title: Evaluation of TLR4 Inhibitor, T5342126, in Modulation of Ethanol-Drinking Behavior in Alcohol-Dependent Mice.
abstract: OBJECTIVE
  Several lines of evidence support a critical role of TLR4 in the neuroimmune responses associated with alcohol disorders and propose inhibitors of TLR4 signaling as potential treatments for alcoholism. In this work, we investigated the effect of T5342126 compound, a selective TLR4 inhibitor, on excessive drinking and microglial activation associated with ethanol dependence.
  
  
  METHODS
  We used 2BC-CIE (two-bottle choice-chronic ethanol intermittent vapor exposure) paradigm to induce ethanol dependence in mice. After induction of the ethanol dependence, we injected T5342126 (i.p., 57 mg/kg) for 14 days while monitoring ethanol intake by 2BC (limited access to ethanol) method.
  
  
  RESULTS
  T5342126 decreased ethanol drinking in both ethanol-dependent and non-dependent mice but T5342126 showed also dose-dependent non-specific effects represented by decreased animal locomotor activity, saccharine intake, and body core temperature. Six days after the last ethanol-drinking session, we examined the immunohistochemical staining of Iba-1 (ionized calcium-binding adapter molecule 1), a microglial activation marker, in the central nucleus of the amygdala (CeA) and dentate gyrus (DG) of the hippocampus. Notably, T5342126 reduced Iba-1 density in the CeA of both ethanol-dependent and non-dependent mice injected with T5342126. There were no significant differences in the DG Iba-1 density among the treatment groups.
  
  
  CONCLUSIONS
  Collectively, our data suggest that T5342126, via blocking TLR4 activation, contributes to the reduction of ethanol drinking and ethanol-induced neuroimmune responses. However, the non-specific effects of T5342126 may play a significant role in the T5342126 effects on ethanol drinking and thus, may limit its therapeutic potential for treatment of alcohol dependence.
  
  
  OBJECTIVE
  T5342126, an experimental TLR4 inhibitor, is effective in reducing ethanol drinking and inhibiting the activation and proliferation of microglia in both ethanol-dependent and non-dependent mice. However, T5342126's use as a potential candidate for the treatment of alcohol addiction may be limited due to its non-specific effects.
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bajo
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Montgomery
authors.affiliation: Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: L N
authors.initials: LN
authors.lastname: Cates
authors.affiliation: Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: T
authors.initials: T
authors.lastname: Nadav
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Delucchi
authors.affiliation: Department of Chemistry and Biochemistry, BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80309, USA.
authors.forename: K
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Department of Chemistry and Biochemistry, BioFrontiers Institute, University of Colorado Boulder, Boulder, CO 80309, USA.
authors.forename: H
authors.initials: H
authors.lastname: Yin
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: E F
authors.initials: EF
authors.lastname: Crawford
authors.affiliation: Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Roberts
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA mroberto@scripps.edu.
authors.forename: M
authors.initials: M
authors.lastname: Roberto
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy*; D000437:Alcoholism / Q000188:drug therapy*; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000378:metabolism; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D015213:Neuroimmunomodulation / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D011412:Propanolamines; D011720:Pyrazoles; C000613613:T5342126; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4