Tags

Type your tag names separated by a space and hit enter

Innate immune factors modulate ethanol interaction with GABAergic transmission in mouse central amygdala.
Brain Behav Immun. 2014 Aug; 40:191-202.BB

Abstract

Excessive ethanol drinking in rodent models may involve activation of the innate immune system, especially toll-like receptor 4 (TLR4) signaling pathways. We used intracellular recording of evoked GABAergic inhibitory postsynaptic potentials (eIPSPs) in central amygdala (CeA) neurons to examine the role of TLR4 activation by lipopolysaccharide (LPS) and deletion of its adapter protein CD14 in acute ethanol effects on the GABAergic system. Ethanol (44, 66 or 100mM) and LPS (25 and 50μg/ml) both augmented eIPSPs in CeA of wild type (WT) mice. Ethanol (44mM) decreased paired-pulse facilitation (PPF), suggesting a presynaptic mechanism of action. Acute LPS (25μg/ml) had no effect on PPF and significantly increased the mean miniature IPSC amplitude, indicating a postsynaptic mechanism of action. Acute LPS pre-treatment potentiated ethanol (44mM) effects on eIPSPs in WT mice and restored ethanol's augmenting effects on the eIPSP amplitude in CD14 knockout (CD14 KO) mice. Both the LPS and ethanol (44-66mM) augmentation of eIPSPs was diminished significantly in most CeA neurons of CD14 KO mice; however, ethanol at the highest concentration tested (100mM) still increased eIPSP amplitudes. By contrast, ethanol pre-treatment occluded LPS augmentation of eIPSPs in WT mice and had no significant effect in CD14 KO mice. Furthermore, (+)-naloxone, a TLR4-MD-2 complex inhibitor, blocked LPS effects on eIPSPs in WT mice and delayed the ethanol-induced potentiation of GABAergic transmission. In CeA neurons of CD14 KO mice, (+)-naloxone alone diminished eIPSPs, and subsequent co-application of 100mM ethanol restored the eIPSPs to baseline levels. In summary, our results indicate that TLR4 and CD14 signaling play an important role in the acute ethanol effects on GABAergic transmission in the CeA and support the idea that CD14 and TLR4 may be therapeutic targets for treatment of alcohol abuse.

Authors+Show Affiliations

Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, USA. Electronic address: mbajo@scripps.edu.Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, USA.Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, USA.Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712, USA.Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, USA.Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, USA.Chemical Biology Research Branch, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, Rockville, MD 20852, USA.Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX 78712, USA.Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 N. Torrey Pines, La Jolla, CA 92037, USA. Electronic address: geobob@scripps.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

24675033

Citation

Bajo, Michal, et al. "Innate Immune Factors Modulate Ethanol Interaction With GABAergic Transmission in Mouse Central Amygdala." Brain, Behavior, and Immunity, vol. 40, 2014, pp. 191-202.
Bajo M, Madamba SG, Roberto M, et al. Innate immune factors modulate ethanol interaction with GABAergic transmission in mouse central amygdala. Brain Behav Immun. 2014;40:191-202.
Bajo, M., Madamba, S. G., Roberto, M., Blednov, Y. A., Sagi, V. N., Roberts, E., Rice, K. C., Harris, R. A., & Siggins, G. R. (2014). Innate immune factors modulate ethanol interaction with GABAergic transmission in mouse central amygdala. Brain, Behavior, and Immunity, 40, 191-202. https://doi.org/10.1016/j.bbi.2014.03.007
Bajo M, et al. Innate Immune Factors Modulate Ethanol Interaction With GABAergic Transmission in Mouse Central Amygdala. Brain Behav Immun. 2014;40:191-202. PubMed PMID: 24675033.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Innate immune factors modulate ethanol interaction with GABAergic transmission in mouse central amygdala. AU - Bajo,Michal, AU - Madamba,Samuel G, AU - Roberto,Marisa, AU - Blednov,Yuri A, AU - Sagi,Vasudeva N, AU - Roberts,Edward, AU - Rice,Kenner C, AU - Harris,R Adron, AU - Siggins,George R, Y1 - 2014/03/24/ PY - 2014/02/11/received PY - 2014/03/12/revised PY - 2014/03/16/accepted PY - 2014/3/29/entrez PY - 2014/3/29/pubmed PY - 2015/3/31/medline KW - Alcohol KW - Drug abuse KW - Extended amygdala KW - Inflammation KW - LPS KW - Neuroimmune KW - Toll-like receptor SP - 191 EP - 202 JF - Brain, behavior, and immunity JO - Brain Behav Immun VL - 40 N2 - Excessive ethanol drinking in rodent models may involve activation of the innate immune system, especially toll-like receptor 4 (TLR4) signaling pathways. We used intracellular recording of evoked GABAergic inhibitory postsynaptic potentials (eIPSPs) in central amygdala (CeA) neurons to examine the role of TLR4 activation by lipopolysaccharide (LPS) and deletion of its adapter protein CD14 in acute ethanol effects on the GABAergic system. Ethanol (44, 66 or 100mM) and LPS (25 and 50μg/ml) both augmented eIPSPs in CeA of wild type (WT) mice. Ethanol (44mM) decreased paired-pulse facilitation (PPF), suggesting a presynaptic mechanism of action. Acute LPS (25μg/ml) had no effect on PPF and significantly increased the mean miniature IPSC amplitude, indicating a postsynaptic mechanism of action. Acute LPS pre-treatment potentiated ethanol (44mM) effects on eIPSPs in WT mice and restored ethanol's augmenting effects on the eIPSP amplitude in CD14 knockout (CD14 KO) mice. Both the LPS and ethanol (44-66mM) augmentation of eIPSPs was diminished significantly in most CeA neurons of CD14 KO mice; however, ethanol at the highest concentration tested (100mM) still increased eIPSP amplitudes. By contrast, ethanol pre-treatment occluded LPS augmentation of eIPSPs in WT mice and had no significant effect in CD14 KO mice. Furthermore, (+)-naloxone, a TLR4-MD-2 complex inhibitor, blocked LPS effects on eIPSPs in WT mice and delayed the ethanol-induced potentiation of GABAergic transmission. In CeA neurons of CD14 KO mice, (+)-naloxone alone diminished eIPSPs, and subsequent co-application of 100mM ethanol restored the eIPSPs to baseline levels. In summary, our results indicate that TLR4 and CD14 signaling play an important role in the acute ethanol effects on GABAergic transmission in the CeA and support the idea that CD14 and TLR4 may be therapeutic targets for treatment of alcohol abuse. SN - 1090-2139 UR - https://www.unboundmedicine.com/medline/citation/24675033/Innate_immune_factors_modulate_ethanol_interaction_with_GABAergic_transmission_in_mouse_central_amygdala_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0889-1591(14)00073-7 DB - PRIME DP - Unbound Medicine ER -