Interaction between hippocampal serotonin and cannabinoid systems in reactivity to spatial and object novelty detection

• Activation or blockade of 5-HT4 receptors impaired spatial memory.
• CB1 receptors activation impaired spatial and novelty, while their blockade facilitated novelty.
• Subthreshold dose of RS67333 restored ACPA response.
• Subthreshold dose of RS23597 differently affect ACPA signaling.
• Effective dose of AM251 blocked the effect of 5-HT4 agents on ACPA responses.

Functional interaction between cannabinoid and serotonin neuronal systems have been reported in different tasks related to memory assessment. The present study investigated the effect of serotonin 5-HT4 agents into the dorsal hippocampus (the CA1 region) on spatial and object novelty detection deficits induced by activation of cannabinoid CB1 receptors (CB1Rs) using arachidonylcyclopropylamide (ACPA) in a non-associative behavioral task designed to forecast the ability of rodents to encode spatial and non-spatial relationships between distinct stimuli. Post-training, intra-CA1 microinjection of 5-HT4 receptor agonist RS67333 or 5-HT4 receptor antagonist RS23597 both at the dose of 0.016 μg/mouse impaired spatial memory, while cannabinoid CB1R antagonist AM251 (0.1 μg/mouse) facilitated object novelty memory. Also, post-training, intraperitoneal administration of CB1R agonist ACPA (0.005-0.05 mg/kg) impaired both memories. However, a subthreshold dose of RS67333 restored ACPA response on both memories. Moreover, a subthreshold dose of RS23597 potentiated ACPA (0.01 mg/kg) and reversed ACPA (0.05 mg/kg) responses on spatial memory, while it potentiated ACPA response at the dose of 0.005 or 0.05 mg/kg on object novelty memory. Furthermore, effective dose of AM251 restored ACPA response at the higher dose. AM251 blocked response induced by combination of RS67333 or RS23597 and the higher dose of ACPA on both memories. Our results highlight that hippocampal 5-HT4 receptors differently affect cannabinoid signaling in spatial and object novelty memories. The inactivation of CB1 receptors blocks the effect of 5-HT4 agents into the CA1 region on memory deficits induced by activation of CB1Rs via ACPA.