Constitutive activity of 5-HT receptors: Factual analysis

Abstract

The constitutive activity of different serotonin receptors (5-HTRs) toward intracellular signaling pathways has been proposed to have physiological and pathological importance. Inverse agonists block the constitutive activity and can be used to probe and silence such a spontaneous activity. The constitutive activity of 5-HTRs can be observed in various heterologous systems of expression in vitro (very high for 5-HT_2CR; very low for 5-HT_2AR). The demonstration of the existence of this activity in native tissues and ultimately in integrative neurobiology and behavior is a real pharmacological challenge. Irrespective of the existence of mutants or polymorphisms that could alter the constitutive activity of 5-HTRs, evidence suggests that spontaneous activity of 5-HT_2CR could impact the activity of neurobiological networks and that of 5-HT₆R and 5-HT₇R the developmental morphogenesis. Some findings exist for 5-HT_2BR and 5-HT_2AR in diverse though rare conditions. The existence of a constitutive activity for 5-HT_1AR, 5-HT_1B/1DR, and 5-HT₄R is still poorly supported. When identified, the constitutive activity may differ according to brain location, state of activity (phasic in nature), and intracellular signaling pathways. A very few studies have reported aberrant constitutive activity of 5-HTRs in animal models of human diseases and patients. The purpose of this review is a critical examination of the available neuropharmacological data on the constitutive activity of 5-HTRs to determine whether this activity is an essential component of the serotonergic system transmission and it may be a possible target for CNS drug development.

Keywords: Antagonist; Biased agonist; Dopamine; G-protein; Inverse agonist; Learning; Spasticity.