GABAB receptor antagonism abolishes the learning impairments in rats with chronic atypical absence seizures

Eur J Pharmacol. 2006 Jul 10;541(1-2):64-72. doi: 10.1016/j.ejphar.2006.04.012. Epub 2006 Apr 26.


Chronic atypical absence seizures are a component of the Lennox-Gastaut syndrome, a disorder invariably associated with severe cognitive impairment in children. However, the cause of this intellectual delay remains unclear. The AY9944 model of chronic atypical absence seizures in rats reliably reproduces the electrographic, behavioral, pharmacological and cognitive features of clinical atypical absence. Using this model, we tested the hypothesis that the cognitive impairment associated with this disorder involves a gamma-aminobutyric acid B (GABA(B)) receptor-mediated mechanism. Therefore, we examined the effect of a specific, high affinity GABA(B) receptor antagonist, CGP35348, on the atypical absence seizures, the working memory deficits, and the altered long-term potentiation that we have observed in the AY9944 model. CGP35348 blocked atypical absence seizures, restored long-term potentiation to normal level, and reversed the cognitive deficit in the AY9944-treated animals. However, dose-response studies showed that lower doses of CGP35348 that failed to influence atypical absence seizure activity, completely reversed the spatial working memory deficit. These data suggest that GABA(B) receptor-mediated mechanisms are responsible for the cognitive dysfunction in the AY9944 model of chronic atypical absence seizures and further, that their cognitive impairment is independent of the seizure activity. The data raise the possibility that GABA(B) receptor antagonists may have therapeutic potential for the treatment of cognitive impairment in epilepsy syndromes where atypical absence seizures are a component.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticholesteremic Agents / toxicity
  • Anticonvulsants / pharmacology
  • Chronic Disease
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Epilepsy, Absence / chemically induced
  • Epilepsy, Absence / physiopathology*
  • Ethosuximide / pharmacology
  • Female
  • GABA Antagonists / pharmacology
  • GABA-B Receptor Antagonists*
  • Hippocampus / physiology
  • Learning Disabilities / physiopathology
  • Learning Disabilities / prevention & control*
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Memory Disorders / physiopathology
  • Memory Disorders / prevention & control
  • Organophosphorus Compounds / pharmacology*
  • Rats
  • Time Factors
  • trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / toxicity


  • Anticholesteremic Agents
  • Anticonvulsants
  • GABA Antagonists
  • GABA-B Receptor Antagonists
  • Organophosphorus Compounds
  • trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride
  • Ethosuximide
  • CGP 35348