Neural Immune mechanisms of heroin withdrawal and stress

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Project Summary/Abstract Opiate withdrawal and post-traumatic stress disorder (PTSD) frequently present together in clinical settings. Clinical data also suggests that opiate abuse is a potential risk factor for PTSD. Understanding the mechanism for co-occurrence and vulnerability to PTSD in opiate users will provide information about the consequences of opiate abuse and inform the development of interventions that mitigate both the symptoms of heroin withdrawal, a known risk factor for relapse, and heroin’s long-term effects on stress disorders. Our laboratory has identified the hippocampal mechanisms required for development of stress enhanced fear learning (SEFL), an animal model of PTSD. We established that the severe stressor in the SEFL paradigm induces dorsal hippocampal (DH) interleukin-1β (IL-1β) in astrocytes, and that directly blocking DH IL-1 signaling with IL-1 receptor antagonist (IL- 1RA) after severe stress prevents subsequent enhanced fear learning. We have developed a pre-clinical model to investigate the effect of heroin withdrawal on enhanced fear learning. We found that withdrawal from escalating heroin administration substitutes for a severe stressor in the SEFL paradigm and that heroin withdrawal similarly increases DH IL-1β and GFAP expression, a marker of astrocyte activation. Accordingly, the plan is to test the innovative unique hypothesis that heroin withdrawal also acts through hippocampal IL-1β and alterations in astrocytes that result in enhanced fear learning. Specific Aim 1 will test the hypothesis that heroin withdrawal- induced enhancement of fear learning is mediated by IL-1β in the DH. Specifically, we will determine (A) whether withdrawal-induced enhanced fear learning is associated with potentiation of IL-1β signaling specifically in astrocytes, (B) whether blockade of DH IL-1 receptors with IL-1RA during withdrawal will protect against the development of enhanced fear learning following heroin withdrawal, (C) whether DH infusion of exogenous IL- 1β will substitute for the effects of stress and/or withdrawal to induce enhanced fear learning, and (D) whether pharmacological blockade of DH IL-1 receptors during heroin withdrawal will prevent withdrawal symptoms. Predicted results are that heroin withdrawal will increase IL-1β levels, primarily in astrocytes, and that the effect of heroin withdrawal on enhanced fear learning will be blocked by IL-1RA and mimicked by infusion of IL-1β in the DH. Also, the symptoms of withdrawal will be attenuated or blocked by the administration of IL-1RA. Collectively, the results elucidate the critical role of DH IL-1 signaling in heroin withdrawal and enhanced fear learning. Specific Aim 2 will use advanced 3-D reconstruction of individual cells to conduct morphometric analysis in combination with assessment of synaptic markers (postsynaptic density 95 and Synapsin 1) to test innovative hypotheses that changes in the morphometric properties of astrocytes, and/or alterations of astrocyte/neuron interactions are associated with the effects of both the heroin withdrawal and the severe stressor used in SEFL, and contingent on IL-1 signaling. These studies test unique hypotheses regarding the underlying mechanism of the effects of heroin withdrawal, and provide new targets for mitigating the long-term effects of heroin abuse.