Genetic and pharmacological modulation of the steroid sulfatase axis improves response control; comparison with drugs used in ADHD.
Maladaptive response control is a feature of many neuropsychiatric conditions, including attention deficit hyperactivity disorder (ADHD). As ADHD is more commonly diagnosed in males than females, a pathogenic role for sex-linked genes has been suggested. Deletion or point mutation of the X-linked STS gene, encoding the enzyme steroid sulfatase (STS) influences risk for ADHD. We examined whether deletion of the Sts gene in the 39,X(Y*)O mouse model, or pharmacological manipulation of the STS axis, via administration of the enzyme substrate dehydroepiandrosterone sulfate or the enzyme inhibitor COUMATE, influenced behavior in a novel murine analog of the stop-signal reaction time task used to detect inhibitory deficits in individuals with ADHD. Unexpectedly, both the genetic and pharmacological treatments resulted in enhanced response control, manifest as highly specific effects in the ability to cancel a prepotent action. For all three manipulations, the effect size was comparable to that seen with the commonly used ADHD therapeutics methylphenidate and atomoxetine. Hence, converging genetic and pharmacological evidence indicates that the STS axis is involved in inhibitory processes and can be manipulated to give rise to improvements in response control. While the precise neurobiological mechanism(s) underlying the effects remain to be established, there is the potential for exploiting this pathway in the treatment of disorders where failures in behavioral inhibition are prominent.
1] Behavioral Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK [2] MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK [3] Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
William
W
Davies
1] Behavioral Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK [2] MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK [3] Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
Trevor
T
Humby
1] Behavioral Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK [2] MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK [3] Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
Simon
S
Trent
1] Behavioral Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK [2] MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Jessica B
JB
Eddy
MRC National Institute for Medical Research, London, Cardiff, UK.
Obah A
OA
Ojarikre
1] Behavioral Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK [2] MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK [3] Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
Lawrence S
LS
Wilkinson
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000503:physiopathology*; D002491:Central Nervous System Agents / Q000008:administration & dosage; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003374:Coumarins / Q000494:pharmacology; D019314:Dehydroepiandrosterone Sulfate / Q000008:administration & dosage; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007266:Inhibition, Psychological; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology; D008822:Mice, Transgenic; D009483:Neuropsychological Tests; D011437:Propylamines / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects* / Q000502:physiology*; D043266:Steryl-Sulfatase / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
C100463:4-methylcoumarin 7-O-sulfamate; D018759:Adrenergic Uptake Inhibitors; D002491:Central Nervous System Agents; D000697:Central Nervous System Stimulants; D003374:Coumarins; D004791:Enzyme Inhibitors; D011437:Propylamines; D013449:Sulfonamides; D008774:Methylphenidate; D019314:Dehydroepiandrosterone Sulfate; D000069445:Atomoxetine Hydrochloride; D043266:Steryl-Sulfatase