The expression of contextual fear conditioning involves the dorsal hippocampus TRPV1 receptor interacting with the NMDA/NO/cGMP signalling pathway

Abstract Background and Purpose The dorsal hippocampus (dHIP) is pivotal for learning, memory, and defensive responses. Transient receptor potential vanilloid type 1 (TRPV1) receptors in the dHIP modulate contextual fear conditioning by triggering a cascade involving glutamate release, nitric oxide (NO) formation and cyclic guanosine monophosphate (cGMP) production. The present study investigated the involvement of dHIP TRPV1 receptors and their interaction with the glutamate/NO/cGMP signalling pathway in modulating the expression of contextual fear conditioning (CFC). Experimental Approach Male Wistar rats were submitted to an aversive contextual conditioning session and, 48 h later, were re‐introduced to the same aversive environment where the freezing response and autonomic activity (evidenced by increased arterial pressure and heart rate and a decrease in tail temperature) were measured. Key Results The results demonstrated that the TRPV1 antagonist 6‐I‐CPS in dHIP reduced the expression of CFC, whereas the agonist capsaicin had the opposite effect. Furthermore, dHIP pre‐treatment with an NMDA receptor antagonist (AP7), neuronal NO synthase inhibitor (N‐propyl‐L‐arginine), NO scavenger (c‐PTIO) or guanylate cyclase inhibitor (ODQ) attenuated capsaicin‐induced increases in CFC. Finally, we observed that re‐exposure to the aversive chamber increased dHIP NO levels in conditioned animals compared with a non‐conditioned group, which was prevented by the administration of the TRPV1 antagonist, 6‐I‐CPS. Conclusion and Implications Our study revealed that TRPV1 receptors in the dHIP play a crucial role in modulating contextual fear expression by acting through the NMDA receptor/NO/cGMP signalling pathway, providing important insights into the underlying mechanisms and potential therapeutic avenues associated with these pathways.