Synthesis and Remarks

The concept of constitutive activity implying that an agonist increases and an inverse agonist decreases the coupling efficiency of a receptor toward its intracellular effector pathway is a pharmacological outcome of in vitro preparations. Its transposition to cerebral function is probably not as clear. Indeed, even if this concept fits with the opposite effects of agonist versus inverse agonist in the control of subcortical DA release in halothane-anesthetized rats regarding 5-HT2C receptors (De Deurwaerdere et al. 2004; Berg et al. 2005), the neurobiological basis of these opposite effects could imply the participation of 5-HT2C receptors at different loci in the brain. Consequently, there is no in vivo evidence to date that a single population of 5-HT2C receptor is able to share its activity from constitutive to tonic and phasic responses.

The existence of a constitutive activity in vitro is associated with the number of copies of the receptor expressed by the heterologous systems, and it is likely that this high expression for numerous GPCR is barely reached endogenously in vivo. There would be two other possibilities for a receptor to display a constitutive activity in vivo. First, the constitutive activity would be related to the very high capacity of the receptor to interact with G proteins. This property has been confirmed in vitro for native forms of 5-HT2C receptors (unedited form of the mRNA) (Berg et al. 1999; Niswender et al. 1999) but not for 5-HT2A receptors (Berg et al. 1999; Grotewiel and Sanders-Bush 1999) although they have been proposed to be constitutively active in conditioned behavioral responses (Harvey et al. 1999). In addition, the constitutive activity for 5-HT2C receptors has been associated with poorly edited forms for which the coupling efficiency and affinity for ligands are high compared with the edited forms (Fitzgerald et al. 1999; Quirk et al. 2001). In vivo, most 5-HT2C receptors are expressed in edited forms (Burns et al. 1997; Schmauss 2003). The reduced functional properties of these edited receptors may require higher doses of inverse agonists and agonists to unmask the constitutive and phasic controls on DA release. This suggests that the nature of the 5-HT2C receptor control may not be only related to the receptor itself. Another possibility would be the own metabolic and electrical activity of the cell expressing the receptor. Regarding 5-HT2C receptors, it is indeed evident that the activity of the cells expressing the receptor dramatically varies in the basal ganglia, ranging from hyper-polarized cells in the striatum to a tonic and sustained activity of discharge of neurons in the substantia nigra pars reticulata and the entopeduncular nucleus. Consequently, the cell's own activity would narrow the impact of 5-HT2C receptors from constitutive to tonic/phasic responses, depending on the host cell considered.

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