Physiological and therapeutic relevance of constitutive activity of 5-HT2A and 5-HT2C receptors for the treatment of depression

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Abstract

Serotonin2A (5-HT2A) and 5-HT2C receptors are highly homologous members of the serotonin2 family of 7-transmembrane-spanning (7-TMS) receptors. Both of these receptor subtypes have been implicated in the aetiology and/or treatment of affective disorders such as anxiety and depression. Regulation of dopaminergic neurotransmission by 5-HT2A and 5-HT2C receptor systems has been well established. In general, agonist activation of 5-HT2A receptors can facilitate stimulated dopamine (DA) release, whereas 5-HT2C agonists inhibit dopaminergic neural activity and DA release under both basal and activated conditions. However, recent experimental evidence suggests that 5-HT2A and 5-HT2C receptors can be constitutively active (agonist-independent activity) in vivo. Alterations in the constitutive activity of 5-HT2A and 5-HT2C receptor systems could be involved in the mechanisms underlying anxiety and depression or exploited for therapeutic benefit. Consequently, drugs with inverse agonist properties may have more activity in vivo to regulate DA neurotransmission than that afforded by simple competitive antagonism.

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.

References (149)

  • P. Chidiac

    Considerations in the evaluation of inverse agonism and protean agonism at G protein-coupled receptors

    Meth. Enzymol.

    (2002)
  • A.M. Cornelio et al.

    Anxiogenic-like effects of mCPP microinfusions into the amygdala (but not dorsal or ventral hippocampus) in mice exposed to elevated plus-maze

    Behav. Brain Res.

    (2007)
  • G. Di Giovanni et al.

    Selective blockade of serotonin-2C/2B receptors enhances mesolimbic and mesostriatal dopaminergic function: a combined in vivo electrophysiological and microdialysis study

    Neuroscience

    (1999)
  • G. Di Giovanni et al.

    m-Chlorophenylpiperazine excites non-dopaminergic neurons in the rat substantia nigra and ventral tegmental area by activating serotonin-2C receptors

    Neuroscience

    (2001)
  • L.W. Fitzgerald et al.

    Messenger RNA editing of the human serotonin 5-HT2C receptor

    Neuropsychopharmacology

    (1999)
  • M.B. Gatch

    Discriminative stimulus effects of m-chlorophenylpiperazine as a model of the role of serotonin receptors in anxiety

    Life Sci.

    (2003)
  • M. Giorgetti et al.

    Contributions of 5-HT(2C) receptors to multiple actions of central serotonin systems

    Eur. J. Pharmacol.

    (2004)
  • I. Gurevich et al.

    Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims

    Neuron

    (2002)
  • R.W. Invernizzi et al.

    Selective activation of 5-HT(2C) receptors stimulates GABA-ergic function in the rat substantia nigra pars reticulata: a combined in vivo electrophysiological and neurochemical study

    Neuroscience

    (2007)
  • K. Iwamoto et al.

    RNA editing of serotonin 2C receptor in human postmortem brains of major mental disorders

    Neurosci. Lett.

    (2003)
  • K. Iwamoto et al.

    Altered RNA editing of serotonin 2C receptor in a rat model of depression

    Neurosci. Res.

    (2005)
  • F. Jenck et al.

    Brain 5-HT1C receptors and antidepressants

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (1994)
  • R.S. Kahn et al.

    m-Chlorophenylpiperazine as a probe of serotonin function

    Biol. Psychiatry

    (1991)
  • K.J. Kellar et al.

    Differential effects of electroconvulsive shock and antidepressant drugs on serotonin-2 receptors in rat brain

    Eur. J. Pharmacol.

    (1981)
  • T. Kenakin

    Agonist-receptor efficacy. II. Agonist trafficking of receptor signals

    Trends Pharmacol. Sci.

    (1995)
  • G.A. Kennett et al.

    Anxiogenic-like effects of mCPP and TFMPP in animal models are opposed by 5-HT1C receptor antagonists

    Eur. J. Pharmacol.

    (1989)
  • G.A. Kennett et al.

    SB 242084, a selective and brain penetrant 5-HT2C receptor antagonist

    Neuropharmacology

    (1997)
  • E. Klein et al.

    Anxiogenic effects of m-CPP in patients with panic disorder: comparison to caffeine's anxiogenic effects

    Biol. Psychiatry

    (1991)
  • P. Leff

    The two-state model of receptor activation

    Trends Pharmacol. Sci.

    (1995)
  • P. Leff et al.

    A three-state model of agonist action

    Trends Pharmacol. Sci.

    (1997)
  • M.T. Lowy et al.

    Stimulation of serum cortisol and prolactin secretion in humans by MK-212, a centrally active serotonin agonist

    Biol. Psychiatry

    (1988)
  • J.R. Martin et al.

    Influence of the 5-HT2C receptor antagonist, SB-242084, in tests of anxiety

    Pharmacol. Biochem. Behav.

    (2002)
  • M.J. Millan

    Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies

    Therapie

    (2005)
  • M.J. Millan

    Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application

    Pharmacol. Ther.

    (2006)
  • G. Milligan et al.

    Inverse agonism and the regulation of receptor number

    Trends Pharmacol. Sci.

    (1997)
  • G. Milligan et al.

    Inverse agonism: pharmacological curiosity or potential therapeutic strategy?

    Trends Pharmacol. Sci.

    (1995)
  • J.L. Moreau et al.

    5HT2C receptor agonists exhibit antidepressant-like properties in the anhedonia model of depression in rats

    Eur. Neuropsychopharmacol.

    (1996)
  • V.J. Aloyo et al.

    Selective and divergent regulation of cortical 5-HT(2A) receptors in rabbit

    J. Pharmacol. Exp. Ther.

    (2001)
  • G. Bagdy et al.

    Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635

    Int. J. Neuropsychopharmacol.

    (2001)
  • D. Bakish et al.

    Ritanserin, imipramine, and placebo in the treatment of dysthymic disorder

    J. Clin. Psychopharmacol.

    (1993)
  • J. Benjamin et al.

    Attenuated response to m-CPP and to pentagastrin after repeated m-CPP in panic disorder

    Psychopharmacology (Berl.)

    (1999)
  • K.A. Berg et al.

    Signal transduction differences between 5-hydroxytryptamine type 2A and Type 2C receptor systems

    Mol. Pharmacol.

    (1994)
  • K.A. Berg et al.

    RNA-editing of the 5-HT(2C) receptor alters agonist-receptor-effector coupling specificity

    Br. J. Pharmacol.

    (2001)
  • K.A. Berg et al.

    Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus

    Mol. Pharmacol.

    (1998)
  • K.A. Berg et al.

    Differential effects of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxyl]-5-pyridyl]carbamoyl]-6-trifluoro methylindone (SB 243213) on 5-hydroxytryptamine(2C) receptor-mediated responses

    J. Pharmacol. Exp. Ther.

    (2006)
  • K.A. Berg et al.

    Novel actions of inverse agonists on 5-HT2C receptor systems

    Mol. Pharmacol.

    (1999)
  • K.A. Berg et al.

    Differences in rapid desensitization of 5-hydroxytryptamine2A and 5-hydroxytryptamine2C receptor-mediated phospholipase C activation

    J. Pharmacol. Exp. Ther.

    (2001)
  • P. Bhansali et al.

    Early life stress alters adult serotonin 2C receptor pre-mRNA editing and expression of the alpha subunit of the heterotrimeric G-protein G q

    J. Neurosci.

    (2007)
  • A. Bilkei-Gorzo et al.

    mCPP-induced anxiety in the light-dark box in rats – a new method for screening anxiolytic activity

    Psychopharmacology (Berl.)

    (1998)
  • V. Boulougouris et al.

    Dissociable effects of selective 5-HT(2A) and 5-HT(2C) receptor antagonists on serial spatial reversal learning in rats

    Neuropsychopharmacology

    (2008)
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