Sleep deprivation (SD) negatively affects memory processes, particularly in the hippocampus. Previous research indicates that 6 hours of SD post-learning causes amnesia in hippocampus-dependent tasks. However, we recently demonstrated that object-location memories (OLMs) formed under SD conditions can be effectively recalled several days later using optogenetic engram reactivation or administration of the PDE4 inhibitor roflumilast. These findings suggest that these memories are not lost, but merely difficult to retrieve.Since both cAMP and cGMP signalling critically contribute to memory processes, we sought to determine whether the FDA-approved drug vardenafil (a PDE5 inhibitor that facilitates cGMP signalling) could also be used to reverse SD-induced amnesia in adult male C57Bl6/j mice. We found that administering vardenafil 30 min prior to testing, one day after training and SD was sufficient to facilitate subsequent retrieval of OLMs. However, vardenafil treatment failed to reserve SD-induced amnesia when the time between drug administration and testing was expanded to multiple days. To achieve more persistent memory retrieval, we decided to combine optogenetic engram stimulation with drug administration. This optogenetic and pharmacological combination made the OLMs more persistently accessible for retrieval, even several days after the manipulation. Complementing these behavioral findings, we showed that the combined treatment also resulted in a greater reactivation of engram cells in the dentate gyrus relative to drug treatment or optogenetic manipulation only.Altogether, these studies advance our understanding of the molecular underpinnings associated SD-induced amnesia, and may contribute to novel therapeutic approaches to treat sleep-related cognitive deficits.