Pharmacological Analysis in Favour of a Physiological Role for the Constitutive Activity of 5-HT2A Receptors in Learning

  • Philippe De Deurwaerdère
  • Guillaume Drutel
  • Giuseppe Di Giovanni
Part of the The Receptors book series (REC, volume 32)


The Serotonin2A (5-hydroxytryptamin, 5-HT2A) receptor is one of the numerous seven transmembrane G protein coupled receptors for serotonin (5-HT) originally described as displaying a low affinity for its endogenous ligand. It is densely expressed in the cortex and the hippocampus of rodents, primates and humans brain. A role of 5-HT2A receptors in learning and memory has been proposed for years. In some behavioural tasks in rodents, 5-HT2A receptors would display a constitutive activity, a spontaneous activity of the receptor occurring without the presence of the endogenous ligand and silenced by inverse agonists. Nonetheless, the demonstration of the existence of such a subtle activity in living organisms relies on specific criteria and on clear-cut pharmacological evaluation. While it has been claimed that 5-HT2A receptor constitutive activity participates in the conditioned eyeblink response in rabbits, such an activity would not be systematically observed in other models of learning and conditioning such as the conditioned avoidance response in rats. Here, we propose a thorough pharmacological analysis of the available data arguing in favour of the involvement of constitutive activity of 5-HT2A receptors, mostly in learning tasks and discuss the functional significance of such an activity.


Pharmacology of 5-HT2 receptors MDL11,939 Selectivity Pavlovian conditioning Conditioned avoidance response Autoshaping learning task Inverse agonism Intracellular signaling pathways Serotonin 






5-HT2A receptor

5-hydroxytryptamine2A receptor

5-HT2C receptor

5-hydroxytryptamine2C receptor


d-bromolysergic acid diethylamide


Conditioned avoidance response


Chinese hamster ovary




(±)-1(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride




G-Protein coupled receptor


Human embryonic kidney 293


Inositol phosphate


d-lysergic acid diethylamide






Phospholipase A2


Phospholipase C


Phospholipase D


Serotonin transporter



The authors are indebted to the EU COST Action CM1103 “Structure-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain” for supporting their international collaboration.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Philippe De Deurwaerdère
    • 1
    • 2
  • Guillaume Drutel
    • 1
    • 3
  • Giuseppe Di Giovanni
    • 4
    • 5
  1. 1.Université de BordeauxBordeauxFrance
  2. 2.Centre National de la Recherche Scientifique UMR 5287BordeauxFrance
  3. 3.Institut National de la Santé et de la Recherche Médicale, U 1215BordeauxFrance
  4. 4.Neuroscience DivisionSchool of Bioscience, Cardiff UniversityCardiffUK
  5. 5.Department of Physiology and BiochemistryUniversity of MaltaMsidaMalta

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