Aggressive Behavior Induced by the Steroid Sulfatase Inhibitor COUMATE and by DHEAS in CBA/H Mice

Brain Res. 2001 Dec 20;922(2):216-22. doi: 10.1016/s0006-8993(01)03171-7.

Abstract

The steroid sulfatase enzyme (STS) regulates the formation of dehydroepiandrosterone (DHEA) from dehydroepiandrosterone-sulfate (DHEAS). DHEAS is a well-known negative allosteric modulator of the GABA(A) receptor-gated chloride channels. It is classified as an excitatory neurosteroid. The implication of GABA(A) receptor activity in aggressive behavior in rodents is well-documented. In addition a genetic correlation between STS level in the liver and aggressive behavior across 12 strains of mice suggest that STS activity could be involved in aggression in mice. We assessed herein whether COUMATE (an STS inhibitor) and DHEAS modulate aggression in CBA/H mice. We hypothesized that inhibiting STS activity in vivo followed by DHEAS injections which increase the level of sulfated steroid that cross the blood-brain barrier and then modulate neurotransmitter receptors could modify the attack behavior in mice. COUMATE (10 mg/kg) was administrated p.o. alone or in combination with the neurosteroid DHEAS (0-50 mg/kg) i.p. Animals were thereafter tested for aggression. A single dose of COUMATE significantly inhibited STS activity both in the brain (70.57%) and in the liver (87%) 24 h following administration. Behavioral tests showed that the inhibitor and DHEAS enhanced aggressive behavior when animals were simultaneously subjected to both molecules. These results confirm the correlation between aggressive behavior and STS concentration in mice. In addition, we confirm that the steroid metabolism can modulate the behavior in rodents.

MeSH terms

  • Aggression / drug effects
  • Aggression / physiology*
  • Animals
  • Arylsulfatases / antagonists & inhibitors
  • Arylsulfatases / metabolism*
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Brain / drug effects
  • Brain / enzymology*
  • Brain / physiopathology
  • Coumarins / pharmacology*
  • Dehydroepiandrosterone Sulfate / metabolism*
  • Dehydroepiandrosterone Sulfate / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Liver / drug effects
  • Liver / enzymology
  • Male
  • Methylcellulose / pharmacology
  • Mice
  • Mice, Inbred CBA
  • Receptors, GABA-A / metabolism*
  • Steryl-Sulfatase
  • Sulfonamides / pharmacology*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • gamma-Aminobutyric Acid / metabolism

Substances

  • 4-methylcoumarin 7-O-sulfamate
  • Coumarins
  • Enzyme Inhibitors
  • Receptors, GABA-A
  • Sulfonamides
  • gamma-Aminobutyric Acid
  • Dehydroepiandrosterone Sulfate
  • Methylcellulose
  • Arylsulfatases
  • Steryl-Sulfatase