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Role of Interleukin-1 System in Alcohol Drinking and Preference
3rd International Conference and Exhibition onClinical & Cellular Immunology
September 29 - October 01, 2014 Baltimore, USA
Michal BajoThe Scripps Research Institute, La Jolla, USAThe Scripps Research Institute, La Jolla, USA
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Szabo and Lippai, International Review of Neurobiology 2014; 118:359–380
Alcohol and Immunity
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IL-1 system in Alcohol Addiction
IL-1β is increased in the brain after alcohol exposure in humans and animal models
Polymorphisms in genes encoding IL-1ra and IL-1have been associated with a susceptibility to alcoholism in Spanish men
Several genes encoding IL-1R1 signaling pathways in brain with genetic predisposition to alcohol consumption in mice
Reduction in alcohol drinking and/or preferences in Il1rn KO mice
Central injection of IL-1 augmented withdrawal-associated anxiety
Recombinant IL-1ra: prevented and protected from advancement of alcohol-induced
liver disease as well as alcohol-induced neuroinflammation
reduced sedation and motor impairment recovery time
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IL-1 system effects on alcohol related behaviors are mediated by
modulation of key neurotransmitter and neuropeptide systems that play
a role in alcohol drinking and development of alcohol dependence.
Hypothesis
Crews et al., Brain, Behav., Immunity, 2011
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Project #1
Brain slices containing CeA prepared from B6129SF2/J mice (# 101045; Jackson Laboratories)
Electrophysiological techniques:
whole-cell recordings
intracellular recording with sharp electrodes
Question 1: What are effects of acute IL-1on GABAergic transmission in Central Nucleus of the Amygdala (CeA)?
Question 2: Are there any interactions between acute ethanol and IL-1effects on the CeA GABAergic transmission?
Methods
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GABAergic transmission
Phasic Transient IPSCs
Mediates ‘point to point’ synaptic transmission
Tonic Persistent inhibitory conductances
Mediates overall cell/network excitability
Farrant and Nusser, Nat. Rev. Neurosci, 2005
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IL-1 Decreases evoked GABA IPSPs in CeA Neurons
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IL-1 Decreases mIPSCs Amplitudes in CeA Neurons
50 ng/ml IL-150 ng/ml IL-1
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Ethanol Increases both Evoked and Spontaneous GABA Transmission in CeA
44 mM EtOH=Maximal ethanol concentration
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IL-1 Does not Affect the Ethanol-induced Increase in GABA Transmission
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Summary
I.I. IL1IL1 decreases GABAergic transmission via postsynaptic decreases GABAergic transmission via postsynaptic mechanisms, but in some neurons, it acts also via presynaptic mechanisms, but in some neurons, it acts also via presynaptic mechanismsmechanisms
I.I. Acute IL-1Acute IL-1 modulation of ethanol effects on CeA GABAergic modulation of ethanol effects on CeA GABAergic transmission via different mechanismstransmission via different mechanisms
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x
Wu et al., Brain Behav Immun 2011; Blednov et al., Addict Biol, 2012; Blednov et al., Brain Behav Immun, in submission 2014
Deletion of Il1rn:
reduces alcohol intake in several behavior tests
increases sensitivity to the sedative/hypnotic effects of ethanol and a GABA-receptor allosteric modulator flurazepam
reduces the severity of acute ethanol withdrawal
recombinant IL-1ra rescues some of the alcohol related behaviors
x
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Bajo et al, in submission; Blednov et al., in submission
Project #2
Brain slices containing CeA prepared from Il1rn KO (B6.129S-Il1rntm1Dih/J; #004754; Jackson Laboratories) and WT mice
Electrophysiological techniques:
whole-cell recordings
intracellular recording with sharp electrodes
Methods
Question 1: Are changes in alcohol related behaviors found in mice with perturbations in IL-1 system associated with alterations of GABAergic system?
Question 2: Does perturbation of IL-1 system alters ethanol effects on GABAergic transmission?
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Basal Evoked GABA Transmission is Elevated in CeA of Il1rn KO compared to WT Mice
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The Frequency of sIPSCs is Significantly Higher in IL1rn KO Compared to WT Mice
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The Number of CeA Neurons Responding to Acute EtOH is Decreased in Il1rn KO Mice
##
Chi-square test
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The Basal Frequency and the EtOH-induced Increase of mIPSCs are Similar in Il1rn KO and WT
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Kineret (exogenous IL-1R antagonist) “Normalized” the Baseline sIPSC Frequency in Il1rn KO Mice
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Kineret “increases” the Number of CeA Neurons Responding to Acute EtOH in Il1rn KO Mice
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Shift in Ongoing Tonic Conductance in CeA Neurons from Il1rn KO mice Compared to WT Mice
Low Threshold Bursting (LTB)Low Threshold Bursting (LTB) Late Spiking (LS)Late Spiking (LS)
Persistent Tonic ConductancePersistent Tonic Conductance
Gabazine 100 μM
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Summary and ConclusionI.I. The baseline GABAergic transmission is significantly higher in The baseline GABAergic transmission is significantly higher in
Il1rnIl1rn KO compared to WT KO compared to WT
II.II. There is a shift in ongoing tonic conductance in CeA neurons from There is a shift in ongoing tonic conductance in CeA neurons from Il1rnIl1rn KO mice compared to WT KO mice compared to WT
III.III. The number of CeA neurons responding to acute ethanol is The number of CeA neurons responding to acute ethanol is decreased in decreased in Il1rnIl1rn KO mice KO mice
IV.IV. Kineret “normalized” the GABAergic transmission in Kineret “normalized” the GABAergic transmission in Il1rnIl1rn KO and KO and “increases” the number of CeA neurons responding to acute “increases” the number of CeA neurons responding to acute ethanol in ethanol in Il1rnIl1rn KO KO
Based on behavioral studies of Blednov et al., IL-1R1 is not involved in alcohol drinking and preference, but it plays an important role in alcohol sedative effects and alcohol withdrawal.
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AcknolwedgementAcknolwedgement
Marisa Roberto:
Sam MadambaSam Madamba
Melissa HermanMelissa Herman
Florence VarodayanFlorence Varodayan
Christopher OleataChristopher Oleata
Dean KirsonDean Kirson
Marian LogripMarian Logrip
Former members
Maureen CruzMaureen Cruz
George LuuGeorge Luu
Collaborators: TSRIGeorge R. SigginsGeorge R. SigginsAmanda RobertsAmanda Roberts
University of TexasR. Adron Harris R. Adron Harris Yuri A. BlednovYuri A. Blednov