Constitutive activity of 5-HT receptors: Factual analysis

Philippe De Deurwaerdère, Rahul Bharatiya, Abdeslam Chagraoui, Giuseppe Di Giovanni
Neuropharmacology. 2020-01-01; : 107967
DOI: 10.1016/j.neuropharm.2020.107967

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Author information:
(1)Centre National de la Recherche Scientifique (Unité Mixte de Recherche 5287), 146 rue Léo Saignat, B.P.281, F-33000, Bordeaux Cedex, France.
(2)Centre National de la Recherche Scientifique (Unité Mixte de Recherche 5287), 146 rue Léo Saignat, B.P.281, F-33000, Bordeaux Cedex, France; Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, SS 554, Km 4,500, 09042, Monserrato, Cagliari, Italy.
(3)Neuronal and Neuroendocrine Differentiation and Communication Laboratory, Institute for Research and Innovation in Biomedicine of Normandy (IRIB), Normandie Univ, UNIROUEN, INSERM, U1239, CHU Rouen, 76000, Rouen, France; Department of Medical Biochemistry, Rouen University Hospital, 76000, Rouen,
(4)Laboratory of Neurophysiology, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, MSD 2080, Msida, Malta; Neuroscience Division, School of Biosciences, Cardiff University, Cardiff, CF10 3AT, UK. Electronic address: .

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-HT2CR; very low for 5-HT2AR). 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-HT2CR could impact the activity of neurobiological networks and that of 5-HT6R and 5-HT7R the developmental morphogenesis. Some findings exist for 5-HT2BR and 5-HT2AR in diverse though rare conditions. The existence of a constitutive activity for 5-HT1AR, 5-HT1B/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.


Auteurs Bordeaux Neurocampus