Differential role of the hippocampal endocannabinoid system in the memory consolidation and retrieval mechanisms.

CB1 cannabinoid receptors are abundantly expressed in the brain, with large concentrations present in the hippocampus, a brain structure essential for memory processing. In the present study, we have investigated the possible modulatory role of the endocannabinoid system in the dorsal hippocampus upon the different phases of memory processing of an aversive task. AM251, a selective antagonist of CB1 receptors, and anandamide, an endogenous agonist of cannabinoid receptors, were bilaterally infused into the dorsal hippocampus of male Wistar rats either before training, immediately after training, or before test in the step-down inhibitory avoidance (IA) task. Results showed that pre-training infusion of CB1 drugs did not influence the acquisition of the task. In contrast, post-training infusion of the CB1 antagonist disrupted while the antagonist facilitated memory consolidation of IA. The post-training results demonstrate that memory consolidation depends on the integrity of the endocannabinoid system in the CA1 region of the dorsal hippocampus. While we still have no direct proof of endocannabinoids released there after an aversive task such as IA, these results suggests that (a) AM251 acts blocking the binding of endogenously released cannabinoids and (b) exogenously supplemented anandamide may be adding its contribution to the action of the endogenously released pool. Considering our data and the higher density of CB1 receptors present in the GABAergic interneurons, we propose them as the putative target of the endocannabinoid modulation of memory, a hypothesis that needs to be proven. In addition, pre-test infusion of the CB1 receptor antagonist facilitated while infusion of the agonist did not affect memory retrieval of IA. The completely opposite action of the same drug upon memory at the post-training (consolidation) and pre-test (recall) contexts suggests that some durable change took place in the CA1 region during the consolidation process that modified the logical attributes of the pharmacological response, i.e., the drug response changed from memory disruption to memory facilitation. A similar phenomenon was previously described by us in the M4 cholinergic muscarinic subsystem in the hippocampus for the same task (Diehl, F., Fürstenau, L. O., Sanchez, G., Camboim, C., de Oliveira Alvares, L., Lanziotti, V. B., et al. (2007). Facilitatory effect of the intra-hippocampal pretest administration of MT3 in the inhibitory avoidance task. Behavioral Brain Research, 177(2), 227-231), but the biological nature of such change in the local neural circuitry remains to be investigated.