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Induction of brain cytokines during times of stress has potent effects on altering behavior, mood, and cognitive functioning. Currently, it is unknown why exposure to some stressors such as tailshock and footshock elevate brain cytokines, while exposure to swim, predator odor, and restraint stress do not. Recent data indicate that brain noradrenergic signaling mediates brain cytokine production suggests magnitude of norepinephrine release during stress may be critical in initiating brain cytokine production. The aim of the current study was to investigate stress-induced brain cytokines between rat strains that differ in their magnitude of stress responsiveness as measured by brain norepinephrine and HPA responses. Sprague-Dawley and Fischer rats were placed in a restraint bag for 1h or 2h and sacrificed immediately following stressor termination. Exposure to restraint significantly elevated hypothalamic IL-1β and IL-1R2 mRNA after 1h and IL-1β protein after 2h in the high stress responsive Fischer rats, but not in Sprague-Dawley rats. IL-6, IL-1R1, Il-1RA and Cox-2 mRNA were not altered and neither was expression of any cytokines in the hippocampus or circulating cytokines in either strain. Administration of desipramine (a norepinephrine reuptake inhibitor) to Sprague-Dawley rats was sufficient either alone or in combination with stress to increase IL-1β mRNA in the hypothalamus and desipramine combined with stress was sufficient to increase IL-1R2 mRNA in the hypothalamus. These data support our hypothesis that there is a critical threshold of brain norepinephrine necessary to stimulate brain cytokines, which may help to explain why severe stressors are more commonly reported to induce brain cytokines. These data also suggest an organisms’ susceptibility to stress-induced brain cytokine production depends on responsiveness and regulation of noradrenergic neurons.

Stress is a strong risk factor in alcoholic relapse and may exert effects that mimic aspects of chronic alcohol exposure on neurobiological systems. With the neuroimmune system becoming a prominent focus in the study of the neurobiological consequences of stress, as well as chronic alcohol exposure proving to be a valuable focus in this regard, the present study sought to compare the effects of stress and chronic ethanol exposure on induction of components of the neuroimmune system. Rats were exposed to either 1 h exposure to a mild stressor (restraint) or exposure to withdrawal from 15 days of chronic alcohol exposure (i.e., withdrawal from chronic ethanol, WCE) and assessed for neuroimmune mRNAs in brain. Restraint stress alone elevated chemokine (C–C motif) ligand 2 (CCL2), interleukin-1-beta (IL-1β), tumor necrosis factor alpha (TNFα) and toll-like receptor 4 (TLR4) mRNAs in the cerebral cortex within 4 h with a return to a control level by 24 h. These increases were not accompanied by an increase in corresponding proteins. Withdrawal from WCE also elevated cytokines, but did so to varying degrees across different cytokines and brain regions. In the cortex, stress and WCE induced CCL2, TNFα, IL-1β, and TLR4 mRNAs. In the hypothalamus, only WCE induced cytokines (CCL2 and IL-1β) while in the hippocampus, WCE strongly induced CCL2 while stress and WCE induced IL-1β. In the amygdala, only WCE induced CCL2. Finally—based on the previously demonstrated role of corticotropin-releasing factor 1 (CRF1) receptor inhibition in blocking WCE-induced cytokine mRNAs—the CRF1 receptor antagonist CP154,526 was administered to a subgroup of stressed rats and found to be inactive against induction of CCL2, TNFα, or IL-1β mRNAs. These differential results suggest that stress and WCE manifest broad neuroimmune effects in brain depending on the cytokine and brain region, and that CRF inhibition may not be a relevant mechanism in non-alcohol exposed animals. Overall, these effects are complex in terms of their neuroimmune targets and neuroanatomical specificity. Further investigation of the differential distribution of cytokine induction across neuroanatomical regions, individual cell types (e.g., neuronal phenotypes and glia), severity of chronic alcohol exposure, as well as across differing stress types may prove useful in understanding differential mechanisms of induction and for targeting select systems for pharmacotherapeutic intervention in alcoholism.

Zimomra ZR, Porterfield VM, Camp RM, Johnson JD. Time-dependent mediators of HPA axis activation following live Escherichia coli . Am J Physiol Regul Integr Comp Physiol 301: R1648-R1657, 2011. First published September 14, 2011 doi:10.1152/ajpregu.00301.2011.-The hypothalamus-pituitary-adrenal (HPA) axis is activated during an immune challenge to liberate energy and modulate immune responses via feedback and regulatory mechanisms. Inflammatory cytokines and prostaglandins are known contributors to HPA activation; however, most previous studies only looked at specific time points following LPS administration. Since whole bacteria have different immune stimulatory properties compared with LPS, the aim of the present studies was to determine whether different immune products contribute to HPA activation at different times following live Escherichia coli challenge. Sprague-Dawley rats were injected intraperitoneally with E. coli (2.5 ϫ 10 7 CFU) and a time course of circulating corticosterone, ACTH, inflammatory cytokines, and PGE2 was developed. Plasma corticosterone peaked 0.5 h after E. coli and steadily returned to baseline by 4 h. Plasma PGE2 correlated with the early rise in plasma corticosterone, whereas inflammatory cytokines were not detected until 2 h. Pretreatment with indomethacin, a nonselective cyclooxygenase inhibitor, completely blocked the early rise in plasma corticosterone, but not at 2 h, whereas pretreatment with IL-6 antibodies had no effect on the early rise in corticosterone but attenuated corticosterone at 2 h. Interestingly, indomethacin pretreatment did not completely block the early rise in corticosterone following a higher concentration of E. coli (2.5 ϫ 10 8 CFU). Further studies revealed that only animals receiving indomethacin prior to E. coli displayed elevated plasma and liver cytokines at early time points (0.5 and 1 h), suggesting prostaglandins suppress early inflammatory cytokine production. Overall, these data indicate prostaglandins largely mediate the early rise in plasma corticosterone, while inflammatory cytokines contribute to maintaining levels of corticosterone at later time points.corticosterone; prostaglandin; IL-6; indomethacin ACTIVATION OF THE hypothalamus-pituitary-adrenal (HPA) axis is one of the critical brain-mediated sickness responses that enhance survival of an organism during an immune challenge. The resulting elevation in circulating glucocorticoids, mainly cortisol in humans and corticosterone in mice and rats, liberate energy necessary to mount a fever and have numerous immunomodulatory effects that reduce the risk of septic shock and increase the chances of survival during infection (52, 53). For example, glucocorticoids suppress proinflammatory cytokines (2, 17, 34) and prostaglandin production (27, 38), stimulate anti-inflammatory cytokine production (16, 20), upregulate Fc receptors and major histocompatibility complex class II molecules on phagocytes (24), increase cell adhesion molecules on endothelial cells (57), enhance acute phase changes in t...

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