Converging Pharmacological and Genetic Evidence Indicates a Role for Steroid Sulfatase in Attention

Biol Psychiatry. 2009 Aug 15;66(4):360-7. doi: 10.1016/j.biopsych.2009.01.001. Epub 2009 Feb 28.

Abstract

Background: Attention-deficit/hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by deficits in attention, increased motor impulsivity, and hyperactivity. Preliminary work in mice and humans has suggested the X-linked gene STS (which encodes the enzyme steroid sulfatase) as a mediator of attentional functioning and as a candidate gene for ADHD.

Methods: The effects of modulating the murine steroid sulfatase axis pharmacologically (through administration of the substrate dehydroepiandrosterone sulfate [DHEAS], 0-40 mg/kg, or acute inhibition of the enzyme by COUMATE, 10mg/kg) or genetically (through loss of the gene in 39,X(Y)*O mice) were assayed using the 5-choice serial reaction time task (5-CSRTT) a test of visuospatial attention and response control, and a locomotor activity paradigm.

Results: DHEAS administration improved 5-CSRTT performance under attentionally demanding conditions, whereas steroid sulfatase inhibition impaired accuracy under the same conditions. Loss of Sts expression constitutively throughout development in 39,X(Y)*O mice resulted in deficits in 5-CSRTT performance at short stimulus durations and reduced anticipatory responding. Neither the pharmacologic nor the genetic manipulations affected basic locomotor activity.

Conclusions: These data provide converging evidence indicating a role for steroid sulfatase in discrete aspects of attentional functioning and are suggestive of a role in motor impulsivity. The findings provide novel insights into the neurobiology of attention and strengthen the notion of STS as a candidate gene for the attentional component of ADHD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Attention / drug effects*
  • Attention / physiology*
  • Attention Deficit Disorder with Hyperactivity / genetics
  • Choice Behavior / drug effects
  • Choice Behavior / physiology
  • Coumarins / pharmacology*
  • Dehydroepiandrosterone Sulfate / pharmacology*
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Reaction Time / drug effects
  • Reaction Time / genetics
  • Steryl-Sulfatase / antagonists & inhibitors*
  • Steryl-Sulfatase / genetics*
  • Sulfonamides / pharmacology*

Substances

  • 4-methylcoumarin 7-O-sulfamate
  • Coumarins
  • Sulfonamides
  • Dehydroepiandrosterone Sulfate
  • Steryl-Sulfatase