Memory Consolidation Depends on Endogenous Hippocampal Levels of Anandamide: CB1 and M4, but Possibly not TRPV1 Receptors Mediate AM404 effects.

The endocannabinoid system is involved in the fine-tuning of local synaptic plasticity in the hippocampus during the initial steps of memory formation/transformation. In spite of extensive studies, endocannabinoid modulation of these processes is still poorly understood. Here we studied the effects of intra-CA1 infused AM404, an anandamide (AEA) transport/metabolism inhibitor, upon an aversive memory consolidation with or without prior systemic administration of metyrapone, as well the concomitant intra-CA1 administration of AM404 plus AM251 (CB1 receptor inverse-agonist), capsazepine (TRPV1 receptor antagonist) or tropicamide (M4 receptor antagonist). We also investigated the effect of AM404 on memory retrieval and Long-Term Potentiation induction. Adult male Wistar rats were trained in the Contextual Fear Conditioning task and tested 48 h later. AM404 disrupted both memory consolidation and retrieval, and abolished LTP induction. The post-training effect, however, was reverted by metyrapone - which was amnestic by itself - corroborating the known co-dependency between glucocorticoids and endocannabinoids, and suggesting that some level of aversiveness is necessary for an adequate consolidation. In the coadministration experiments, while AM251 and tropicamide were able to revert the AM404 amnestic effect, capsazepine had no effect. This confirms that CB1 actually mediate the amnestic effect caused by the augmented AEA pool, but TRPV1 does not. The tropicamide result suggests an interesting comodulatory interaction between the endocannabinoid and the cholinergic systems. We propose a steady-state model centered in the idea of an optimal, stable extracellular concentration of anandamide as a necessary condition to ensure the consolidation of a stable memory trace in the CA1 area.