Sub‐chronic administration of AM6545 enhances cognitive performance and induces hippocampal synaptic plasticity changes in naïve mice

Abstract Background and Purpose There is evidence of crosstalk between the brain and peripheral tissues. However, how the periphery contributes to brain function is not well understood. The cannabinoid CB 1 receptor is classically pictured to have a relevant role in cognitive function. We previously demonstrated a novel mechanism where acute administration of the CB 1 receptor antagonist AM6545, largely restricted to the periphery, prolonged memory persistence in mice. Here, we have assessed the effects of repeated exposure to AM6545 on cognitive improvements. Experimental Approach We evaluated, in young adult male and female mice, the behavioural consequences of sub‐chronic treatment with AM6545. An unbiased transcriptomic analysis, as well as electrophysiological and biochemical studies, was carried out to elucidate the central cellular and molecular consequences of such action at peripheral receptors. Key Results Sub‐chronic AM6545 enhanced memory in low and high arousal conditions in male and female mice. Executive function was facilitated after repeated AM6545 administration in male mice. Transcriptional analysis of hippocampal synaptoneurosomes from treated mice revealed a preliminary, sex‐dependent, modulation of synaptic transcripts by AM6545. Notably, AM6545 occluded long‐term potentiation in CA3‐CA1 synapses while enhancing input–output relation in male mice. This was accompanied by an increase in hippocampal expression of Bdnf and Ngf . Conclusion and Implications Our results showed that repeated administration of AM6545 contributed to the modulation of memory persistence, executive function and hippocampal synaptic plasticity in mice, further indicating that peripheral CB 1 receptors could act as a target for a novel class of nootropic compounds.