title: ACTH Prevents Deficits in Fear Extinction Associated with Early Life Seizures.
abstract: OBJECTIVE
  Early life seizures (ELS) are often associated with cognitive and psychiatric comorbidities that are detrimental to quality of life. In a rat model of ELS, we explored long-term cognitive outcomes in adult rats. Using ACTH, an endogeneous HPA-axis hormone given to children with severe epilepsy, we sought to prevent cognitive deficits. Through comparisons with dexamethasone, we sought to dissociate the corticosteroid effects of ACTH from other potential mechanisms of action.
  
  
  RESULTS
  Although rats with a history of ELS were able to acquire a conditioned fear learning paradigm and controls, these rats had significant deficits in their ability to extinguish fearful memories. ACTH treatment did not alter any seizure parameters but nevertheless was able to significantly improve this fear extinction, while dexamethasone treatment during the same period did not. This ACTH effect was specific for fear extinction deficits and not for spatial learning deficits in a water maze. Additionally, ACTH did not alter seizure latency or duration suggesting that cognitive and seizure outcomes may be dissociable. Expression levels of melanocortin receptors, which bind ACTH, were found to be significantly lower in animals that had experienced ELS than in control animals, potentially implicating central melanocortin receptor dysregulation in the effects of ELS, and suggesting a mechanism of action for ACTH.
  
  
  CONCLUSIONS
  Taken together, these data suggest that early treatment with ACTH can have significant long-term consequences for cognition in animals with a history of ELS independently of seizure cessation and may act in part through a CNS melanocortin receptor pathway.
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USA; Department of Biological Sciences, University of Bath, Bath, UK.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Massey
authors.affiliation: College of Arts and Sciences, Dartmouth College , Hanover, NH , USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Lerner
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine , Burlington, VT , USA.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Holmes
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USA; Institute of Child Health, University College London, London, UK.
authors.forename: Rod C
authors.initials: RC
authors.lastname: Scott
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine , Burlington, VT , USA.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Hernan
keywords: ACTH; cognition; development; epilepsy; melanocortins; prefrontal cortex