Double dissociation in the involvement of noradrenergic and endocannabinoid systems in classical and higher-order conditioning in newborn rabbits

Eva-Gunnel Ducourneau, Patricia Duchamp-Viret, Giovanni Marsicano, Gérard Coureaud, Guillaume Ferreira
Neurobiology of Learning and Memory. 2026-09-01; 227: 108189
DOI: 10.1016/j.nlm.2026.108189

1. Neurobiol Learn Mem. 2026 Jul 2;227:108189. doi: 10.1016/j.nlm.2026.108189.
Online ahead of print.

Double dissociation in the involvement of noradrenergic and endocannabinoid
systems in classical and higher-order conditioning in newborn rabbits.

Ducourneau EG(1), Duchamp-Viret P(2), Marsicano G(3), Coureaud G(4), Ferreira G(5).

Author information:
(1)Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, Bordeaux, France.
(2)Centre de Recherche en Neurosciences de Lyon, U1028 INSERM, UMR 5292 CNRS,
Univ. Claude Bernard Lyon 1, Univ. Jean Monnet, France.
(3)Univ. Bordeaux, INSERM, NeuroCentre Magendie, U1215, Bordeaux, France.
(4)Centre de Recherche en Neurosciences de Lyon, U1028 INSERM, UMR 5292 CNRS,
Univ. Claude Bernard Lyon 1, Univ. Jean Monnet, France. Electronic address:
.
(5)Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, Bordeaux, France.
Electronic address: .

Since Ivan Pavlov first demonstrated classical conditioning by pairing a neutral
stimulus with a reinforcer, researchers have applied this approach to understand
not only direct associations, but also more complex learning processes, such as
sensory preconditioning and second-order conditioning. Despite their relative
immaturity, very young mammals such as newborn rabbits exhibit robust classical
and higher-order conditioning. However, the neuromodulatory systems involved in
these different types of neonatal conditioning remain to be identified. Here, we
compared the role played by the noradrenergic and the endocannabinoid systems in
classical conditioning, sensory preconditioning and second-order conditioning in
newborn rabbits. Intraperitoneal injections of Propranolol, an antagonist of
beta-adrenergic receptors, blocked classical conditioning promoted by the
mammary pheromone in newborn rabbits but had no effect on sensory
preconditioning or second-order conditioning. Conversely, intraperitoneal
injections of Rimonabant, an antagonist of the main cannabinoid receptor CB1,
had no effect on classical conditioning but blocked sensory preconditioning and
second-order conditioning, indicating a specific impact on unreinforced
association. Moreover, an effect of Rimonabant on memory reconsolidation was
also revealed. These findings demonstrate a double dissociation in the role of
noradrenergic and endocannabinoid modulations in first- and higher-order
conditioning in newborn rabbits. Whereas our results indicate the noradrenergic
system specifically promotes reinforced association in pups, they also establish
that the endocannabinoid system selectively mediates higher-order conditioning
by regulating unreinforced association in newborns. This also highlights that
the rabbit is an excellent model for further investigating the neurobiology of
neonatal first- and higher-order memory.

DOI: 10.1016/j.nlm.2026.108189
PMID: 42392520

Conflict of interest statement: Declaration of competing interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.