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.