Dorsal hippocampal interleukin-1 signaling mediates heroin withdrawal-enhanced fear learning

Abstract

Converging evidence suggests opioid abuse can increase the incidence and severity of post-traumatic stress disorder (PTSD) in clinical populations. Interestingly, opioid withdrawal alone can produce symptoms similar to those of PTSD. Despite this association, the neural mechanisms underlying the relationship of opioid abuse, withdrawal, and PTSD is poorly understood. Our laboratory has investigated the neurobiological underpinnings of stress-enhanced fear learning (SEFL), an animal model of PTSD-like symptoms. We have previously shown that, in SEFL, a severe footshock induces an increase in dorsal hippocampal (DH) interleukin-1β (IL-1β), and subsequent fear learning is blocked by DH IL-1 receptor antagonism (IL-1RA). Given that opioids and stress engage similar neuroimmune mechanisms, the present experiments investigate whether the same mechanisms drive heroin withdrawal to induce a PTSD-like phenotype. First, we tested the effect of a chronic escalating heroin dose and withdrawal regimen on fear learning and found it produces enhanced future fear learning. Heroin withdrawal also induces a timedependent, region-specific increase in IL-1β and glial fibrillary acidic protein (GFAP) immunoreactivity within the dentate gyrus of the DH. IL-1β was significantly colocalized with GFAP, indicating astrocytes may be involved in increased IL-1β. Moreover, intra-DH infusions of IL-1RA 0, 24, and 48 h into heroin withdrawal prevents the development of enhanced fear learning but does not alter withdrawal-induced weight loss. Collectively, our data suggests heroin withdrawal is sufficient to produce enhanced fear learning, astrocytes may play a role in heroin withdrawal-induced IL-1β, and DH IL-1 signaling during withdrawal mediates the development of heroin withdrawal-enhanced fear learning.

Hippocampal TNF-α Signaling Mediates Heroin Withdrawal-Enhanced Fear Learning and Withdrawal-Induced Weight Loss

“…Exposure to chronic heroin administration and withdrawal increases TNF-α immunoreactivity within the DG up to 48 h into withdrawal. This finding complements our recently published IL-1 findings [21]; however, IL-1 was only seen to be upregulated during the 24-h withdrawal period. The current experiments demonstrate both chronic heroin administration and withdrawal increase TNF-α immunoreactivity, as TNF-α was also increased at the non-withdrawal 0-h timepoint.…”

“…Our analysis focused on the DH as this region has been shown to be critical to context-dependent fear learning and conditioning [35][36][37]. Specifically, we focused on the DG subregion, as this is where we observed increased IL-1β expression during heroin withdrawal [21]. We identified increased TNF-α immunoreactivity within the DG following chronic heroin administration 0, 24, and 48 h into withdrawal.…”

“…We have recently developed an animal model for chronic escalating heroin administration and withdrawal that we use in combination with the enhanced fear learning paradigm [ 21 ]. This model produces reliable withdrawal behaviors such as wet dog shakes, diarrhea, and teeth chattering 24 h after the last heroin dose.…”

“…Importantly, this model also produces significant weight loss in heroin-treated animals, a hallmark sign of rodent opioid withdrawal. Strikingly, this model of heroin administration and withdrawal is capable of producing enhanced fear learning and long-lasting hyperarousal [ 21 ]. This exciting finding suggests that prolonged opioid exposure and subsequent withdrawal elicit increased stress vulnerability and produce persistent hyperreactivity in a rodent model.…”

“…This exciting finding suggests that prolonged opioid exposure and subsequent withdrawal elicit increased stress vulnerability and produce persistent hyperreactivity in a rodent model. In addition to the behavioral consequences, heroin withdrawal induces a similar region-specific increase in IL-1β immunoreactivity within the DG [ 21 ]. Critically, intra-DH IL-1RA during heroin withdrawal prevented the development of heroin withdrawal-enhanced fear learning [ 21 ].…”