Anandamide blocks spatial memory reconsolidation in male rats through a CB1 receptor dependent mechanism

Memory reconsolidation is a process through which previously consolidated memories become temporarily labile after retrieval and require molecular mechanisms, including protein synthesis and degradation, to be stabilized again. The endocannabinoid system, particularly cannabinoid receptors CB1 and CB2, has been implicated in several forms of learning and memory. However, the specific role of CB1 receptors in the regulation of protein turnover during spatial memory reconsolidation remains incompletely understood. Therefore, this study investigated whether cannabinoid receptor activation in the hippocampal CA1 region influences the reconsolidation of spatial memory.

Spatial memory was evaluated using the Morris water maze task. After training, animals underwent an early non-reinforced test session 24 hours later to reactivate the previously acquired spatial memory. Immediately after this retrieval session, anandamide (AEA) or oleamide, a CB1 receptor agonist, was bilaterally infused into the CA1 region of the hippocampus. To investigate the involvement of CB1 receptors, some animals received a CB1 receptor antagonist together with the agonists. Additional experiments evaluated whether the amnesic effects of oleamide were dependent on protein degradation mechanisms and whether activation of CB1 receptors could modulate the effects produced by inhibition of protein synthesis.

Bilateral administration of AEA and oleamide into the hippocampal CA1 region immediately after memory retrieval impaired the reconsolidation of spatial memory, producing anterograde amnesia. Oleamide primarily affected the early long-term phase of spatial memory, whereas AEA impaired later phases of memory. The disruptive effect on memory reconsolidation was prevented by co-administration of a CB1 receptor antagonist, indicating that the observed effects were mediated by CB1 receptor activation. Furthermore, the amnesic effect induced by oleamide was dependent on protein degradation mechanisms. Conversely, the impairment caused by inhibition of protein synthesis could be reversed through inverse activation of CB1 receptors. These findings indicate an interaction between CB1 receptor signaling and the molecular mechanisms responsible for protein turnover during memory reconsolidation.

The findings demonstrate that CB1 cannabinoid receptors in the hippocampal CA1 region play a direct role in the reconsolidation of spatial memory. Activation of these receptors can interfere with memory stabilization after retrieval by modulating protein degradation and protein synthesis mechanisms. Therefore, the endocannabinoid system, particularly CB1 receptor signaling, appears to be an important regulator of the molecular processes underlying the persistence and modification of long-term spatial memories.