title: The Class I-Specific HDAC Inhibitor MS-275 Decreases Motivation to Consume Alcohol and Relapse in Heavy Drinking Rats.
abstract: BACKGROUND
  New strategies for the treatment of alcohol dependence are a pressing need, and recent evidence suggests that targeting enzymes involved in epigenetic mechanisms seems to have great potential. Among these mechanisms, alteration of histone acetylation by histone deacetylases is of great importance for gene expression and has also been implicated in addiction. Here, we examined whether intra-cerebroventricular administration of MS-275, a class I-specific histone deacetylase inhibitor, could alter ethanol self-administration, motivation to consume ethanol, and relapse in heavy drinking rats.
  
  
  METHODS
  Male Long Evans rats trained to self-administer high levels of ethanol received intra-cerebroventricular micro-infusions of MS-275 (250 µM, 500 µM, and 1000 µM) 3 hours prior to the self-administration sessions.
  
  
  RESULTS
  First, we demonstrated that intra-cerebroventricular infusion of MS-275 increases acetylation of Histone 4 within the nucleus accumbens nucleus accumbens and the dorsolateral striatum. Second, we observed that MS-275 decreases ethanol self-administration by about 75%. We found that 2 consecutive daily injections are necessary to decrease ethanol self-administration. Additionally, the dose-response curve test indicated that MS-275 has a U-shape effect on ethanol self-administration with the dose of 500 µM as the most efficient dose. Furthermore, we showed that MS-275 also diminished the motivation to consume ethanol (25% decrease), and finally, we demonstrated that MS-275 reduced relapse (by about 50%) and postponed reacquisition even when the treatment was stopped.
  
  
  CONCLUSIONS
  Our study confirms the potential therapeutic interest of targeting epigenetic mechanisms in excessive alcohol drinking and strengthens the interest of focusing on specific isoforms of histone deacetylases.
authors.affiliation: INSERM ERI 24, Groupe de Recherche sur l'Alcool et les Pharmacodépendances, Université de Picardie Jules Verne, Centre Universitaire de Recherche en Santé, Centre Hospitalo-Universitaire (CHU sud), Amiens, France (Drs J. Jeanblanc, Lemoine, Alaux-Cantin, and Naassila); Plateforme Animalerie du Pôle Santé - Université de Picardie Jules Verne, Amiens France (Ms V. Jeanblanc). jerome.jeanblanc@u-picardie.fr.
authors.forename: Jerome
authors.initials: J
authors.lastname: Jeanblanc
authors.affiliation: INSERM ERI 24, Groupe de Recherche sur l'Alcool et les Pharmacodépendances, Université de Picardie Jules Verne, Centre Universitaire de Recherche en Santé, Centre Hospitalo-Universitaire (CHU sud), Amiens, France (Drs J. Jeanblanc, Lemoine, Alaux-Cantin, and Naassila); Plateforme Animalerie du Pôle Santé - Université de Picardie Jules Verne, Amiens France (Ms V. Jeanblanc).
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lemoine
authors.affiliation: INSERM ERI 24, Groupe de Recherche sur l'Alcool et les Pharmacodépendances, Université de Picardie Jules Verne, Centre Universitaire de Recherche en Santé, Centre Hospitalo-Universitaire (CHU sud), Amiens, France (Drs J. Jeanblanc, Lemoine, Alaux-Cantin, and Naassila); Plateforme Animalerie du Pôle Santé - Université de Picardie Jules Verne, Amiens France (Ms V. Jeanblanc).
authors.forename: Virginie
authors.initials: V
authors.lastname: Jeanblanc
authors.affiliation: INSERM ERI 24, Groupe de Recherche sur l'Alcool et les Pharmacodépendances, Université de Picardie Jules Verne, Centre Universitaire de Recherche en Santé, Centre Hospitalo-Universitaire (CHU sud), Amiens, France (Drs J. Jeanblanc, Lemoine, Alaux-Cantin, and Naassila); Plateforme Animalerie du Pôle Santé - Université de Picardie Jules Verne, Amiens France (Ms V. Jeanblanc).
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Alaux-Cantin
authors.affiliation: INSERM ERI 24, Groupe de Recherche sur l'Alcool et les Pharmacodépendances, Université de Picardie Jules Verne, Centre Universitaire de Recherche en Santé, Centre Hospitalo-Universitaire (CHU sud), Amiens, France (Drs J. Jeanblanc, Lemoine, Alaux-Cantin, and Naassila); Plateforme Animalerie du Pôle Santé - Université de Picardie Jules Verne, Amiens France (Ms V. Jeanblanc).
authors.forename: Mickaël
authors.initials: M
authors.lastname: Naassila
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy*; D000437:Alcoholism / Q000188:drug therapy*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D057967:Infusions, Intraventricular; D008297:Male; D009042:Motivation / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D012008:Recurrence
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; C118739:entinostat
keywords: Heavy drinking; alcohol addiction; epigenetic; relapse; treatment