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Brain Sci. 2016, 6(3), 25; doi:10.3390/brainsci6030025

Stress and Withdrawal from Chronic Ethanol Induce Selective Changes in Neuroimmune mRNAs in Differing Brain Sites

1
Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, CB7178, Chapel Hill, NC 27599-7178, USA
2
Department of Psychiatry, The University of North Carolina at Chapel Hill, CB7178, Chapel Hill, NC 27599-7178, USA
3
Curriculum in Neurobiology, The University of North Carolina at Chapel Hill, CB7178, Chapel Hill, NC 27599-7178, USA
4
Department of Pharmacology, The University of North Carolina at Chapel Hill, CB7178, Chapel Hill, NC 27599-7178, USA
5
UNC Neuroscience Center, The University of North Carolina at Chapel Hill, CB7178, Chapel Hill, NC 27599-7178, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Donna Gruol
Received: 16 April 2016 / Revised: 10 July 2016 / Accepted: 20 July 2016 / Published: 27 July 2016
(This article belongs to the Special Issue Advances in Neuroimmunology)
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Abstract

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. View Full-Text
Keywords: restraint stress; chronic ethanol withdrawal; cytokine mRNAs; CRF; alcohol; CP154,526 restraint stress; chronic ethanol withdrawal; cytokine mRNAs; CRF; alcohol; CP154,526
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Knapp, D.J.; Harper, K.M.; Whitman, B.A.; Zimomra, Z.; Breese, G.R. Stress and Withdrawal from Chronic Ethanol Induce Selective Changes in Neuroimmune mRNAs in Differing Brain Sites. Brain Sci. 2016, 6, 25.

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