Introduction

It is generally acknowledged that neurotransmitters influence their targets in a tonic and/or phasic manner via their receptors. Additionally, numerous G-protein-coupled receptors (GPCR) may spontaneously activate intracellular pathways independently from the presence of the endogenous neurotransmitter. The so-called constitutive activity of GPCR is quite easy to study on heterologous cell expression system in vitro in which the level of endogenous ligand can be controlled and the pharmacological ligands can be used and/or characterized adequately. In vivo, none of the two later requirements can be properly controlled so that the postulate that the constitutive activity of a GPCR can physiologically influence cellular and system activity should be viewed with caution. In addition, it can not be a universal property for a given receptor, as the influence of one receptor varies among tissues and regions in the body. Yet, the existence of physiological constitutive activity has been proposed for numerous GPCR including the histaminergic H3 autoreceptor (Morisset et al. 2000), the serotonin-2A receptor (Harvey et al. 1999), and the serotonin-2C (5-HT2C) receptor (De Deurwaerdere et al. 2004), implying that a given receptor could, in theory, cumulate phasic, tonic, and constitutive influences.

The 5-HT2C receptor is one of the main examples available to illustrate the diversity of interaction of a receptor toward its various cerebral targets, putatively mixing the three above-mentioned modalities of interaction. This peculiarity would be a physiological property of 5-HT2C receptors in the basal ganglia, a group of subcortical brain regions involved in motor control. A closer look at the available data in vivo, however, raises concerns about the transposition of the concept of constitutive activity from in vitro settings to the living animals. This chapter presents briefly how 5-HT2C receptors share their constitutive activity with the phasic and tonic controls in theory. Then, we will present the experimental arguments

Laboratoire Mouvement Adaptation Cognition - UMR CNRS 5227 Université Victor Segalen Bordeaux 2146 rue Léo Saignât, Zone Nord, Bât. 2A 33076, Bordeaux, France e-mail: [email protected]

G. Di Giovanni et al. (eds.), 5-HT2C Receptors in the Pathophysiology of CNS Disease, 187

The Receptors 22, DOI 10.1007/978-1-60761-941-3_10, © Springer Science+Business Media, LLC 2011

obtained from the study of various 5-HT2C drugs (numerous antagonists, inverse agonists) in the control of dopamine release in vivo. This will raise the idea that the control exerted by the constitutive activity of 5-HT2C receptors is dependent on the use of anesthetics, the level of activity of dopamine neurons, and the region of basal ganglia considered. Then, we will bring up data on Fos expression in basal ganglia and oral activity in rats favoring the existence of the three modalities of interaction of 5-HT2C receptors in freely behaving animals. These new data will directly and indirectly address whether the three modalities, namely, phasic, tonic, and constitutive, are related to the same 5-HT2C receptors in basal ganglia.

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