Physiological and therapeutic relevance of constitutive activity of 5-HT2A and 5-HT2C receptors for the treatment of depression
Introduction
Serotonin2A (5-HT2A) and 5-HT2C receptors are members of the super-family of 7-transmembrane-spanning (7-TMS) receptors, also known as G protein-coupled receptors. Grouped within the subclass of 5-HT2 receptors, these receptors share a high degree of amino acid sequence homology (≈80% in the transmembrane regions). As might therefore be expected, the pharmacological characteristics of these receptors are quite similar, with relatively few selective ligands available. In addition, some of the signalling cascades that are activated by these receptors are the same [e.g. phospholipase C (PLC) and PLA2]. In spite of these similarities, there are also significant differences between the 5-HT2A and 5-HT2C receptor systems (Roth et al., 1986, Roth et al., 1998; Berg et al., 1994, Berg et al., 2001b; Grotewiel and Sanders-Bush, 1999; Boulougouris et al., 2008; Robinson et al., 2008). 5-HT2A and 5-HT2C receptors are widely distributed throughout the brain, notably present in corticolimbic areas, such as the amygdala, hippocampus, frontal cortex, ventral tegmental area (VTA), nucleus accumbens (NAc) and hypothalamus. Consequently, it is not surprising that these receptors have been implicated in the aetiology of various affective disorders, including depression and anxiety (Wood, 2003; Leysen, 2004; Millan, 2005, Millan, 2006a).
Section snippets
5-HT2C receptors and depression and anxiety
There is a large literature that points to a role of the 5-HT2C receptor in depression (for reviews see Wood, 2003; Giorgetti and Tecott, 2004; Esposito, 2006; Millan, 2005, Millan, 2006a). 5-HT2C receptor density and responsiveness is enhanced in experimental models of depression and in humans (Moreau et al., 1993; Fone et al., 1996; Iwamoto and Kato, 2003; Yang et al., 2004). Various treatments for depression [including selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase
5-HT2C receptor and mRNA editing
The 5-HT2C receptor is, to date, the only 7-TMS receptor found to undergo the post-transcriptional process of mRNA editing, which generates unique isoforms of proteins in a cell- and/or tissue-specific manner (Simpson and Emeson, 1996; Smith et al., 1997). mRNA transcripts of the rat and human 5-HT2C receptors undergo adenosine-to-inosine editing events at five sites that encompass amino acids 156–160 within the putative second intracellular domain of the encoded human receptor, resulting in
5-HT2A receptor and depression
Early observations that chronic treatment of rats with antidepressant drugs produced a decrease in the [3H]-spiperone (a non-selective 5-HT2A receptor antagonist) binding density in cortex (Peroutka and Snyder, 1980; Kellar et al., 1981) led to the hypothesis that 5-HT2A receptors were involved in the aetiology of depression. Consistent with this hypothesis, prolonged tricyclic antidepressant treatment reduces 5-HT2A binding sites in rat cortex (Lafaille et al., 1991; Moreau et al., 2001). 5-HT
5-HT2A and 5-HT2C receptor-mediated regulation of dopaminergic neurotransmission
Regulation of dopaminergic neurotransmission by 5-HT2A and 5-HT2C receptors is well established (for reviews, see Esposito, 2006; Bubar and Cunningham, 2007). Both receptors are found in the substantia nigra and VTA (where dopaminergic cell bodies are located) and in forebrain target areas of dopaminergic neurons (Eberle-Wang et al., 1997; Mengod et al., 1997; Barnes and Sharp, 1999). In general, in the mesocorticolimbic system, activation of 5-HT2A receptors can facilitate stimulated, but not
Constitutive receptor activity
Historically, receptors in a population were thought to exist in a quiescent state, until activated by a ligand that possessed both affinity (ability to bind to receptors) and intrinsic efficacy (ability to activate receptors). Receptor activation involved induction of a change in conformation that would allow the receptor to regulate the activity of various cellular signal transduction cascades. Within this framework, two general classes of ligands existed. Ligands with zero intrinsic efficacy
5-HT2A and 5-HT2C constitutive receptor activity in vitro
In vitro, both 5-HT2A and 5-HT2C receptors have been shown to exhibit constitutive activity. In general, it appears that the constitutive activity of the 5-HT2C receptor towards the PLC pathway is higher than that of the 5-HT2A receptor. Agonist-independent activity towards PLC is readily observed for the 5-HT2C receptor (Barker et al., 1994; Westphal et al., 1995; Niswender et al., 1999; Herrick-Davis et al., 1999, Herrick-Davis et al., 2000; Berg et al., 2006, Berg et al., 1999); however,
5-HT2A constitutive receptor activity in vivo
Although the constitutive activity of the 5-HT2A receptor studied in vitro appears to be weak (see above), a series of studies by Harvey et al. reveal that the 5-HT2A receptor can display a significant level of constitutive activity in vivo (Welsh et al., 1998; Harvey et al., 2004, Harvey et al., 1999; Romano et al., 2000, Romano et al., 2006; Harvey, 2003; Berg et al., 2005; Dave et al., 2007). The collective work by the Harvey group found that drugs previously characterized as antagonists did
5-HT2C constitutive receptor activity in vivo
Evidence for a role of 5-HT2C constitutive receptor activity in vivo comes from microdialysis studies (De Deurwaerdére et al., 2004) assessing the role of central 5-HT2C receptors in the tonic inhibitory control of ascending dopamine pathways activity in the rat brain. Systemic administration of purported 5-HT2C antagonists (SB 242084, SB 206553) significantly enhances basal DA release in DA-innervated areas of the rat brain, such as the frontal cortex, the NAc and the striatum (Gobert et al.,
Concluding remarks
It seems clear that both 5-HT2A and 5-HT2C receptors can display constitutive activity in vivo, which has physiological relevance for acquisition of an associative-learning response and for regulation of DA release, respectively. Furthermore, the discovery of drugs with inverse agonist properties, which reduce constitutive activity, allows for an additional dimension for control of 5-HT2A and 5-HT2C receptor activity and has greatly increased the richness of our pharmacological treasure chest.
Abbreviations
- AA
arachidonic acid
- BOL
bromo-lysergic acid diethylamide
- CR
conditioned response
- DA
dopamine
- 5,7-DHT
5,7-dihydroxytryptamine
- DOI
2,5-dimethoxy-4-iodophenylisopropylamine
- DOM
2,5-dimethoxy-4-methylphenylisopropylamine
- 5-HT
5-hydroxytryptamine, serotonin
- IP
inositol phosphates
- LSD
lysergic acid diethylamide
- MDA
3,4-methylenedioxyamphetamine
- MDMA
3,4-methylenedioxymethamphetamine
- NAc
nucleus accumbens
- 8-OH-DPAT
8-hydroxy-2-(di-n-propylamino)tertraline
- PLA2
phospholipase A2
- PLC
phospholipase C
- SSRI
selective serotonin reuptake
Acknowledgements
The authors wish to acknowledge support from the National Institutes of Health (USPHS grants GM58652 and MH16841-40), the National Alliance for Research on Schizophrenia and Depression and the Institut National de la Santé et de la Recherche Médicale (INSERM)–Bordeaux 2 University.
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