title: GABAB receptor antagonist SGS742 improves spatial memory and reduces protein binding to the cAMP response element (CRE) in the hippocampus.
abstract: 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.
authors.affiliation: Department of Psychological and Brain Sciences, The Johns Hopkins University, 3400 North Charles St., 102 Ames Hall, Baltimore, MD 21218, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Helm
authors.forename: R P
authors.initials: RP
authors.lastname: Haberman
authors.forename: S L
authors.initials: SL
authors.lastname: Dean
authors.forename: E C
authors.initials: EC
authors.lastname: Hoyt
authors.forename: T
authors.initials: T
authors.lastname: Melcher
authors.forename: P K
authors.initials: PK
authors.lastname: Lund
authors.forename: M
authors.initials: M
authors.lastname: Gallagher
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000378:metabolism / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018080:Receptors, GABA-B / Q000378:metabolism; D020218:Response Elements; D013037:Spatial Behavior / Q000187:drug effects* / Q000502:physiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D009687:Nuclear Proteins; D009943:Organophosphorus Compounds; D018080:Receptors, GABA-B; D015534:Trans-Activators; C079148:(3-aminopropyl)(n-butyl)phosphinic acid; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat