Sex-differences in anxiety, neuroinflammatory markers, and enhanced fear learning following chronic heroin withdrawal

Abstract

Post-traumatic stress disorder (PTSD) and opioid use disorder (OUD) are comorbid in clinical populations. However, both pre-clinical and clinical studies of these co-occurring disorders have disproportionately represented male subjects, limiting the applicability of these findings. Our previous work has identified chronic escalating heroin administration and withdrawal can produce enhanced fear learning. This behavior is associated with an increase in dorsal hippocampal (DH) interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and glial fibrillary acidic protein (GFAP) immunoreactivity. Further, we have shown that these increases in IL-1β and TNF-α are mechanistically necessary for the development of enhanced fear learning. Although these are exciting findings, this paradigm has only been studied in males. The current studies aim to examine sex differences in the behavioral and neuroimmune effects of chronic heroin withdrawal and future enhanced fear learning. In turn, we determined that chronic escalating heroin administration can produce withdrawal in female rats comparable to male rats. Subsequently, we examined the consequence of heroin withdrawal on future enhanced fear learning and IL-1β, TNF-α, and GFAP immunoreactivity. Strikingly, we identified sex differences in these neuroimmune measures, as chronic heroin administration and withdrawal does not produce enhanced fear learning or immunoreactivity changes in females. Moreover, we determined whether heroin withdrawal produces short-term and long-term anxiety behaviors in both female and males. Collectively, these novel experiments are the first to test whether heroin withdrawal can sensitize future fear learning, produce neurobiological changes, and cause short-term and long-term anxiety behaviors in female rats.

Amelioration of morphine withdrawal syndrome by systemic and intranasal administration of mesenchymal stem cell‐derived secretome in preclinical models of morphine dependence

“…Another possible explanation for the absence of increased oxidative stress in our animal model could be attributed to sex differences observed in response to opioid exposure 97–99 . A significant proportion of the reports showing an increase in brain oxidative stress are based on studies conducted in male rats, 69,100–104 unlike the present studies in female rats, suggesting that sex of the animal might also be an important variable 105 …”

“…[97][98][99] A significant proportion of the reports showing an increase in brain oxidative stress are based on studies conducted in male rats, 69,[100][101][102][103][104] unlike the present studies in female rats, suggesting that sex of the animal might also be an important variable. 105 Neuroinflammation and oxidative stress self-potentiate each other, 106 and both processes have been associated with a reduction of the levels and activity of the key glutamate transporters GLT-1 and system X c − , [27][28][29][30] resulting in the imbalance of glutamatergic neurotransmission and to the potentiation of withdrawal symptoms and drug relapse. 31 glutamate determination induced by the secretome treatment, suggesting a potential effect on glutamate elimination dynamics, however, it did not significantly affect the expression of the glutamate transporters GLT-1 or system X c − .…”

“… 97 , 98 , 99 A significant proportion of the reports showing an increase in brain oxidative stress are based on studies conducted in male rats, 69 , 100 , 101 , 102 , 103 , 104 unlike the present studies in female rats, suggesting that sex of the animal might also be an important variable. 105 …”