Temporal dynamics of PDE4 inhibition in modulating novel object recognition memory consolidation and reconsolidation

Object recognition memory (ORM) allows individuals to discriminate between familiar and novel stimuli, providing a fundamental model for studying non-emotional memory in rodents. ORM reactivation during retrieval in the presence of a new object renders this memory labile and susceptible to interference during reconsolidation, a process with potential translational impact, as it contributes to the maintenance and updating of stored memories. Despite this relevance, the mechanisms underlying ORM reconsolidation are not well understood. Phosphodiesterase-4 (PDE4) regulates cyclic adenosine monophosphate (cAMP) signaling, a key pathway in synaptic plasticity and memory formation. While PDE4 inhibition is known to enhance ORM consolidation, its role in ORM reconsolidation remains unclear. Here, we investigated the effects of PDE4 inhibition with roflumilast (ROF; 0.1 mg/kg, i.p.) on reconsolidation of ORM in male Wistar rats. We used a protocol designed to simultaneously engage reconsolidation of familiar objects and consolidation of novel ones. ROF administered 5 min after retrieval increased the discrimination index 24 h later, suggesting an enhancement of ORM reconsolidation. However, the same treatment reduced the discrimination index of novel objects, indicating an impairment in consolidation. In independent groups of animals, the treatment with ROF 3 h post-retrieval did not affect reconsolidation and improved consolidation. When memory retrieval was omitted, ROF effects on reconsolidation were abolished, while consolidation enhancement persisted when ROF was administered 3 h after training. Moreover, pharmacological blockade of memory destabilization with nimodipine (16 mg/kg, i.p.) abolished the effects of ROF on reconsolidation. Our results demonstrate that PDE4 inhibition modulates ORM in a time-dependent manner, favoring early reconsolidation and late consolidation phases. These results reveal a dynamic role of PDE4 in shaping the temporal boundaries of non-emotional memory processing and highlight its potential as a target for cognitive enhancement therapies.