Dorsal hippocampal interleukin-1 signaling mediates heroin withdrawal-enhanced fear learning
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ORIGINAL INVESTIGATION
Dorsal hippocampal interleukin-1 signaling mediates heroin withdrawal-enhanced fear learning Shveta V. Parekh 1 & Jacqueline E. Paniccia 1 & Christina L. Lebonville 1 & Donald T. Lysle 1 Received: 15 June 2020 / Accepted: 17 August 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Glia . Heroin . Neuroimmunology . Opioid . PTSD . Withdrawal
Introduction Post-traumatic stress disorder (PTSD) is a complex and devastating mental disorder with a myriad of psychological and physiological consequences, including dysregulation of immune systems (Gill et al. 2009; Xia et al. 2013). Atrisk populations include active military personnel, emergency responders, and abused individuals (Thomas et al. 2010). Importantly, evidence indicates significant comorbidity between PTSD and opioid use disorders (Jacobsen et al. 2001; McCauley et al. 2012; Meier et al. 2014; Patel et al. 2017). Heroin use disorder is associated with
* Donald T. Lysle [email protected] 1
Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, CB#3270, Chapel Hill, NC 27599-3270, USA
increased anxiety diagnoses and can increase severity of PTSD symptoms in clinical populations (Jacobsen et a
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