Abstract Peripheral inputs to the brain continuously shape its function and adjust non-emotional memory, but the mechanisms involved are not fully understood. Cannabinoid type-1 receptors (CB1Rs), widely distributed in the organism, are well recognized players in memory performance and their systemic modulation significantly influence memory function. By assessing non-emotional memory in mice, we found a relevant role of peripheral CB1R in memory persistence. Indeed, peripherally restricted CB1R antagonist AM6545 showed a mnemonic effect occluded in adrenalectomized mice, after peripheral adrenergic blockade, or when vagus nerve was chemogenetically inhibited. Genetic CB1R deletion in dopamine β-hydroxylase-expressing cells enhanced memory persistence, supporting a role of peripheral CB1Rs modulating the adrenergic tone. Notably, while brain connectivity was slightly affected by peripheral CB1R inhibition, locus coeruleus activity and extracellular norepinephrine in the hippocampus, were increased, and intra-hippocampal β-adrenergic blockade prevented AM6545 mnemonic effects. Together, we disclose a novel peripheral mechanism relevant for non-emotional memory persistence modulation.

Peripheral CB1 receptor blockade acts as a memory enhancer through an adrenergic-dependent mechanism