Endocannabinoid-dopamine interactions mediate incidental associations in the hippocampus

Fundazuri, U. B.; Barrera-Conde, M.; Rampini, E.; Gomez-Sotres, P.; Ioannidou, C.; Pinho, J.; Gonzalez-Portilla, M.; Beriain, S.; Busquets-Garcia, A.; Ferreira, G.; Marsicano, G.

doi:10.64898/2026.08.24.746680

bioRxiv · 10.64898/2026.08.24.746680

Endocannabinoid-dopamine interactions mediate incidental associations in the hippocampus

Fundazuri, U. B.·Barrera-Conde, M.·Rampini, E.·Gomez-Sotres, P.·Ioannidou, C.·Pinho, J.·Gonzalez-Portilla, M.·Beriain, S.·Busquets-Garcia, A.·Ferreira, G.·Marsicano, G.

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Abstract

Reinforced conditioning allows individuals predicting future events with high confidence. However, many daily behaviours rely on unreinforced connections of neutral stimuli, called Incidental Associations (IAs), which enhance predictive capacity in unstable environments and are observed across species. IAs can be studied through sensory preconditioning paradigms, where two neutral stimuli (S1/S2) are presented together in a preconditioning phase, followed by classical conditioning of S1 with a potent reinforcer. As a result, subjects present a direct response to the S1 stimulus, but also display mediated responses to the S2 stimulus never explicitly reinforced, indicating IA formation during preconditioning. Our previous work demonstrated that type-1 cannabinoid receptors (CB1 receptors) in the hippocampus are essential for this IA formation. As dopamine signaling is also important for this process, we investigate the role of interactions between these dopamine-cannabinoid systems in IA memory formation in the hippocampus. Extending our previous work on odor-taste association, using light-sound association we showed that global CB1 receptor knock-out or specific hippocampal CB1 receptor deletion also blocked mediated responses to sound (S2) while direct response to light (S1) was unaltered. Focusing on dopamine, we then found hippocampal dopaminergic activity is enhanced during paired presentations of S1 and S2 and that blockade of dopamine D1 receptor during preconditioning S1-S2 associations abolished mediated response to S2. Interestingly, mice lacking CB1 receptors specifically in D1-receptor-expressing cells (D1-CB1-KO) failed to show mediated responses for either light-sound or odor-taste associations, identifying this CB1 receptor population as critical for IA formation. Enhanced activation of CB1 receptors, through either increase of endocannabinoids (using degradation enzyme inhibition) or exogenous stimulation by cannabis-derived Delta-9-tetrahydrocannabinol (THC), was able to promote the formation of IAs under insufficient conditions. The effect of endogenous CB1 activation, but not THC, was blocked in D1-CB1-KO mice indicating that IA-facilitation by endogenous and exogenous receptor activation rely on different mechanisms. Overall, these data uncover new mechanisms underlying unreinforced associative learning.

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Fundazuri, U. B., Barrera-Conde, M., Rampini, E., Gomez-Sotres, P., Ioannidou, C., Pinho, J., Gonzalez-Portilla, M., Beriain, S., Busquets-Garcia, A., Ferreira, G., Marsicano, G.. 2026-08-27. Endocannabinoid-dopamine interactions mediate incidental associations in the hippocampus. https://doi.org/10.64898/2026.08.24.746680

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