title: Role of interleukin-10 (IL-10) in regulation of GABAergic transmission and acute response to ethanol.
abstract: Mounting evidence indicates that ethanol (EtOH) exposure activates neuroimmune signaling. Alterations in pro-inflammatory cytokines after acute and chronic EtOH exposure have been heavily investigated. In contrast, little is known about the regulation of neurotransmission and/or modulation by anti-inflammatory cytokines in the brain after an acute EtOH exposure. Recent evidence suggests that interleukin-10 (IL-10), an anti-inflammatory cytokine, is upregulated during withdrawal from chronic EtOH exposure. In the present study, we show that IL-10 is increased early (1 h) after a single intoxicating dose of EtOH (5 g/kg, intragastric) in Sprague Dawley rats. We also show that IL-10 rapidly regulates GABAergic transmission in dentate gyrus neurons. In brain slice recordings, IL-10 application dose-dependently decreases miniature inhibitory postsynaptic current (mIPSC) area and frequency, and decreases the magnitude of the picrotoxin sensitive tonic current (Itonic), indicating both pre- and postsynaptic mechanisms. A PI3K inhibitor LY294002 (but not the negative control LY303511) ablated the inhibitory effects of IL-10 on mIPSC area and Itonic, but not on mIPSC frequency, indicating the involvement of PI3K in postsynaptic effects of IL-10 on GABAergic transmission. Lastly, we also identify a novel neurobehavioral regulation of EtOH sensitivity by IL-10, whereby IL-10 attenuates acute EtOH-induced hypnosis. These results suggest that EtOH causes an early release of IL-10 in the brain, which may contribute to neuronal hyperexcitability as well as disturbed sleep seen after binge exposure to EtOH. These results also identify IL-10 signaling as a potential therapeutic target in alcohol-use disorders and other CNS disorders where GABAergic transmission is altered.
authors.affiliation: Department of Pharmaceutical Sciences, University of the Sciences, Philadelphia College of Pharmacy, Philadelphia, PA 19104, USA. Electronic address: a.suryanarayanan@usciences.edu.
authors.forename: A
authors.initials: A
authors.lastname: Suryanarayanan
authors.affiliation: Department of Psychology, Center for Development and Behavioral Neuroscience, Binghamton University, Binghamton, NY 13902, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Carter
authors.affiliation: Department of Psychology, Center for Development and Behavioral Neuroscience, Binghamton University, Binghamton, NY 13902, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Landin
authors.affiliation: Departments of Psychiatry and Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Morrow
authors.affiliation: Department of Psychology, Center for Development and Behavioral Neuroscience, Binghamton University, Binghamton, NY 13902, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Werner
authors.affiliation: Division of Oral Biology & Medicine, School of Dentistry, 63-078 CHS, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: igor@ucla.edu.
authors.forename: I
authors.initials: I
authors.lastname: Spigelman
mesh_terms: D000818:Animals; D063425:Binge Drinking / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D016753:Interleukin-10 / Q000378:metabolism*; D008297:Male; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D012890:Sleep / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol; D006993:Hypnotics and Sedatives; D016753:Interleukin-10; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid
keywords: Alcohol; Anti-inflammatory; GABAA; Interleukin-10; Neuroimmune; mIPSC