performance D013256:Steroids D054322:tat Gene Products, Human Immunodeficiency Virus
trans-activator of transcription opioids antalarmin hypothalamic-pituitary-adrenal axis mifepristone (RU-486) ovariectomy