Posttraumatic stress disorder (PTSD) has been shown to be associated with pro-inflammatory markers, including elevated plasma levels of interleukin-1β (IL-1β). However, the precise role of neuroinflammation and central immune signaling on the development of this debilitating psychological disorder is not known. Here, we used stress-enhanced fear learning (SEFL), an animal model of the disorder, to examine the role of central IL-1β in PTSD. The results show that the severe stressor in SEFL induces a time-dependent increase in IL-1β immunoreactivity and mRNA expression within the dentate gyrus of the dorsal hippocampus (DH). There was no increase in IL-1β in the basolateral amygdala or the perirhinal cortex. Moreover, blocking the action of IL-1β following the severe stressor with IL-1 receptor antagonist (10 μg, intracerebroventricular (i.c.v.), 24 and 48 h after the stressor) prevented the development of SEFL. To provide further support for the role of IL-1β in the development of SEFL, we show that systemic morphine, a treatment which is known to reduce both PTSD and SEFL, also reduces IL-1β expression in the DH induced by the severe stressor. These studies provide the first evidence that IL-1 is involved SEFL and suggest that IL-1 signaling in the brain may have a critical role in the development of PTSD.

Post-traumatic stress disorder (PTSD) is associated with immune dysregulation. We have previously shown that severe stress exposure in a preclinical animal model of the disorder, stress-enhanced fear learning (SEFL), is associated with an increase in hippocampal interleukin-1β (IL-1β) and that blocking central IL-1 after the severe stress prevents the development of SEFL. Here, we tested whether blocking hippocampal IL-1 signaling is sufficient to prevent enhanced fear learning and identified the cellular source of stress-induced IL-1β in this region. Experiment 1 tested whether intra-dorsal hippocampal (DH) infusions of interleukin-1 receptor antagonist (IL-1RA, 1.25µg per hemisphere) 24 and 48h after stress exposure prevents the development of enhanced fear learning. Experiment 2 used triple fluorescence immunohistochemistry to examine hippocampal alterations in IL-1β, glial fibrillary acidic protein (GFAP), an astrocyte-specific marker, and ionized calcium binding adaptor molecule -1 (Iba-1), a microglial-specific marker, 48h after exposure to the severe stressor of the SEFL paradigm. Intra-DH IL-1RA prevented SEFL and stress-induced IL-1β was primarily colocalized with astrocytes in the hippocampus. Further, hippocampal GFAP immunoreactivity was not altered, whereas hippocampal Iba-1 immunoreactivity was significantly attenuated following severe stress. These data suggest that hippocampal IL-1 signaling is critical to the development of SEFL and that astrocytes are a predominant source of stress-induced IL-1β.

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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.

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Opioid-associated environmental stimuli elicit robust immune-altering effects via stimulation of a neural circuitry that includes the basolateral amygdala and nucleus accumbens. These brain regions are known to have both direct and indirect connections with the hippocampus. Thus, the present study evaluated whether the dorsal hippocampus (DH), and more specifically interleukin-1 beta (IL-1β) within the DH, is necessary for the expression of heroin-induced conditioned immunomodulation. Rats received five Pavlovian pairings of systemic heroin administration (1.0 mg/kg, SC) with placement into a distinct environment (conditioned stimulus, CS). Six days after conditioning, a GABAA/B agonist cocktail or IL-1β small interfering RNA (siRNA) was microinfused into the DH to inhibit neuronal activity or IL-1β gene expression prior to CS or home cage exposure. Control animals received saline or negative control siRNA microinfusions. Furthermore, all rats received systemic administration of lipopolysaccharide (LPS) to stimulate proinflammatory nitric oxide production. CS exposure suppressed LPS-induced nitric oxide production relative to home cage exposure. Inactivation of, or IL-1β silencing in, the DH disrupted the CS-induced suppression of nitric oxide production relative to vehicle or negative control siRNA treatment. These results are the first to show a role for DH IL-1β expression in heroin-conditioned suppression of a proinflammatory immune response.