Interest of new alkylsulfonylhydrazide-type compound in the treatment of alcohol use disorders

Psychopharmacology (Berl). 2018 Jun;235(6):1835-1844. doi: 10.1007/s00213-018-4917-5. Epub 2018 Apr 30.

Abstract

Rationale: Recent preclinical research suggested that histone deacetylase inhibitors (HDACIs) and specifically class I HDAC selective inhibitors might be useful to treat alcohol use disorders (AUDs).

Objective: The objective of this study was to find a new inhibitor of the HDAC-1 isoenzyme and to test its efficacy in an animal model of AUDs.

Methods: In the present study, we prepared new derivatives bearing sulfonylhydrazide-type zinc-binding group (ZBG) and evaluated these compounds in vitro on HDAC-1 isoenzyme. The most promising compound was tested on ethanol operant self-administration and relapse in rats.

Results: We showed that the alkylsulfonylhydrazide-type compound (ASH) reduced by more than 55% the total amount of ethanol consumed after one intracerebroventricular microinjection, while no effect was observed on motivation of the animals to consume ethanol. In addition, one ASH injection in the central amygdala reduced relapse.

Conclusions: Our study demonstrated that a new compound designed to target HDAC-1 is effective in reducing ethanol intake and relapse in rats and further confirm the interest of pursuing research to study the exact mechanism by which such inhibitor may be useful to treat AUDs.

Keywords: Alkylsulfonylhydrazide; Ethanol self-administration; Histone deacetylase; Inhibition; Rats; Zinc-binding group.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcoholism / drug therapy*
  • Alcoholism / enzymology
  • Alcoholism / psychology
  • Animals
  • Ethanol / administration & dosage*
  • Histone Deacetylase 1 / antagonists & inhibitors*
  • Histone Deacetylase 1 / chemistry
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Male
  • Molecular Docking Simulation / methods
  • Motivation / drug effects
  • Motivation / physiology
  • Rats
  • Rats, Long-Evans
  • Self Administration
  • Sulfatases / chemistry
  • Sulfatases / pharmacology
  • Sulfatases / therapeutic use
  • Treatment Outcome

Substances

  • Histone Deacetylase Inhibitors
  • Ethanol
  • Sulfatases
  • alkylsulfatase
  • Hdac1 protein, rat
  • Histone Deacetylase 1