GABAB receptor antagonist SGS742 improves spatial memory and reduces protein binding to the cAMP response element (CRE) in the hippocampus

Neuropharmacology. 2005 Jun;48(7):956-64. doi: 10.1016/j.neuropharm.2005.01.019.


Memory storage in the brain requires protein synthesis initiated through signaling pathways that control transcription. Such mechanisms are under active investigation for therapies in disorders involving cognitive dysfunction. Long-term memory can be improved by inhibiting activation or reducing expression of transcription factors such as ATF4/CREB2 and some C/EBP family members which appear to serve as memory suppressors. Here, we provide evidence that GABAB receptor antagonists may enhance cognition, at least in part, by this mechanism. We tested a GABAB receptor antagonist, SGS742 (CGP36742), on hippocampal-dependent memory and hippocampal nuclear CRE-binding activity in rats. As a result, acute in vivo administration of SGS742 both improved memory and reduced total hippocampal CRE-binding activity of which a large proportion in the basal state could be immunoneutralized with CREB2 antibodies. Consistent with its activity on information storage mechanisms, acute SGS742 effectively improved long-term memory in retrograde protocols, in which drug was given at times when memory formation can be interrupted by blocking new protein production. In conclusion, GABAB antagonists may provide a pharmacological therapy for cognitive impairment, sharing mechanistic features with genetic approaches to reduce CREB2 activity and to augment long-term memory.

Publication types

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

MeSH terms

  • Animals
  • CREB-Binding Protein
  • Dose-Response Relationship, Drug
  • GABA Antagonists / metabolism
  • GABA Antagonists / pharmacology
  • GABA-B Receptor Antagonists*
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Memory / drug effects*
  • Memory / physiology
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / metabolism*
  • Organophosphorus Compounds / metabolism
  • Organophosphorus Compounds / pharmacology*
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Rats
  • Receptors, GABA-B / metabolism
  • Response Elements
  • Spatial Behavior / drug effects*
  • Spatial Behavior / physiology
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / metabolism*


  • GABA Antagonists
  • GABA-B Receptor Antagonists
  • Nuclear Proteins
  • Organophosphorus Compounds
  • Receptors, GABA-B
  • Trans-Activators
  • (3-aminopropyl)(n-butyl)phosphinic acid
  • CREB-Binding Protein
  • Crebbp protein, rat