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

Abstract

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.