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

Martinez-Torres, S.; Bergada-Martinez, A.; Ortega, J.; Galera-Lopez, L.; Hervera Abad, A.; Ortega-Alvaro, A.; Remmers, F.; Munoz-Moreno, E.; Soria, G.; del Rio, J. A.; Lutz, B.; Ruiz-Ortega, J. A.; Meana, J. J.; Maldonado, R.; Ozaita, A.

doi:10.1101/2021.06.16.448227

bioRxiv · 10.1101/2021.06.16.448227

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

Martinez-Torres, S.·Bergada-Martinez, A.·Ortega, J.·Galera-Lopez, L.·Hervera Abad, A.·Ortega-Alvaro, A.·Remmers, F.·Munoz-Moreno, E.·Soria, G.·del Rio, J. A.·Lutz, B.·Ruiz-Ortega, J. A.·Meana, J. J.·Maldonado, R.·Ozaita, A.

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Abstract

Peripheral inputs to the brain continuously shape its function and can influence the formation of non-emotional memory, but the underlying mechanisms have not been fully understood. Cannabinoid type-1 receptors (CB1R), widely distributed in the organism, is a well-recognized player in memory performance, and its systemic modulation significantly influences memory function. By assessing non-emotional memory in mice, we have now found a relevant role of peripheral CB1R in the formation of persistent memory. Indeed, peripherally restricted CB1R antagonism by using AM6545 showed a mnemonic effect that was occluded in adrenalectomized mice, after peripheral adrenergic blockade, or when vagus nerve was chemogenetically inhibited. Genetic CB1R deletion in dopamine {beta}-hydroxylase-expressing cells enhanced the formation of persistent memory, supporting a role of peripheral CB1R modulating the adrenergic tone. Notably, brain connectivity was affected by peripheral CB1R inhibition, and locus coeruleus activity and extracellular hippocampal norepinephrine, were increased. In agreement, intra-hippocampal {beta}-adrenergic blockade prevented AM6545 mnemonic effects. Together, we disclose a novel peripheral mechanism relevant for the modulation of the formation of persistent non-emotional memory.

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Martinez-Torres, S., Bergada-Martinez, A., Ortega, J., Galera-Lopez, L., Hervera Abad, A., Ortega-Alvaro, A., Remmers, F., Munoz-Moreno, E., Soria, G., del Rio, J. A., Lutz, B., Ruiz-Ortega, J. A., Meana, J. J., Maldonado, R., Ozaita, A.. 2021-06-17. Peripheral CB1 receptor blockade acts as a memory enhancer through an adrenergic-dependent mechanism. https://doi.org/10.1101/2021.06.16.448227

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