Serotonin 5-HT2C Receptors as a Target for the Treatment of Depressive and Anxious States: Focus on Novel Therapeutic Strategies

PHARMACOLOGIE

Thérapie 2005; 60 (5): 441-460 0040-5957/05/0005-0441/$34.95/0 © 2005 Société Française de Pharmacologie

Serotonin 5-HT2C Receptors as a Target for the Treatment of Depressive and Anxious States: Focus on Novel Therapeutic Strategies Le récepteur 5-HT2C comme cible dans le traitement des états dépressifs et anxieux : nouvelles stratégies thérapeutiques Mark John Millan Institut de Recherches Servier, Croissy-sur-Seine, France

Abstract

Serotonin (5-HT)2C receptors play an important role in the modulation of monoaminergic transmission, mood, motor behaviour, appetite and endocrine secretion, and alterations in their functional status have been detected in anxiodepressive states. Further, 5-HT2C sites are involved in the actions of several classes of antidepressant. At the onset of treatment, indirect activation of 5-HT2C receptors participates in the anxiogenic effects of selective 5-HT reuptake inhibitors (SSRIs) as well as their inhibition of sleep, sexual behaviour and appetite. Conversely, progressive down-regulation of 5-HT2C receptors parallels the gradual onset of clinical efficacy of SSRIs. Other antidepressants, such as nefazodone or mirtazapine, act as direct antagonists of 5-HT2C receptors. These observations underpin interest in 5-HT2C receptor blockade as a strategy for treating depressive and anxious states. This notion is supported by findings that 5-HT2C receptor antagonists stimulate dopaminergic and adrenergic pathways, exert antidepressant and anxiolytic actions in behavioural paradigms, and favour sleep and sexual function. In addition to selective antagonists, novel strategies for exploitation of 5-HT2C receptors embrace inverse agonists, allosteric modulators, ligands of homo/heterodimers, modulators of interactions with ‘postsynaptic proteins’, dual melatonin agonists/5-HT2C receptor antagonists and mixed 5-HT2C/α2-adrenergic antagonists. Intriguingly, there is evidence that stimulation of regionally discrete populations of 5-HT2C receptors is effective in certain behavioural models of antidepressant activity, and promotes neurogenesis in the hippocampus. This article explains how these ostensibly paradoxical actions of 5-HT2C antagonists and agonists can be reconciled and discusses both established and innovative strategies for the exploitation of 5-HT2C receptors in the improved management of depressed and anxious states. Keywords: 5-HT2C receptors, SSRI, depression, antidepressant, anxiety, anxiolytic

Résumé

Les récepteurs à la sérotonine (5-HT)2C jouent un rôle important dans la modulation de la transmission monoaminergique, l’humeur, le comportement moteur, l’appétit, la sécrétion endocrinienne. Les changements de leur statut fonctionnel ont été détectés dans les états anxiodépressifs. De plus, les sites 5-HT2C sont impliqués dans les actions de plusieurs classes d’antidépresseurs. Ainsi, en début de traitement, l’activation indirecte des récepteurs 5-HT2C participe aux effets anxiogènes des inhibiteurs sélectifs de recapture de la sérotonine (ISRS) comme à leur inhibition du sommeil, du comportement sexuel et de l’appétit. Inversement, la désensibilisation progressive des récepteurs 5-HT2C suit l’efficacité clinique graduelle des ISRS. D’autres antidépresseurs, comme la néfazodone et la mirtazapine sont des antagonistes des récepteurs 5-HT2C. Ces observations étayent l’intérêt d’un blocage des récepteurs 5-HT2C comme stratégie pour traiter les états dépressifs et anxieux. Cette idée est appuyée par des données montrant que les antagonistes 5-HT2C stimulent les voies dopaminergiques et adrénergiques, exercent des activités anxiolytiques et antidépressives dans les modèles comportementaux, et favorisent le sommeil et la fonction sexuelle. En plus des antagonistes sélectifs, de nouvelles stratégies d’exploitation des récepteurs 5-HT2C incluent : des agonistes inverses, des modulateurs allostériques, les ligands d’homo/hétérodimères, des modulateurs d’interaction avec les « partenaires protéiques postsynaptiques », des agonistes mélatoninergiques/antagonistes 5-HT2C doubles et des antagonistes combinés 5-HT2C/α2adrénergiques. Très curieusement, il semblerait que la stimulation de populations particulières de récepteurs est

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efficace dans certains modèles comportementaux d’activité antidépressive, et favorise la neurogénèse dans l’hippocampe. Cet article explique comment ces actions ostensiblement paradoxales des antagonistes et agonistes peuvent être réconciliées et discute des stratégies à la fois établies et innovantes pour l’exploitation des récepteurs 5-HT2C dans la prise en charge des états dépressifs et anxieux. Mots clés : récepteurs 5-HT2C, ISRS, dépression, antidépresseur, anxiété, anxiolytique

1. Major Depression and its Current Treatment

1.1 The Nature and Prevalence of Depressive States

Major depression is a disabling and common disorder with a life-time risk of about 10–15%, depending upon a number of variables such as gender, country, economic and cultural status: it represents a substantial social and economic burden.[1] Though highly prevalent in the elderly (not necessarily co-morbid dementia), the mean age for a first depressive episode is around 25 years, and depression is increasingly encountered in adolescents and children.[2-5] Precocious and sustained treatment is recommended – whether pharmacotherapy, cognitive-behavioural therapy or electroconvulsive therapy, etc. – in order to achieve effective and lasting remission.[6] The core symptoms of depression include melancholy, anhedonia (inability to feel pleasure), worthlessness, loss of hope, inability to concentrate and take decisions, and disturbed sleep – usually insomnia, though hypersomnia can be associated with excessive fatigue and psychomotor retardation.[7] There is increasing recognition of the additional burden of comorbidity, which is correlated with poor prognosis.[8] Thus, symptoms of anxiety are common, together with decreased libido, pain and other somatic symptoms, weight loss or gain, and cognitive dysfunction – particularly of attention, executive function and both short- and long-term verbal memory.[9-11] Further, depression is not infrequently a common denominator of other

serious disorders which fail to respond satisfactorily to treatment, notably cardiovascular dysfunction, Parkinson’s and Alzheimer’s disease, psychosis, substance abuse and diabetes.[2-5] Individual depressed patients tend to display specific constellations of symptoms underlying the notion of ‘endophenotypes’.[7] However, it is not clear whether dissimilar genetic, developmental and/or environmental factors lead to contrasting depressive states, whether the underlying neuronal pathologies differ, and whether distinct remedies should be proposed for specific subpopulations of patients.[7,12]

1.2 Insufficiencies of Current Antidepressants: the Need for Improved Treatment

A first major goal of novel drugs – and alternative non-pharmacological strategies – for treating depression is the relief of core and accompanying co-morbid symptoms that are either poorly controlled (such as cognitive deficits) or even exacerbated (such as sexual dysfunction) by selective serotonin (5-HT) reuptake inhibitors (SSRIs) and certain other classes of currently available antidepressants.[9,13,14] Secondly, ‘selective’ serotonin (5-HT)/noradrenaline (norepinephrine) reuptake inhibitors (SNRIs) such as venlafaxine,[15] and older ‘non-selective’ 5-HT/noradrenaline reuptake inhibitors such as the tricyclic amitriptyline, are probably more effective than SSRIs such as fluoxetine. Nonetheless, about 30% of pa-

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Fig. 2. Potential role of multiple classes of serotonergic receptor in the antidepressant actions of selective serotonin (5-HT) reuptake inhibitors (SSRIs). As depicted, the deficiency in serotonergic transmission thought to participate in the genesis of depressed states is triggered by a variety of interacting genetic, developmental and environmental factors. Serotonergic networks are recruited by SSRIs and certain other classes of antidepressant. SSRIs increase extracellular concentrations of 5-HT which subsequently recruits various postsynaptic 5-HT receptors, thereby exerting a beneficial influence on mood. Several have been implicated, though contradictory data exist for all, and it is more likely that many receptors are involved cooperatively as a function of: (i) the symptom under discussion, such as mood versus psychomotor retardation versus anhedonia; and (ii) the cerebral structure concerned, such as hippocampus versus frontal cortex. Note that SSRIs brake their own actions by acting at inhibitory 5-HT1A and 5-HT1B autoreceptors on cell bodies and terminals, respectively (not shown). They may also attenuate their postsynaptic effects indirectly via liberating 5-HT onto 5-HT2C receptors which, via GABAergic interneurons, inhibit serotonergic pathways (see section 4.2.1).

tients are resistant to all drugs.[6,15-18] In addition, remission is generally incomplete and residual symptoms, such as cognitive dysfunction and fatigue, remain a major problem.[6,7] Thus, the efficacy of novel agents needs to be improved. Thirdly, drugs generally require several weeks to exert maximal efficacy, though some alleviation may be seen more quickly with SNRIs and the precise length of treatment needed for antidepressant activity is still debated.[19-21] In any case, more rapidly active drugs are required. Despite the current preoccupation with neurogenesis and other long-term ‘plastic’ events potentially underlying antidepressant efficacy,[22,23] the almost immediate effects of sleep deprivation and intravenous administration of tricyclics suggest that a quicker onset of action should be achievable.[19,20] Fourthly, SSRIs and SNRIs are better tolerated than their tricyclic counterparts, since they interact less widely with cardiac ion channels and they do not antagonise histaminergic H1, α1-adrenergic (AR) and muscarinic receptors.[24,25] Nevertheless, they also provoke a spectrum of undesirable side effects including, as mentioned above, sexual dysfunction, insomnia, nausea and, at the initiation of treatment, anxiety[14,24,26-28] – though after 4–6 weeks of exposure they reduce anxiety in depressed, anxious and anxiodepressive subjects.[29-31] Thus, it remains important to improve the tolerance of novel classes of antidepressant agent. The present review focuses on the pharmacotherapy of depression, specifically via actions at 5-HT2C receptors, but the importance of non-drug based approaches – either alone or used as adjuncts to antidepressants in poorly responsive patients – is  2005 Société Française de Pharmacologie

willingly acknowledged. Moreover, neuroimaging, neuropsychological and experimental studies of electroconvulsive therapy and sleep deprivation, for example, are providing vital insights into current and novel drug-based strategies. In fact, both these approaches modulate serotonergic transmission and mimic the down-regulating influence of antidepressant drugs on 5-HT2C receptors.[32-36]

2. Serotonergic Mechanisms for Treating Depressive States: Roles of Multiple Serotonin (5-HT) Receptor Subtypes Enhanced serotonergic transmission is not an absolute precondition for antidepressant efficacy, as demonstrated by the therapeutic efficacy of: (i) reboxetine and other selective noradrenaline reuptake inhibitors; (ii) bupropion, a dopamine/noradrenaline reuptake inhibitor; and (iii) the ‘atypical’ agents mianserin and mirtazapine, which primarily harness catecholaminergic not serotonergic pathways.[18,37-42] Nevertheless, many classes of antidepressant, including SSRIs, SNRIs and most tricyclics, elevate extracellular levels of 5-HT and, according to tryptophan depletion studies in man, they require 5-HT for the expression of their therapeutic actions.[43-45] Ipso facto, the question arises as to which of the 14 known subtypes mediate their actions (figure 1).[46-48] Perhaps curiously, there is currently no definitive answer to this question. It is scarcely conceivable that all their beneficial and deleterious actions could be assigned to a single subtype. Even their therapeutic effects probably inThérapie 2005 Sep-Oct; 60 (5)

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Neuronal excitability Gene expression Fig. 3. A schematic overview of the assembly, binding sites and coupling patterns of 5-HT2C receptors. Several isoforms of functionally active 5-HT2C receptors are known which are generated by mRNA editing: alternative splicing also appears to happen, but probably leads to truncated, inactive forms of the receptor. In addition to the ‘orthosteric’ site, 5-HT2C receptors may bear ‘allosteric’ sites responsive to exogenous ligands. They have been shown to form homodimers with themselves and may, in theory, generate heterodimers with other classes of receptor. 5-HT2C receptors couple primarily via Gq (alpha subunit) to phospholipase C (PLC) but other coupling modes are known, for example to Gi and phospholipase A2 (PLA2). In addition to G-proteins, several other classes of protein (‘partners’) interact with and modulate the functional status (coupling, intracellular cycling, desensitisation, etc.) of 5-HT2C receptors: these include ‘PSD-95’, calmodulin (CaM) and nitric oxide synthase (NOS) I. There is evidence that 5-HT2C receptors are constitutively active: i.e. they couple to G-proteins even in the absence of 5-HT. Finally, 5-HT and other agonists do not necessarily affect coupling to G-proteins and receptor sensitivity etc. in the same way: i.e. there is evidence for ‘strength of signalling’ or directed ‘trafficking’. See section 7.1 for details.

volve multiple clusters acting in cooperation, and the identities of those implicated likely vary as a function of the symptom under consideration and the locus of antidepressant action.[45,48-52] For example, 5-HT receptors reducing despair may well differ to those restituting normal reserves of energy or restoring the valency of rewarding stimuli. Moreover, experimental studies of the roles of specific receptors in the actions of antidepressants, and of the actions of selective 5-HT receptor agonists, have tended to employ acute administration despite the need for extended treatment prior to therapeutic efficacy. These reflections have not, of course, hindered many authors from espousing key roles of their favourite subtypes. Though contradictory findings have been generated for all, the leading candidates are currently 5-HT1A sites (‘top of the pops’ for most experts), possibly 5-HT1B or 5-HT2A sites and, as discussed below and not uncontroversially, 5-HT2C sites (figure 2).[48,49,51-53]

3. 5-HT2C Receptors: Transduction, Organisation and Functional Roles An important feature of 5-HT2C receptors is the existence of structurally different isoforms reflecting mRNA editing (figure  2005 Société Française de Pharmacologie

3).[54-57] Accordingly, several different functional species exist in the brain which show differential affinity and efficacy for 5-HT and other ligands. Further, processing of 5-HT2C receptors is altered in the depressed brain and modified by antidepressant treatment.[57-61] Like their closely related 5-HT2A and 5-HT2B relatives, 5-HT2C receptors exert an essentially excitatory influence on neuronal activity, reflecting their positive coupling via Gq to phospholipase C: other G-proteins and cascades may also be recruited, such as phospholipase A2, but they need not detain us here.[46,62-68] As shown in figure 4, several methods have been developed which allow for determination of ligand efficacy at 5-HT2C receptors: antibodies directed against Gq permit, by use of modified immunoprecipitation assays, direct evaluation of the activation and blockade of 5-HT2C receptors, while the influence of drugs on phospholipase C can best be evaluated by determining the depletion of its substrates, phosphoinositides.[65-67,69] Agonist and antagonist actions of novel drugs, including potential antidepressants can, then, be established at 5-HT2C receptors. Providing an organisational foundation for their role in the control of mood, motor function, sleep patterns, appetite, endocrine secretion and sexual function,[47,70,71] 5-HT2C receptors are Thérapie 2005 Sep-Oct; 60 (5)

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concentrated in the cortex, hippocampus, amygdala, periaqueductal grey, nucleus accumbens and other corticolimbic regions, and they are also enriched in the hypothalamus, striatum, septum and brainstem.[29,47,72-74] The influence of 5-HT2C receptors on mood is considered in detail below but, in line with their localisation, selective activation of 5-HT2C receptors suppresses motor function, perturbs sleep patterns, reduces food intake and stimulates prolactin secretion.[29,47,57,70,75,76] Agonists at 5-HT2C receptors also elicit penile erections and lordosis in, strangely enough, male and female rats, respectively, but these (spinally mediated) actions do not appear to be relevant to the role of 5HT2C receptors in the control of sexual behaviour in humans, probably because they are overshadowed by the inhibitory influence of 5-HT2C receptors in the hypothalamus on sexual desire (libido), arousal and performance.[77-79] 4. 5-HT2C Receptors in the Control of Mood 4.1 Anxious States: Anxiolytic Properties of Antagonists

There is a substantial body of data supporting a facilitatory influence of 5-HT2C receptors on anxiety:[29,80,81]

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1. In several behavioural procedures in rodents, such as the social interaction test, agonists like Ro60,0175 [5-HT2C receptor agonist], WAY163,909 and meta-chlorophenylpiperazine (mCPP) [figure 5] display anxiogenic effects.[29,81] 2. By contrast, robust anxiolytic actions of selective antagonists, like SB206,553 and SB247,853 (figure 5), have been seen both in procedures of untrained behaviours and in conflict-based protocols[29,75,76,81-84] (figure 6). 3. Though the cerebral loci at which the anxiogenic actions of agonists are expressed remain poorly defined, sites in the amygdala and hippocampus are probably involved.[29,85] Providing one possible substrate for such actions, 5-HT2C receptors interfere with the operation of γ-aminobutyric acid (GABA)A receptors in limbic structures:[86,87] accordingly, they substitute for the anxiogenic agent and GABAA antagonist pentylenetetrazol in a drug discrimination procedure.[88] 4. Anxiogenic effects of 5-HT2C receptor agonists are mimicked by the anxiogenic phenotype of mice with genetically deleted 5-HT2C receptors.[89] 5. Anxiolytic actions of 5-HT2 receptor (subtype non-selective) antagonists ritanserin and metergoline have been reported

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Fig. 4. Coupling of 5-HT2C receptors to intracellular transduction mechanisms and their experimental evaluation. Binding of drugs to cloned, human 5-HT2C receptors can be 3 evaluated using the radioligand [ H]mesulergine, though selective radioligands have not been described. 5-HT2C receptors recruit the enzyme phospholipase C (PLC) via a Gq protein. Activation of Gq can be determined by use of highly selective antibodies and a modified immunoprecipitation (scintillation proximity assay) technique which measures 3

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phosphate. This results in activation of protein kinase C, leading in turn to an increase in intracellular concentrations of Ca . Other coupling modes, such as phospholipase A, are not shown for the sake of clarity. The use of the aforementioned techniques is illustrated with the potent 5-HT2C antagonist SB206,553, which fully blocks the actions of 5-HT.

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in humans, whereas the preferential 5-HT2C receptor agonist mCPP (figure 5) elicits robust anxiogenic and panicogenic effects.[29,70,90] These observations provide a potential framework for relief of generalised anxiety, conditioned fear and social phobia by 5-HT2C receptor antagonists in man. In fact, the situation is complicated by some experimental[9193] and clinical[29] findings suggesting that activation and blockade of 5-HT2C receptors may respectively abrogate and enhance unconditioned fear and panic attacks. These actions appear, interestingly, to reflect actions in the dorsomedial hypothalamus and the periaqueductal grey.[29,85,94] Increased susceptibility to panic attacks with 5-HT2C antagonists might also reflect activation of adrenergic projections (see below) which have been hypothesised to be hyperactive in panic patients.[95,96] However, as reviewed recently:[29] (i) many studies do not support a panicogenic role of 5-HT2C receptor blockade; (ii) mCPP is quite definitely anxiogenic and panicogenic in patients;[29,70,90] and (iii) certain antidepressants possessing potent antagonist properties at 5-HT2C receptors (notably, mianserin and mirtazapine) exert anxiolytic rather than anxiogenic actions in rodents and in man.[29,97] Thus, the predominant effect of 5-HT2C receptor blockade is attenuated anxiety. However, it will be necessary to undertake thorough and focused studies with selective 5-HT2C receptor antagonists in patients with specific anxiety disorders for a further

understanding of their complex roles and appropriate therapeutic niches. It should be noted that there is some – albeit conflicting – evidence that blockade of 5-HT2A receptors is associated with anxiolytic properties, whereas stimulation of 5-HT2B sites in the amygdala may exert anxiolytic effects.[29,98,99] Though there is no evidence that antagonism of 5-HT2B sites counters the anxiolytic effects of 5-HT2C receptor blockade, these points should be borne in mind in developing drugs active at 5-HT2C sites, since absolute selectivity versus their 5-HT2A and 5-HT2B counterparts is difficult to achieve.[64,66-68] 4.2 Depressive States and 5-HT2C Receptors 4.2.1 Antidepressant Properties of Antagonists

Several lines of evidence support potential antidepressant properties of 5-HT2C receptor antagonists. Firstly, as mentioned in section 3, 5-HT2C receptors are strategically localised throughout corticolimbic structures implicated in the aetiology and management of depressive states. Further, in line with a possible causal role in affective disorders, their density and functional status is elevated in experimental models of depression, as well as in patients.[33,60,61,100,101] Depletion of 5-HT stores in rats and in man (mimicking the serotonergic deficits of depression) also functionally up-regulates 5-HT2C receptors.[101-103]

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Secondly, and in contrast, electroconvulsive shock and sleep deprivation are associated with a decreased functional responsiveness of 5-HT2C receptors.[33,36] Likewise, long-term treatment with SSRIs and other classes of antidepressant has been found – with few exceptions[104,105] – to progressively down-regulate the functional activity of 5-HT2C receptors in rats and man.[106-112] Thirdly, via activation of GABAergic interneurons,[41,113] 5-HT2C receptors exert a tonic inhibitory influence on the activity of locus coeruleus-derived adrenergic pathways innervating corticolimbic structures: they likewise tonically inhibit midbrain dopaminergic cell clusters innervating the frontal cortex[41,114116] and, according to certain though not all studies, the nucleus accumbens and striatum.[116-121] These pathways, which exercise a favourable influence upon mood and cognitive function, may be deficient in depressive states and their activation is associated with antidepressant properties.[42,122-124] Activation of ascending dopaminergic and adrenergic projections provides, then, at least one substrate for antidepressant properties of 5-HT2C receptor antagonists. Techniques have been developed for directly motoring the influence of 5-HT2C receptor ligands on the activity of  2005 Société Française de Pharmacologie

dopaminergic and adrenergic compared with serotonergic neurons. These include, as illustrated in figure 7, a complementary electrophysiological and neurochemical approach which respectively measures the electrical activity of perikarya in the cell clusters or origin, and the release of dopamine and noradrenaline into the extracellular space in downstream structures, such as the frontal cortex. Thus, in figure 8 it can be seen that selective 5HT2C receptor antagonists markedly augment the release of dopamine and noradrenaline in frontal cortex, whereas the selective agonist Ro60,0175 reduces release of dopamine and noradrenaline. Fourthly, paralleling the reduced release of dopamine,[116,120] 5-HT2C agonists exert a pronounced inhibitory influence on motor function, which can be interpreted as a ‘surrogate’ model of psychomotor retardation and probably reflects interference with mesolimbic and nigrostriatal dopaminergic transmission.[125,126] In line with these observations, the agonist mCPP elicits psychomotor slowing, characteristic of depressed states, in man.[127] Moreover, as depicted in figure 6, selective 5-HT2C receptor antagonists possess antidepressant properties in certain behavioural models in rodents.[128] Antidepressant propThérapie 2005 Sep-Oct; 60 (5)

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Ventral tegmental area Fig. 7. Complementary electrophysiological and neurochemical procedures for monitoring the influence of 5-HT2C receptor ligands on the activity of ascending dopaminergic, noradrenergic and serotonergic pathways. Electrophysiological procedures are conducted in anaesthetised rats: extracellular recording of the electrical activity of dopaminergic, noradrenergic and serotonergic perikarya localised in the ventral tegmental area, the locus coeruleus and the dorsal raphe nucleus, respectively. Neurochemical studies are undertaken in freely moving subjects in which a concentric dialysis probe introduced into the frontal cortex (or other regions) is used to obtain samples of extracellular fluid; concentrations of monoamines are quantified by high-performance liquid chromatography. 5-HT = serotonin; DA = dopamine; NA = noradrenaline (norepinephrine).

erties of 5-HT2 antagonists, such as ritanserin, have moreover been documented in small-scale studies in humans.[129] Finally, numerous clinically effective antidepressants act as antagonists at 5-HT2C receptors, including amitriptyline and clomipramine (tricyclics), trazodone, nefazodone, mianserin and mirtazapine (figure 9) [which are discussed in section 5.2] and (weakly) the SSRI, fluoxetine.[57,130-134] 4.2.2 Antidepressant Effects of Agonists?

Distinct from antagonists, preferential 5-HT2C receptor agonists exert a marked suppressive influence on dopaminergic and adrenergic projections (figure 8).[41,116] In particular, loss of dopaminergic input to the nucleus accumbens may further compromise the decreased activity of dopaminergic reward mechanisms which underlies anhedonia and melancholy.[135,136] Loss of dopaminergic innervation of the frontal cortex would also be expected to further reduce cognitive capacities. Further, the agonist mCPP elicits an essentially negative influence on mood in patients, though acute exposure does not suffice to trigger depression per se. Moreover, 5-HT2C agonists indirectly decrease serotoninergic transmission by reducing raphe firing.[137,138] In view of these essentially negative effects of agonists, it is remarkable that selective activation of 5-HT2C receptors was reported in certain (though not all) studies to be effective in selected behavioural models of antidepressant activity.[51,139-143] There is no obvious  2005 Société Française de Pharmacologie

substrate for such actions, but one possibility would be the hippocampus, where 5-HT2C receptors may facilitate neurotrophic expression and neurogenesis after long-term stimulation,[144,145] a phenomenon possibly involved in therapeutic effects of antidepressant agents.[22,146-148] 4.2.3 Contrasting Substrates of Action for 5-HT2C Antagonists versus Agonists

A broad body of evidence supports potential antidepressant effects of selective 5-HT2C receptor blockade, which would also be associated with anxiolytic and other desirable actions (see section 4.1). One likely major substrate is the recruitment of catecholaminergic pathways. On the other hand, activation of other populations of 5-HT2C receptors may be associated with other facets of antidepressant activity. This notion of differential roles of specific, anatomically – and functionally – distinct populations of 5-HT2C receptors is depicted in figure 9. As always, feedback from clinical studies with selective agonists and antagonists will be necessary to further elucidate this apparent ‘paradox’. But is it really a paradox? It may be naïve to assume a unitary and global function for receptors as broadly distributed and physiologically important as 5-HT2C sites. Indeed, for several other classes of receptor, complex site- and condition-dependent influences on mood and other behaviours are well known: for example, 5-HT1A, dopamine D2, metabotropic glutamatergic, Thérapie 2005 Sep-Oct; 60 (5)

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GABAB and nicotinic receptors.[29,149-152] Nonetheless, most authorities today would advocate antagonists rather than agonists as the most promising basis for antidepressant properties. As appears to be happening, 5-HT2C receptor agonists may be best exploited as anorexic agents, novel antipsychotics, or for the treatment of substance abuse, based upon their inhibitory influence on mesolimbic transmission which is hyperactive or oversensitive in schizophrenia.[153-156] 5. Implication of 5-HT2C Receptors in the Actions of SSRIs and Other Antidepressant Agents 5.1 SSRIs and Other Drugs that Enhance Levels of 5-HT

Underpinning optimism concerning beneficial effects of drugs with antagonist properties at 5-HT2C receptors are the fol-

lowing observations concerning their role in the effects of antidepressant agents. As mentioned in section 4.2.1, sustained administration of SSRIs eventually down-regulates 5-HT2C receptors in parallel with their gradual onset of antidepressant actions. Though there is, as yet, no proof of a causal relationship, there is direct evidence that this process of desensitisation accounts for the progressive disappearance of the acute anxiogenic actions of SSRIs which in time become anxiolytic.[29,111] This explains the clinical use of SSRIs in the long-term control of anxiety disorders.[29-31] Supporting this contention, experimental models have shown that the acute anxiogenic properties of SSRIs are mediated by 5-HT2C receptors.[111,157,158] By analogy, the hypophagic actions of SSRIs and their suppressive influence on motor behaviour are also blocked by 5-HT2C receptor antagonists, and 5-HT2C receptors are also implicated in their induction of prolactin secretion,

Firing rate (% change from baseline)

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* −50 0

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Fig. 8. Influence of selective blockade or activation of 5-HT2C receptors on the activity of ascending dopaminergic, noradrenergic and serotonergic neurons. Studies were undertaken employing techniques illustrated in figure 7 and with the agonist and antagonist at 5-HT2C receptors, Ro60,0175 and SB206,553, respectively. In panel c it can be seen that SB206,553 enhances extracellular levels of dopamine and noradrenaline (norepinephrine) in the frontal cortex, whereas levels of serotonin (5-HT) are unaffected. Likewise, as shown in panel d, the agonist Ro60,0175 decreases levels of dopamine and noradrenaline without affecting those of 5-HT. Mirroring these findings, as shown in panel a, SB206,553 increases the firing rate of dopaminergic and noradrenergic but not serotonergic perikarya while Ro60,0175 suppresses the firing rate of dopaminergic and adrenergic but not serotonergic cell bodies (panel b). For panels a and b, asterisks show the significance of SB206,553 versus vehicle differences in Dunnett’s test following analysis of variance. [41,116]

Effects of drugs were also significant in the dialysis studies, but vehicle values (no effect) are omitted for clarity.

FCX = frontal cortex; IV = intravenous; LC = locus coeruleus;

SC = subcutaneous; VEH = vehicle; VTA = ventral tegmental area; * p < 0.05.

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their interoceptive properties and their interference with sexual function.[70,81,159,160] As shown in figure 10, then, 5-HT2C receptors appear to mediate several of the acute undesirable effects of SSRIs, and their down-regulation may even be related to onset of antidepressant efficacy. It should be mentioned that some authors have reported that 5-HT2C receptor antagonists blunt antidepressant actions of SSRIs in rats,[51,143] but data are contradictory, and the present authors have not been able to reproduce such findings (Brocco M and Millan MJ, unpublished observations). Moreover, as pointed out above, drugs with ‘SSRI’ and 5-HT2C receptor antagonist properties do exert antidepressant properties in patients, while adjunctive use of mianserin and mirtazapine (antidepressants with 5-HT2C antagonist properties) potentiates rather than abrogates antidepressant effects of SSRIs.[108,161-163] Moreover, 5HT2C receptor blockade enhances the influence of SSRIs on 5-HT levels.[138] Thus, it cannot be entirely discounted that a component of the antidepressant effect of SSRIs involves engagement of 5-HT2C receptors,[145] but the general pattern of data clearly supports the assertions that: (i) 5-HT2C receptors principally participate in the undesirable actions of SSRIs; and (ii) blockade rather than stimulation of 5-HT2C receptors is accompanied by clinical antidepressant effects.

5.2 Antidepressants Possessing 5-HT2c Receptor Antagonist Properties

As alluded to in section 4.2.1, certain clinically proven antidepressants possess antagonist properties at 5-HT2C receptors: none are agonists. Nefazodone and trazodone both behave as weak inhibitors of 5-HT reuptake and as antagonists at 5-HT2C and 5-HT2A receptors (figure 11).[25,45,164-166] These 5-HT2C receptor antagonist properties not only contribute to their antidepressant effects, but also preserve sexual function and improve sleep, in contrast to pure SSRIs.[14,28,167-169] The benefits of 5-HT2C receptor blockade are evident. Unfortunately, however, trazodone and nefazodone are far from perfect drugs owing to their pronounced antagonist properties at H1 receptors.[25] Blockade of these sites elicits pronounced somnolence and encourages weight gain.[24,165,170] Indeed, trazodone is more widely used to treat sleep disorders than depression.[170] Moreover, both drugs are metabolically unstable.[70,165] Finally, nefazodone was recently withdrawn owing to hepatotoxicity. Thus, as shown in figure 12, there remains considerable interest in developing improved dual 5-HT2C antagonists/5-HT reuptake inhibitors lacking the disadvantages of trazodone and nefazodone.

O N N

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Cl

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N

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Nefazodone

Mianserin

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N Cl

N

Clomipramine

N N N

O

N

N

N Trazodone

Mirtazapine

Amitryptiline

Fig. 9. Structures of antidepressants known to interact with 5-HT2C receptors. Clomipramine and amitriptyline are tricyclics, mianserin and mirtazapine are tetracylics, and trazodone and nefazodone are derivatives of mCPP (meta-chlorophenylpiperazine) [see figure 5].

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Orbital cortex

Antagonists Antidepressant Frontal cortex

Agonists(/Antagonists) Anti-impulsive?

5-HT2C Hippocampus

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Agonists Antidepressant?

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Antagonists Anxiolytic Nucleus accumbens

Antagonists Anxiolytic Agonists Panicolytic

5-HT2C

Antagonists Antidepressant Antagonists Antidepressant

DRN & MRN

Agonists Panicolytic? DA VTA

NA LC

Antagonists Antidepressant

Fig. 10. Schematic overview of potentially beneficial actions of 5-HT2C receptor antagonists and agonists in the control of depressive and anxious states. The figure is based on the notion that blockade of 5-HT2C receptors is associated with (i) broad-based antidepressant actions due to reinforcement of ascending dopaminergic and adrenergic transmission and (ii) anxiolytic actions due to effects mediated in the amygdala and, probably, the hippocampus. At least under certain conditions, activation of 5-HT2C receptors may exert: (i) antidepressant actions via induction of neurogenesis in the hippocampus; (ii) panicolytic actions via actions in the periaqueductal grey (PAG), and in the locus coeruleus (LC) to reduce acute overactivation of noradrenergic pathways during panic attacks; and (iii) anti-impulsive effects in obsessive-compulsive disorders by actions in the orbital cortex. Note, however, that experimental and clinical evidence for beneficial activities of 5-HT2C receptor antagonism are robust and well documented, whereas clinical evidence for efficacy of 5-HT2C agonists is lacking. Further, the agonist mCPP (meta-chlorophenylpiperazine) is anxiogenic and exerts an overall negative influence on mood even though it does not provoke depressive symptoms per se. DA = dopamine; DRN = dorsal raphe nucleus; MRN = median raphe nucleus; NA = noradrenaline (norepinephrine); VTA = ventral tegmental area.

The second class of clinically active antidepressants possessing antagonist properties at 5-HT2C receptors comprises mianserin and its successor, mirtazapine (figure 11).[38,40,166,171] Both of these drugs also behave as antagonists of α2-ARs and 5-HT3 receptors, and mianserin interacts with the noradrenaline transporter but neither mianserin nor mirtazapine recognise 5-HT reuptake sites.[25,40,166] Blockade of α2-ARs further reinforces dopaminergic and adrenergic transmission, since dopaminergic and adrenergic pathways are likewise subject to inhibition by α2-ARs.[40,41,120,172,173] Mianserin and mirtazapine exert wellcharacterised antidepressant actions, essentially without the sexual dysfunction and insomnia triggered by SSRIs.[14,38,171,174,175] Indeed, they have both been used as adjuncts to abrogate such side effects of SSRIs.[176,177] Mianserin and mirtazapine may also possess anxiolytic properties, though these have not been well characterised in the clinic.[29,99,171] By analogy to trazodone and nefazodone,[164] the principal problem of mianserin and mirtazapine is their antagonist properties at α1-ARs, muscarinic and, most prominently, H1 receptors.[25,165] Mirtazapine, in particular, has pronounced sedative effects and can provoke severe obesity.[24,165,171] There is thus considerable interest in drugs  2005 Société Française de Pharmacologie

sharing their combined antagonist properties at 5-HT2C receptors and α2-ARs, yet devoid of their antagonist actions at histamine H1 receptors. A final class of agent (depicted in figure 12) consists of combined antagonists at 5-HT2C receptors and agonists at 5-HT1A sites, several of which are, or have been, in development.[149,178,179] However, these drugs have not proven very useful by analogy to pure 5-HT1A receptor agonists and probably due to the distressing side effects associated with high efficacy activation of postsynaptic 5-HT1A receptors. Possibly, partial agonist activity at 5-HT1A sites (analogous to buspirone) would have a greater chance of success.[149]

6. Novel Classes of Antidepressants Possessing Antagonist Properties at 5-HT2C Receptors From the above discussion several other concepts for the exploitation of 5-HT2C receptors in the improved treatment of depressed states may be elaborated (figure 12). Thérapie 2005 Sep-Oct; 60 (5)

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Frontal cortex, limbic system

5-HT

Corticolimbic

+ 5-HT1A

Improved mood

+ 5-HT2C

↑ Anxiety ↓ Libido ↓ Sleep ↓ Appetite ↑ Prolactin

5-HT

SSRI

Fig. 11. Involvement of 5-HT2C receptors in the induction of side effects by selective serotonin (5-HT) reuptake inhibitors (SSRIs). The figure shows that several acute undesirable actions of SSRIs – such as their anxiogenic actions, their diminution of libido and their perturbation of sleep architecture – may involve the recruitment of 5-HT2C receptors. Blockade of 5-HT2C receptors should attenuate the undesirable actions of SSRIs yet leave their therapeutic influence on mood intact (though see section 5.1 for a more critical discussion of the role of 5-HT2C receptors in the modulation of mood).

that antidepressant treatment is accompanied by an elevation in circulating levels of melatonin.[190,191] Further, there is experimental evidence (albeit limited) that activation of melatonin receptors may exert a favourable influence on mood.[192-194] These reflections prompted the conception of drugs integrating antagonist properties at 5-HT2C receptors and agonist properties at melatoninergic (MT1/MT2) receptors, which led to the subsequent discovery of agomelatine (figure 13).[69,195-197] Recent clinical studies have demonstrated that agomelatine, the first combined 5-HT2C receptor antagonist/melatonin agonist, is a clinically effective antidepressant agent.[198-201] These data coincide with experimental studies showing that agomelatine increases frontocortical release of dopamine and noradrenaline and displays antidepressant properties in behavioural models in rodents[69,202-204] – actions reflecting blockade of 5-HT2C receptors. The 5-HT2C receptor antagonist actions of agomelatine likewise account for its anxiolytic profile in several experimental models

6.1 Selective 5-HT2c Antagonists

Despite their potential clinical utility, selective antagonists at 5-HT2C receptors remain to be exploited as therapeutic agents. From the foregoing comments it would be hoped that such agents express combined antidepressant and – both rapid and sustained – anxiolytic properties. Such agents should improve rather than compromise sexual function and encourage rather that disrupt sleep. Further, they may be particularly useful in subjects with excessive fatigue and psychomotor retardation. Regarding possible side effects, the potential disadvantage of obesity must be borne in mind. On the basis of studies in mice genetically deprived of 5-HT2C receptors,[57,180] however, recent analyses of their phenotype and of the actions of selective antagonists indicate that blockade of 5-HT2C receptors alone (in the absence of H1 antagonism) is unlikely to be a serious problem.[75,76,165,181,182] Care should initially be exercised in patients exhibiting panic attacks (see section 4.1) or obsessive-compulsive disorders in which a facilitatory role of 5-HT2C receptors (in the orbital cortex) was proposed (figure 12).[89,183,184] However, supporting data are not extensive and the most robust treatment for obsessive-compulsive disorder known is clomipramine, which has potent antagonist actions at 5-HT2C receptors. Moreover, the longterm anti-impulsive efficacy of SSRIs may reflect down-regulation of 5-HT2C receptors (see section 4.2.1).[25,185]

+ Inhibition of 5-HT or 5-HT/noradrenaline reuptake

+ Melatonin (MT1/MT2) agonist

Selective 5-HT2C receptor antagonist/ inverse agonist

+ 5-HT1A Partial agonist + 5-HT1B Antagonist

+ α2A/C-Adrenergic antagonist

Fig. 12. Summary of possible strategies for therapeutically exploiting 5-HT2C receptors for the improved management of depressed and anxious states. One possibility is the use of selective antagonists or inverse agonists (see section 6.1 and figure 14) at 5-HT2C receptors. Alternatively, multi-target strategies may be envisaged, such as coupling of 5-HT2C receptor antagonist properties to agonist actions at melatonin (MT) receptors, exemplified by the clinically active agent agomelatine. Such drugs should improve perturbed circadian and sleep rhythms. The introduction of 5-HT2C receptor properties into drugs inhibiting reuptake of serotonin (5-HT) and/or noradrenaline (norepinephrine) may lead to effective and better-tolerated agents. Clinical precedents for such drugs include nefazodone (now withdrawn). Association of 5-HT2C receptor antagonist actions with agonist properties at 5-HT receptors mediating antidepressant actions could also be envisaged. For example, certain high efficacy 5-HT1A agonists/5-HT2C receptor antagonists have been described but they reveal poor tolerance, hence the mention of partial agonists. Other receptors potentially involved in transducing antidepressant actions, such as 5-HT1B receptors, might also be targeted. Finally, dual antagonists at

6.2 Mixed 5-HT2c Antagonists/Melatonin Agonists: Agomelatine

5-HT2C and α2-adrenergic receptors may prove to be robust antidepressant agents which lack sleep perturbation and sexual dysfunction, and exert a positive influence on cognitive function. A clinical predecessor would be mirtazapine (see section 5.2). How-

There is evidence that a perturbation in the secretion of melatonin secretion may be related to clinical depression,[186-189] and  2005 Société Française de Pharmacologie

ever, like nefazodone, it is limited by antagonist actions at α1-adrenergic receptors, muscarinic receptors and, very potently, histaminergic H1 receptors.

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Serotonin 5-HT2C Receptors and Mood

though, under certain conditions, recruitment of melatonin receptors may be involved in relieving anxious states.[200,205-208] Similarly, blockade of 5-HT2C sites probably predominates in the improvement of effect by agomelatine, but a possible contribution of melatonin receptors should not be discounted.[200,205-208] The ability of agomelatine to resynchronise perturbed chronobiological rhythms in experimental studies primarily reflects its agonist effects at melatoninergic receptors, probably in the suprachiasmatic nucleus,[209-214] though it should be noted that 5-HT2C receptors have also been implicated in the control of circadian rhythms, expressing their actions in the suprachiasmatic nucleus and in interaction with melatonin.[215,216] Both 5-HT2C receptor blockade[166,216] and activation of melatonin receptors[211,212,217] may, possibly in interaction,[218] improve sleep patterns and enhance sexual function.[219] Irrespective of the relative contributions of 5-HT2C receptor antagonist and/or melatonin agonist properties in the distinctive functional profile of agomelatine, it may be clinically useful not only in treating core symptoms of depression but also in countering co-morbid symptoms of anxiety, sexual dysfunction and insomnia, normalising perturbed circadian patterns, and possibly in treating seasonal affective disorder.[200,212,220,221] This remains to be seen. Agomelatine is well tolerated and evokes neither insomnia nor sexual dysfunction,[198,199,201] in line with the favourable influence of 5-HT2C receptor blockade and stimulation of melatonin receptors upon sleep patterns and sexual behaviour (see above).[67,81] Agomelatine is, then, a promising and original drug for the management of depressed states.

6.3 Dual Ligands at 5-HT2C Receptors and Non-Monoaminergic Targets

More speculatively, there seems no reason why novel multitarget strategies oriented around 5-HT2C receptors should not incorporate non-monoaminergic targets to provide complementary components of activity. For example, inhibition of acetylcholinesterase or agonist actions at nicotinic receptors to improve cognitive function.[222,223] Selective neurokinin (NK)1 receptor antagonists have not proven reliably effective in depression, but antagonists at these sites enhance the release of dopamine and noradrenaline in the frontal cortex,[224,225] reinforce the influence of SSRIs on 5-HT release,[226] and display anxiolytic and antidepressant actions in rodents.[227-230] Thus, the association of NK1 receptor and 5-HT2C receptor blockade is an intriguing proposition. Of interest is also combined antagonist actions at 5-HT2C and corticotrophic factor1 receptors, selective antagonists which manifest antidepressant and anxiolytic properties.[231-234] This is just a small selection of many possible permutations of poten 2005 Société Française de Pharmacologie

453

NHCOCH3

CH3O

Agomelatine

Fig. 13. Structure of the novel antidepressant and 5-HT2C antagonist/melatonin agonist, agomelatine. Agomelatine is a naphthalene derivative.

tially interesting agents, and recent analyses indicate that the chemistry required to succeed with such hybrid drugs may be less onerous and challenging than generally assumed.[235] 7. Novel Therapeutic Concepts for Manipulating 5-HT2C Receptors 7.1 Isoforms; Homo/Heterodimers; Allosteric Modulators; Trafficking and Intracellular Proteins

Several isoforms of 5-HT2C receptors have been described with contrasting pharmacological and coupling properties, and differentially distributed in the rodent and human brain.[54-57,236] Interestingly, their differential generation may be altered in depressive states[58-60,237] and mRNA editing is also altered by cytokines which can provoke depression in man,[61,238,239] further underpinning the relationship between mood disorders and 5HT2C receptors. It is conceivable that 5-HT2C receptor isoforms which mediate favourable actions of 5-HT2C receptor antagonists, in the amygdala for example, are distinct from those which mediate beneficial effects of agonists, for example in the hippocampus (see section 4.2). This implies the possibility of their differential manipulation by drugs specific for individual isoforms, though it remains to be seen whether this is possible. Other novel prospects for modulating activity at 5-HT2C receptors may be via recently described allosteric sites unresponsive to 5-HT.[240] A further opportunity would emerge if the binding characteristics of hypothetical 5-HT2C receptor heterodimers present novel pharmacological and functional properties relative to monomers and homodimers.[241] Interesting, though hypothetical, possibilities include heterodimers between 5-HT2C receptors and co-localised α2-ARs, 5-HT1A, melatonin (MT1 and/or MT2) receptors and/or GABAB receptors. An interesting feature of 5-HT2C receptors is their coupling to several transduction pathways: not only Gq/phospholipase C, Thérapie 2005 Sep-Oct; 60 (5)

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5-HT

5-HT

Status

Mechanism

Corticolimbic

5-HT1A + 5-HT2C − 5-HTX +

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5-HT1A/X and 5-HT2C balanced

Corticolimbic

5-HT1A + 5-HT2C − 5-HTX +

Mood

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5-HT2C (CA) unopposed

Corticolimbic

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Mood

‘Treated’ (after delay)

5-HT1A/X restored and 5-HT2C down-regulated

Corticolimbic

5-HT1A + 5-HT2C − 5-HTX +

‘Treated’ (rapid?)

5-HT2(CA) blocked and ↑ NA/DA release

SSRI

5-HT

5-HT

− NA/DA

Mood +

5-HT2C inverse agonist Frontocortical

Fig. 14. Potential significance of constitutively active (CA) 5-HT2C receptors to affective disorders and their treatment. Compared with the ‘normal’ state, serotonergic transmission is decreased in depression. Accordingly, activity at 5-HT1A and other (unknown) postsynaptic sites with a favourable influence on mood is reduced, whereas constitutively active 5-HT2C receptors – which do not need 5-HT for activity and which negatively influence mood – is maintained. Hence, they contribute to the pathogenesis of depressed states. Treatment with a selective 5-HT reuptake inhibitor has a double benefit: (i) it restores activity at sites favourably influencing mood; and (ii) it down-regulates 5-HT2C receptors, thereby reducing their activity. Finally, an inverse agonist at 5-HT2C receptors could improve mood directly (and rapidly) in depressed patients by deleting activity at constitutively active 5-HT2C receptors and disinhibiting dopaminergic and adrenergic receptors. DA = dopamine; NA = noradrenaline (norepinephrine); SSRI = selective serotonin reuptake inhibitor.

their principal means of signalling, but also other subtypes of G-protein and enzymes. Certain agonists (and perhaps antagonists?) may favour one pathway over another.[56,66,242-245] Supposing that coupling cascades are differentially related to beneficial versus deleterious actions, one could conceive of drugs that preferentially act on the former pathway. The preceding comment implies drugs that act at the level of ligand-recognition sites on 5-HT2C receptors. However, there is increasing interest in intracellular mechanisms of transduction as targets for novel psychotropic agents,[147,246-248] and a final possibility would to be alter activity at 5-HT2C receptors by acting on intracellular proteins other than Gq which associate with the receptor and modify its function: in this regard, several classes of postsynaptic protein modulating, coupling and desensitisation of 5-HT2C receptors may be evoked.[249-251] For this strategy, the ideal approach might be a multi-target ligand that, say, blocked (or activated) 5-HT2C receptors and, concurrently, acted downstream in the cellular signalling cascade to strengthen its own effects. This sounds highly speculative but the other side of the coin is that many drugs which we assume to act exclusively at 5-HT2C receptors or other G-protein coupled receptors may turn  2005 Société Française de Pharmacologie

out to enter neurons and have additional intracellular actions (at innumerable kinases for example) which we simply ignore. 7.2 Constitutive Activity, Inverse Agonists and Depressed States: a Theory

One final possibility derives from recent observation that cerebral (unedited) 5-HT2C receptors, at least those inhibitory to dopaminergic projections,[121] are constitutively active.[54,55,237,252] This implies that the induction of dopamine liberation may reflect direct (‘dopamine-independent’) actions of ‘inverse agonists’ rather than blockade of the actions of spontaneously released dopamine by ‘neutral’ antagonists. In fact, both processes may occur. In figure 14, an hypothesis is outlined which suggests that constitutive activity at 5-HT2C receptors may be of broader significance to the induction and control of depressed states. The idea is basically that constitutively active 5HT2C receptors exert a tonic negative influence upon mood which opposes favourable effects of other classes, such as postsynaptic 5-HT1A receptors,[49,52] which require spontaneous release of 5HT for their actions. In depression, 5-HT release is reduced leading to a preponderant, deleterious influence of constitutively acThérapie 2005 Sep-Oct; 60 (5)

Serotonin 5-HT2C Receptors and Mood

tive 5-HT2C receptors which do not require 5-HT. SSRIs will improve mood by: (i) restoring activity at 5-HT1A receptors; and (ii) down-regulating constitutively active 5-HT2C receptors. Indeed, inverse agonists at 5-HT2C receptors should themselves be effective antidepressant agents, perhaps more powerful than ‘neutral’ antagonists. This hypothesis will require direct evaluation, and ideally we would wish to compare actions in depressed patients of selective inverse agonists versus those of selective neutral antagonists. This is not currently possible, but their actions can be systematically explored in experimental models of depression. A further good starting point to illuminate this idea would be to systematically determine precisely which antidepressant agents behave as inverse agonists or neutral antagonists at 5-HT2C receptors, an approach which we are currently exploring employing a diversity of cellular approaches (Chanrion B et al., unpublished observations). In any case, support for the 5-HT2C inverse agonist concept of antidepressant action is afforded by work demonstrating that at least mianserin and mirtazapine behave as inverse agonists of cloned, human 5-HT2C receptors.[253-257]

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cially paradoxical, but by means unusual for receptors of genuine pathophysiological significance (see section 4.2.3) – justifies further exploration. Finally, several novel concepts for the exploitation of antagonist properties at 5-HT2C receptors justify further experimental and clinical evaluation, such as the benefits of inverse agonist rather than neutral antagonist properties. Our understanding of the functional roles of 5-HT2C receptors is likely to further increase in the coming years. Among monoaminergic receptors they remain of central interest regarding their significance in the aetiology and control of depressive states and other CNS disorders.

Acknowledgements The authors would like to thank A. Dekeyne, B. Di Cara and J.-M. Rivet for logistical support.

References 1.

2.

8. Concluding Comments 3.

Major depression is a heterogeneous and multifactorial disorder for which improved treatment is urgently required, both pharmacotherapy and/or complementary non-drug based strategies. All currently available antidepressants act via monoaminergic networks – which are likewise recruited by electroconvulsive shock and other alternative treatment modes.[7,48] It would, however, be naïve to assume that monoaminergic approaches to the treatment of depressed states have been exhausted: there is considerable mileage still to be gained from their imaginative exploitation, particularly as concerns multi-target agents integrating monoaminergic and non-monoaminergic mechanisms of action.[48] In this regard, 5-HT2C receptors appear of unique interest in view of compelling evidence from experimental and clinical studies that they play a major role in the control of affect and in the actions of antidepressant drugs. In this respect, it appears that their blockade is associated with therapeutic benefit, not only in terms of elevated mood but also of improved sleep, restored sexual function and concomitant relief of symptoms of anxiety. However, there is evidence that they may not fulfil a unitary role inasmuch as specific and anatomically distinct sub-populations (and/or isoforms?) appear to differentially influence mood and depressive states. Accordingly, there is some experimental support for the notion that activation of discrete clusters of 5-HT2C receptor may ameliorate certain components of anxiodepressive states. This fascinating possibility of opposing actions – superfi 2005 Société Française de Pharmacologie

4.

5.

6. 7. 8. 9. 10. 11. 12. 13.

14.

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Correspondence and offprints: Mark John Millan, Institut de Recherches Servier, 125 chemin de ronde, 78230 Croissy-sur-Seine, France. E-mail: [email protected]

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