The serotonin2B receptor and neurochemical regulation in the brain

C H A P T E R

7 The serotonin2B receptor and neurochemical regulation in the brain Umberto Spampinato1,2,*, Adeline Cathala1,2, Ce´line Devroye1,2 1

Universite´ de Bordeaux, Bordeaux, France; 2Inserm U1215, Neurocentre Magendie, Physiopathology of Addiction and Traumatic Memories Group, Bordeaux, France *Corresponding author.

I. INTRODUCTION The serotonin2B receptor (5-HT2BR), a member of the seven transmembrane spanning receptor superfamily, commonly referred to as G proteinecoupled receptors, is the most recent addition to the 5-HT2R family, which also includes the 5-HT2AR and the 5-HT2CR subtypes (Hannon & Hoyer, 2008). As for the other members of the 5-HT2R family, the 5-HT2BR couples preferentially to Gaq/11 and to the phosphoinositol hydrolysis signal transduction system to stimulate inositol 1,4,5 trisphosphate (IP3) accumulation and intracellular calcium (Ca2þ) release (Hannon & Hoyer, 2008). Studies in peripheral tissue preparations or in cell lines expressing the 5-HT2BR have shown that this receptor can recruit additional intracellular signalization pathways (Cox & Cohen, 1995; Launay et al., 1996; Locker et al., 2006; Manivet et al., 2000; Schneider et al., 2006) whose functional significance in the brain, however, remains to be established (Devroye, Cathala, Piazza, & Spampinato, 2018). The 5-HT2BR, formerly called 5-HT2FR, was first cloned and characterized in the rat stomach fundus (Foguet et al., 1992; Kursar, Nelson, Wainscott, Cohen, & Baez, 1992), then in the mouse (Loric, Launay, Colas, & Maroteaux, 1992) and in the human (Bonhaus et al., 1995; Kursar, Nelson, Wainscott, & Baez, 1994; Schmuck, Ullmer, Engels, & Lu¨bbert, 1994). Its presence has been demonstrated in various peripheral tissues in both rodents (liver, kidney, heart, uterus, trachea, small intestine, blood vessels) (Bonhaus et al., 1995; FioricaHowells, Maroteaux, & Gershon, 2000; Foguet et al., 1992; Kursar et al., 1994; Schmuck et al., 1994; Ullmer, Schmuck, Kalkman, & Lu¨bbert, 1995; Watts & Thompson, 2004) and humans (endothelial and smooth muscle

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cells of the pulmonary vasculature, liver Kupffer cells and tumor-associated macrophages, monocyte-derived dendritic cells, heart valves, intestine) (Borman et al., 2002; de Las Casas-Engel et al., 2013; Fitzgerald et al., 2000; Szabo et al., 2018; Ullmer et al., 1995). Along with its peripheral expression, this receptor has been shown to participate in the control of cell differentiation and proliferation (i.e., enteric neurons, hepatocytes, cardiomyocytes, and retinal cells), as well as in the regulation of gastrointestinal, vascular, pulmonary, cardiac, and immune functions (Cox & Cohen, 1995; De Lucchini et al., 2005; Elangbam, 2010; Ellis, Byrne, Murphy, Tilford, & Baxter, 1995; Fiorica-Howells et al., 2000; Launay et al., 2012; Lesurtel et al., 2006; Nebigil et al., 2003; Szabo et al., 2018; Wouters et al., 2007). In this context, it has to be reminded that the implication of 5-HT2BRs in heart valve pathogenesis led to the discontinued use of pharmacological compounds with 5-HT2BR agonist properties in drug research and development because of the important peripheral side effects induced by 5-HT2BR stimulation (Elangbam, 2010; McCorvy & Roth, 2015). The 5-HT2BR has also been shown to be present in various brain regions of the mammalian brain (Bevilacqua et al., 2010; Bonaventure et al., 2002; Bonhaus et al., 1995; Duxon et al., 1997; Helton, Thor, & Baez, 1994). Thus, over the last decade, a growing number of studies demonstrated the key role of central 5-HT2BRs in controlling the activity of 5-HT and dopamine (DA) networks, as well as its potential as a new pharmacological target for the treatment of several neuropsychiatric disorders (Devroye et al., 2018; Maroteaux et al., 2017). Hence, this chapter, after a short reminder of the central nervous system (CNS) expression of the 5-HT2BR and the 5-HT2B pharmacological tools available today,

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affords an overview of the role of the 5-HT2BR in the control of 5-HT and DA neuron activity, encompassing neurochemical and electrophysiological data from in vitro and in vivo studies in rodents. Also, we provide a functional basis supporting the therapeutic relevance of 5-HT2BR antagonists for treating DA-dependent neuropsychiatric disorders, in particular schizophrenia and drug addiction.

II. THE CENTRAL 5-HT2BR: BRAIN LOCALIZATION AND PHARMACOLOGY A. Brain localization Although the first studies investigating the expression of the 5-HT2BR in the mammalian brain failed to detect its presence (Kursar et al., 1992; Pompeiano, Palacios, & Mengod, 1994), subsequent investigations in the rat have shown that the 5-HT2BR mRNA is expressed in the spinal cord (Helton et al., 1994) as well as in several regions of the CNS, such as the dorsal raphe nucleus (DRN), locus coeruleus, cerebellum, habenula, hippocampus, and hypothalamic paraventricular nucleus (Bonaventure et al., 2002). Furthermore, immunohistochemistry studies assessing the 5-HT2BR protein expression in the rat brain have shown its presence in the frontal cortex, the cerebellum, the lateral septum, the dorsal hypothalamus, and the medial amygdala (Duxon et al., 1997). In humans, 5-HT2BR mRNA was detected in the whole brain, and in particular in the cerebellum, the occipital cortex, and the frontal cortex (Bevilacqua et al., 2010; Bonhaus et al., 1995). However, at present, the cellular localization of 5-HT2BRs within the CNS is poorly elucidated, with available information provided predominantly from in vitro studies in mice. Thus, in mice, 5-HT2BRs are expressed in primary astrocyte cultures from the neocortex (Li et al., 2008), in SERT-expressing primary neurons from embryonic raphe nuclei (Launay, Schneider, Loric, Da Prada, & Kellermann, 2006), in 5-HT neurons of raphe nuclei (Diaz et al., 2012), and in primary culture of microglia from P1 pups (Kolodziejczak et al., 2015). Also, a recent study, combining retrograde tracing with single-cell mRNA amplification, described the selective expression of 5-HT2BRs in a subpopulation of ventral tegmental area (VTA) DA neurons sending axons to the nucleus accumbens (NAc) shell subregion (Doly et al., 2017). In rats, the presence of 5-HT2BRs has been demonstrated in primary astrocyte cultures of the cerebral cortex, hippocampus, colliculus, cerebellum, and brainstem (Hirst, Cheung, Rattray, Price, & Wilkin, 1998; Sande´n, Thorlin, Blomstrand, Persson, & Hansson, 2000), although a previous study has failed to detect the 5-HT2BR in rat brain astrocytes (Duxon et al., 1997). Of note, in the rodent, all the

available studies, except those by Duxon et al. (1997), Launay et al. (2006), and Sande´n et al. (2000), investigated the presence of the 5-HT2BR mRNA, which is not necessarily predictive of the presence of the protein. Additional investigations are warranted to precisely determine the brain expression of the 5-HT2BR. In this context, the recent development of fluorescent probes targeting the 5-HT2BR may allow significant advances in the future (Azuaje et al., 2017).

B. Pharmacology In keeping with the high degree of sequence homology and very similar pharmacology shared by the 5-HT2R subtypes (Hoyer, Hannon, & Martin, 2002; Kursar et al., 1992), most compounds were initially unable to differentiate the 5-HT2BR from the 5-HT2AR and the 5-HT2CR. Nevertheless, over the past 20 years, several potent and selective 5-HT2BR ligands have been developed and characterized (see Table 7.1). In the mid-1990s, SB 204741 [N-(l-Methyl-5-indolyl)N’-(3-methyl-5-isothiazoly1)urea] was introduced as a 5-HT2BR antagonist (Forbes, Jones, Murphy, Holland, & Baxter, 1995). This compound, while displaying a higher selectivity for the 5-HT2BR over the 5-HT2CR, the 5-HT2AR, and numerous other receptors, possesses a relatively low affinity for the 5-HT2BR (Baxter, 1996; Bonhaus TABLE 7.1 Binding affinities of some antagonist and agonist ligands at human recombinant 5-HT2 receptor subtypes. Receptor subtypes 5-HT2A

5-HT2B

5-HT2C

References

ANTAGONISTS SB 204741

<5 <5 n.d.

7.1 6.90 7.29

5.7 5.56 5.67

Bonhaus et al. (1995) Knight et al. (2004) Cussac et al. (2002)

LY 266097

7.96 n.d.

9.28 9.70

7.63 7.17

Gleason et al. (2001)a Cussac et al. (2002)

RS 127445

6.3 6.03

9.5 8.97

6.4 6.33

Bonhaus et al. (1999) Knight et al. (2004)

BF-1

8.55

10.05

7.64

Schmitz et al. (2015)

BW 723C86

7.20 6.63

7.33 7.85

7.11 7.11

Knight et al. (2004) Cussac et al. (2008)

Ro 60e0175

7.44 6.80

8.27 8.66

8.22 7.67

Knight et al. (2004) Cussac et al. (2008)

AGONISTS

Values correspond to pKi; avalues given in Ki have been transformed; n.d. ¼ not determined. Adapted from Devroye, C., Cathala, A., Piazza, P. V., & Spampinato, U. (2018). The central serotonin2B receptor as a new pharmacological target for the treatment of dopamine-related neuropsychiatric disorders: Rationale and current status of research. Pharmacology & Therapeutics, 181, 143e155.

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III. ROLE OF THE CENTRAL 5-HT2BR IN THE CONTROL OF THE 5-HT AND DA NETWORK

et al., 1995; Forbes et al., 1995). Later, two compounds, LY 266097 [1-[(2-Chloro-3,4-dimethoxyphenyl)methyl]2,3,4,9-tetrahydro-6-methyl-1H-pyrido[3,4-b]indole] and RS 127445 [2-amino-4-(4-fluoronaphth-1-yl)-6-isoprop ylpyrimidine], were identified as potent and highaffinity antagonists (pKi ¼ 9.7 for LY 266097 and 9.5 for RS 127445), with more than 100-fold and 1000-fold selectivity for the 5-HT2BR over the other 5-HT2R subtypes, respectively (Audia et al., 1996; Bonhaus et al., 1999; Cussac et al., 2002; Gleason, Lucaites, Shannon, Nelson, & Leander, 2001). More recently, BF-1 (4-(thioxanthene9-ylidene)-piperidine) was introduced as an antagonist with the best affinity (pKi ¼ 10.05) and at least 100-fold selectivity for the 5-HT2BR over numerous other receptors (Schmitz et al., 2015). No selective 5-HT2BR agonists are available today. The compound BW 723C86 [(a-methyl-5(2-thienylmethoxy)-1H-indole-3-ethanamine], classically used to assess the effects of 5-HT2BR stimulation (Auclair et al., 2010; Gobert et al., 2000; Kennett, Bright, Trail, Baxter, & Blackburn, 1996), is only a preferential agonist, as it displays a poor affinity and low selectivity for the 5-HT2BR (Baxter, 1996; Knight et al., 2004). In addition, there are substantial differences in BW 723C86 affinities for 5-HT receptors depending on the species or tissue preparations in which its binding properties are assessed (Baxter, 1996). Finally, it is noteworthy that Ro 60e0175 [(aS-6-chloro-5-fluoroa-methyl-1H-indole-1-ethanamine], initially characterized as a highly selective 5-HT2CR agonist (Martin et al., 1998), could be a good 5-HT2BR agonist. Indeed, Ro 60e0175 was discovered to be a potent (pEC50 ¼ 9.05) and high-efficacy agonist (79%) at 5-HT2BRs (Porter et al., 1999), with better affinity and functional selectivity over the 5-HT2CR (Cussac et al., 2008; Knight et al., 2004). It is therefore important to consider that several effects of Ro 60e0175 reported in the literature and attributed to the 5-HT2CR may actually result from 5-HT2BR stimulation.

III. ROLE OF THE CENTRAL 5-HT2BR IN THE CONTROL OF THE 5-HT AND DA NETWORK A. Regulation of 5-HT neuron activity In vitro studies in 1C11 cells and mouse primary neurons from raphe nuclei identified the 5-HT2BR as a key player in controlling the overall 5-HT transport system. Indeed, it has been shown that 5-HT2BR stimulation, by promoting the phosphorylation of the 5-HT transporter (SERT) and the Naþ, Kþ-ATPase pump (the energy source of the SERT), governs 5-HT transport by means of two distinct and contrasting mechanisms (Launay

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et al., 2006). On the one hand, in the absence of external 5-HT, the 5-HT2BR coupling to protein kinase G (PKG)dependent nitric oxide (NO) production ensures the basal phosphorylation of SERT, allowing maximal 5-HT uptake capacities and antidepressant drug (SERT inhibitors) binding, these effects likely resulting from 5-HT2BR intrinsic activity. On the other hand, in the presence of 5-HT, the 5-HT2BR-protein kinase C (PKC) coupling promotes additional phosphorylation of both SERT and Naþ, Kþ-ATPase pump, impairing the electrochemical gradient necessary to 5-HT uptake functioning as well as antidepressant drug recognition. Several in vivo studies performed in rodents have confirmed that 5-HT2BRs participate in the control of 5-HT neuron activity. Thus, in the mouse, the intra-DRN administration of the preferential 5-HT2BR agonist BW 723C86 increased local 5-HT outflow, this effect being suppressed by the local perfusion of the selective 5-HT2BR antagonist RS 127445, which per se had no influence on basal 5-HT outflow (Doly et al., 2008). In the same study, pharmacological blockade as well as genetic ablation of the 5-HT2BR suppressed 3,4-methylendioxymethamphetamine (MDMA)-induced 5-HT outflow in the NAc and the VTA. These findings, together with in vitro data reported above, suggest that 5-HT2BRs exert two SERT-dependent regulations on 5-HT outflow: a phasic excitatory control and a permissive control on basal and MDMA-induced 5-HT outflow, respectively. However, these observations contrast with recent findings showing that, in rats, 5-HT2BRs exert a tonic inhibitory control on 5-HT neuron activity (Devroye et al., 2017). Indeed, peripheral administration of RS 127445 increased the firing rate of DRN 5-HT neurons and 5-HT outflow in the medial prefrontal cortex (mPFC), this latter effect being also observed after the intra-DRN administration of RS 127445 (Devroye et al., 2017). Furthermore, the same authors have found that the intra-DRN perfusion of RS 127445 or BW 723C86 increased and decreased local 5-HT outflow, respectively, this latter effect being blocked by the intra-DRN administration of RS 127445 (unpublished data). These findings argue against the possibility that blockade of DRN 5-HT2BRs would activate 5-HT neurons by inducing a SERT-dependent decrease in DRN extracellular 5-HT levels, leading to decreased endogenous tone at inhibitory 5-HT1A autoreceptors (Devroye et al., 2017). Thus, the mechanisms whereby the 5-HT2BR modulates DRN 5-HT neuron activity in the rat remain to be established. In this regard, the cellular localization of 5-HT2BRs in the rat DRN is unknown and required to allow a better understanding of the discrepancies observed between rats and mice in this regulatory control. In keeping with the involvement of 5-HT in depression (Alex & Pehek, 2007), several findings illustrate the 5-HT2BR as a permissive factor for the therapeutic effect

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of selective SERT-inhibitors (SSRIs) in this disease. Indeed, genetic inactivation and pharmacological blockade of 5-HT2BRs abolished the acute and longterm behavioral and neurogenic effects of SSRIs in mice, whereas agonist-induced 5-HT2BR stimulation elicited SSRI-like effects (Diaz et al., 2012). Also, the SSRI-induced increase in hippocampal 5-HT extracellular levels was reduced by the peripheral administration of the selective 5-HT2BR antagonist RS 127445 or in 5-HT2BR knock-out mice (Diaz et al., 2012). Altogether these observations, buttressing their critical role for the therapeutic efficacy of SSRIs, indicate that 5-HT2BRs exert a positive regulation of 5-HT neuron activity. This conclusion is confirmed by recent electrophysiological and behavioral studies in mice which, in addition, by conditional genetic ablation of the 5-HT2BR in DRN 5-HT neurons, demonstrate the direct nature of the 5-HT2BR-dependent control of 5-HT neuron activity (Belmer et al., 2018).

B. Regulation of DA neuron activity Studies in rats failed to detect an effect of 5-HT2BR stimulation on DA neuron activity. Indeed, BW 723C86 had no effect on the firing rate of VTA DA neuron (Di Matteo, Di Giovanni, Di Mascio, & Esposito, 2000), as well as on basal DA outflow in the mPFC, the NAc, and the dorsal striatum (Auclair et al., 2010; Di Matteo et al., 2000; Gobert et al., 2000). These results, in keeping with the efficacy of 5-HT2BR antagonists on basal DA outflow (see next section “Basal conditions”), could reflect the existence of a high endogenous 5-HT tone at central 5-HT2BRs (Auclair et al., 2010). Also, haloperidol-induced accumbal and striatal DA outflow remained unaltered by BW 723C86 administration (Auclair et al., 2010), providing additional support to the insensitivity of the mesocorticolimbic DA network to 5-HT2BR stimulation. Additional studies using agonists with better selectivity than BW 723C86 are necessary to confirm this conclusion. At variance with 5-HT2BR agonists, compelling in vivo biochemical and electrophysiological data demonstrate that 5-HT2BR antagonists modulate DA neuron activity under both basal and activated conditions. 1. Regulation of DA neuron activity by 5-HT2BR antagonists: basal conditions Electrophysiological findings in rats have shown that selective blockade of 5-HT2BRs had no effect at the level of the substantia nigra pars compacta but decreased the firing rate of DA neurons in the VTA, presumably those projecting to the shell subregion of the NAc (Devroye et al., 2016). In line with these results, RS 127445 and LY 266097 did not modify basal DA outflow in the dorsal

striatum and in the core part of the NAc (Auclair et al., 2010; Devroye et al., 2015), but reduce it in the NAc shell (Auclair et al., 2010; Devroye et al., 2015). Altogether these findings demonstrate that 5-HT2BR exert a tonic excitatory control on the activity of the mesoaccumbal DA pathway (Auclair et al., 2010). This conclusion contrasts with that offered by the first study assessing the effect of these receptors on basal DA outflow (Gobert et al., 2000), and reporting that the 5-HT2BR antagonist SB 204741 had no effect on DA outflow in the NAc and the dorsal striatum (Gobert et al., 2000). As discussed elsewhere (Auclair et al., 2010), differences in microdialysis probe placements could be responsible for the observed discrepancies. Furthermore, in keeping with the poor affinity of SB 204741 for the 5-HT2BR (see Table 7.1), and considering that this compound was administered at a dose much higher than the efficacious doses used in other studies (Knowles & Ramage, 1999; Yonezawa et al., 2008), nonspecific effects of SB 204741 cannot be ruled out. For similar reasons, it is not surprising to find contradictory results at the level of the mesocortical DA pathway in the literature. Indeed, while SB 204741 had no effect on mPFC DA outflow in the study by Gobert et al. (2000), it has been shown that both RS 127445 and LY 266097 increased DA outflow in this brain region (Devroye et al., 2016). Interestingly, recent findings demonstrate that the differential effect of 5-HT2BR antagonists on mPFC and NAc DA outflow result from a functional interaction with 5-HT1ARs involving polysynaptic corticalesubcortical pathways (Fig. 7.1). Indeed, peripheral or intra-DRN 5-HT2BR blockade, by increasing cortical 5-HT outflow, triggers the stimulation of 5-HT1ARs located onto mPFC GABAergic interneurons (Santana, Bortolozzi, Serrats, Mengod, & Artigas, 2004), thereby leading to the activation of pyramidal glutamatergic neurons (Llado´-Pelfort, Santana, Ghisi, Artigas, & Celada, 2012) which drive opposite changes in mPFC and NAc DA outflow through direct or indirect interactions with VTA DA neurons (Devroye et al., 2017). These results provide the first evidence of a functional role of a specific 5-HT2BR population in the regulatory control of DA neuron activity, and point out the DRN as a key structure driving the 5-HT2BR-DA system interaction. Although the cellular mechanisms involved in this interaction remain to be established, it is noteworthy that 5-HT2BRs exert an independent control on the activity of the three ascending DA pathways, by specifically providing tonic excitatory and inhibitory controls on NAc and mPFC DA outflow, respectively, and no effect in the dorsal striatum. From a therapeutic point of view, this particular pattern of effects led to the suggestion that 5-HT2BR antagonists may represent a useful tool for improved treatment of pathological conditions requiring an independent modulation of the activity of ascending

I. FUNCTIONAL ANATOMY OF THE SEROTONERGIC SYSTEM

III. ROLE OF THE CENTRAL 5-HT2BR IN THE CONTROL OF THE 5-HT AND DA NETWORK

FIGURE 7.1 Schematic drawing of the putative neuronal circuits involved in the functional interaction between 5-HT2BRs and 5-HT1ARs driving the opposite effect of 5-HT2BR antagonists on DA outflow in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). The 5-HT2BR is expressed in the dorsal raphe nucleus (DRN), which contains 5-HT neurons projecting to the mPFC. The 5-HT1AR is expressed by DRN 5-HT neurons, as well as by mPFC GABA interneurons and pyramidal glutamatergic (Glu) neurons. In the ventral tegmental area (VTA), mPFC Glu neurons provide a direct excitatory and a GABA-mediated inhibitory control on the mesocortical and mesoaccumbal DA ascending pathways, respectively. Blockade of DRN 5-HT2BRs increases mPFC 5-HT outflow, which could trigger the stimulation of 5-HT1ARs expressed by GABA interneurons in this brain region. Consequent disinhibition of mPFC pyramidal neurons could respectively stimulate and inhibit the activity of the mesocortical and mesoaccumbal DA pathways, thereby leading to increased and decreased DA outflow in the mPFC and the NAc, respectively. Adapted from Devroye, C., Haddjeri, N., Cathala, A., Rovera, R., Drago, F., Piazza, P.V., et al. (2017). Opposite control of mesocortical and mesoaccumbal dopamine pathways by serotonin2B receptor blockade: Involvement of medial prefrontal cortex serotonin1A receptors. Neuropharmacology, 119, 91e99.

DA pathways, such as schizophrenia (Devroye et al., 2018, 2016; Meltzer & Huang, 2008; Newman-Tancredi & Kleven, 2011). Indeed, 5-HT2BR antagonists have been proposed as a new class of atypical antipsychotic drugs (APDs). This proposal is further supported by recent studies reporting the efficacy of 5-HT2BR antagonists in behavioral models [phencyclidine (PCP)induced hyperlocomotion, novel object recognition test] classically used to predict the ability of APDs to alleviate the positive and cognitive symptoms of schizophrenia (Devroye et al., 2016; 2018). In addition, 5-HT2BRs could contribute to the therapeutic benefit of atypical APDs given that numerous antipsychotics (e.g., clozapine, amisulpride, asenapine, aripiprazole, cariprazine) display antagonist properties at the 5-HT2BR (Abbas et al., 2009; Kiss et al., 2010; Shahid, Walker, Zorn, & Wong, 2009; Shapiro et al., 2003) and the DA D2R, together with partial agonist properties toward the 5-HT1AR (Newman-Tancredi & Kleven, 2011).

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This hypothesis is supported by the ability of 5-HT2BR blockade to potentiate and decrease haloperidolinduced DA outflow in the mPFC and the NAc, respectively (Devroye et al., 2016), together with the role of 5-HT1AR stimulation in the 5-HT2BR-mediated control of DA outflow (Devroye et al., 2017). However, these conclusions favoring the potential of 5-HT2BR antagonists as APDs contrast with studies in mice showing that constitutive genetic ablation of 5-HT2BRs generate an antipsychotic-sensitive schizophrenic-like phenotype (Pitychoutis, Belmer, Moutkine, Adrien, & Maroteaux, 2015). Importantly, constitutive knockout models do not reflect the physiological role of a given receptor expressed in a specific locus but rather the developmental adaptations triggered by the total and chronic suppression of this receptor in the entire organism. In particular, considering the role of 5-HT2BRs in brain maturation (Kolodziejczak et al., 2015), the phenotype of 5-HT2BR knockout mice could be related to profound neural adaptations triggered by the permanent lack of this receptor. Accordingly, in 5-HT2BR knockout mice, accumbal DA levels were unaltered as compared to wild-type animals, whereas RS 127445 decreases accumbal DA outflow in rats. On the other hand, DA levels in the dorsal striatum were lower in 5-HT2BR knockout mice as compared to controls, whereas RS 127445 had no effect on DA outflow in the rat dorsal striatum (Auclair et al., 2010; Doly et al., 2009; Pitychoutis et al., 2015). Although additional investigations are warranted to determine whether these discrepancies result from species-related differences or total versus acute inactivation of 5-HT2BRs, altogether these findings support the role of 5-HT2BRs in the neurobiology and/or improved treatment of schizophrenia. 2. Regulation of DA neuron activity by 5-HT2BR antagonists:activated conditions It is well established that 5-HT2BRs are also able to control DA neurons under activated conditions. This is demonstrated by several studies reporting the modulatory influence of 5-HT2BR antagonists on DA outflow induced by several drugs targeting the DA system, such as the APD haloperidol and various psychostimulant drugs (amphetamine, MDMA, cocaine). In rats, 5-HT2BR blockade, with no effect at the level of the dorsal striatum, suppressed amphetamine and haloperidol-induced DA outflow in the NAc, and potentiated haloperidol-induced DA outflow in the mPFC, thereby confirming the region-dependent control exerted by 5-HT2BRs on ascending DA pathways (Auclair et al., 2010; Devroye et al., 2016). As discussed elsewhere (Auclair et al., 2010; Devroye et al., 2016), the inhibitory effects of 5-HT2BR antagonists on NAc DA outflow could result from an inhibitory action at the level of neuronal DA synthesis and/or DA neuronal

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firing (Auclair et al., 2010). Also, in keeping with the tight relationship between mesoaccumbens DA pathway activity and locomotion (Dunnett & Robbins, 1992), it has been proposed that the ability of 5-HT2BR antagonists to block amphetamine-evoked DA outflow in the NAc could account for their suppressant action on amphetamine-induced hyperlocomotion (Auclair et al., 2010). Studies in mice have shown that pharmacological blockade with RS 127445 or genetic ablation of the 5-HT2BR reversed MDMA-induced increase in NAc DA outflow (Doly et al., 2008). As well, the behavioral effects of MDMA (MDMA-induced hyperlocomotion, locomotor sensitization, and conditioned place preference) were no longer observed in 5-HT2BR knockout mice or in wild-type mice following the systemic administration of RS 127445 (Doly et al., 2008, 2009). Once again, it is tempting to suggest that 5-HT2BR blockade may inhibit MDMA-induced hyperlocomotion by suppressing MDMA-induced DA outflow in the NAc (Doly et al., 2008). However, RS 127445 has been shown to block MDMA-induced increased 5-HT outflow in the NAc and the VTA (Doly et al., 2008), and the relative contributions of DA and 5-HT in the behaviors evoked by MDMA are far from clear (Bankson & Cunningham, 2001; Devroye et al., 2018). Furthermore, it should be considered that the suppressive effect of RS 127445 on MDMA-induced hyperlocomotion may be directly related to the 5-HT2BR agonist properties of MDMA (Setola et al., 2003). During the last years, two studies (Devroye et al., 2015; Doly et al., 2017) have investigated the role of 5-HT2BRs in the control of cocaine responses. In rats, at variance with amphetamine and haloperidol, cocaineinduced increase in DA outflow in the NAc and the dorsal striatum was insensitive to 5-HT2BR blockade (Devroye et al., 2015). This is not so surprising when considering that the effect of 5-HT2BR antagonists on DA outflow could result from an inhibitory action on DA synthesis and/or DA neuronal firing (Auclair et al., 2010), and that both parameters are already inhibited by cocaine, thereby precluding the action of 5-HT2BR antagonists on cocaine-induced DA outflow (Devroye et al., 2015). Of note, 5-HT2BR antagonists were able to reduce cocaine-induced hyperlocomotion in the absence of changes of accumbal or striatal DA outflow. This observation led to the proposal that this suppressive effect could result from a direct postsynaptic effect on subcortical DA transmission (Devroye et al., 2015). This conclusion is supported by the ability of 5-HT2BR antagonists to inhibit quinpirole-induced late-onset hyperlocomotion, which is known to result from direct stimulation of postsynaptic DAeD2

receptors (Devroye et al., 2015). As previously discussed, the mPFC may play a key role in this interaction (Devroye et al., 2015). Indeed, the mPFC is anatomically and functionally linked to the NAc and the dorsal striatum, and is known to participate in cocaine-induced behavioral responses (Filip & Cunningham, 2003; Leggio et al., 2009; Tzschentke, 2001). Furthermore, several studies have shown that mPFC DA activity exerts an inhibitory control on subcortical DA transmission (Kolachana, Saunders, & Weinberger, 1995; Louilot, Le Moal, & Simon, 1989) and on behaviors depending on subcortical DA transmission (Lacroix, Spinelli, White, & Feldon, 2000; Vezina, Blanc, Glowinski, & Tassin, 1991). Interestingly, recent studies from our laboratory have shown that 5-HT2BR blockade potentiates cocaineinduced mPFC DA outflow (unpublished results). This finding, together with the above reported considerations, led to the suggestion that this excitatory effect at the level of the mPFC could drive the suppressive effect of 5-HT2BR blockade on cocaine-induced hyperlocomotion via glutamatergic and/or GABAergic polysynaptic corticoesubcortical pathways afferent to the NAc and/or the dorsal striatum (Devroye et al., 2015; 2018). Additional studies are needed to address this hypothesis and to determine the 5-HT2BR population involved in this interaction. Once again, a different picture is offered by studies in mice (Doly et al., 2017). Indeed, genetic ablation of 5-HT2BRs is associated with normal basal DA extracellular levels (vs. wild-type mice), yet reduces cocaineinduced DA outflow in the NAc without altering basal and cocaine-induced 5-HT outflow. Also, VTA DA neurons in 5-HT2BR knockout mice exhibit increased burst firing, leading to a stronger inhibition of VTA DA neuron firing rate in response to cocaine (Doly et al., 2017). Finally, at variance with the acute injection of the selective 5-HT2BR antagonist RS 127445 which alters neither basal nor cocaine-induced locomotor activity, chronic treatment with RS 127445 as well as genetic ablation of the 5-HT2BR increased cocaine-induced hyperlocomotion. This effect has been suggested to result from increased postsynaptic responsiveness in subcortical DA regions leading to increased DA transmission (Doly et al., 2017). Nonetheless, although the mechanisms and the anatomofunctional substrates underlying these effects remain to be fully determined, these results altogether emphasize the potential of the 5-HT2BR as a new pharmacological target for the treatment of drug addiction (Doly et al., 2017; Devroye et al., 2016; 2018), a proposal buttressed by recent findings reporting that mice lacking the 5-HT2BR show a trend toward reduction of cocaineself administration (Doly et al., 2017).

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IV. CONCLUSIONS AND PERSPECTIVES In conclusion, this chapter provides an updated overview of the substantial advances to the understanding of the physiological role of the central 5-HT2BR and complement the current knowledge of the therapeutic relevance of 5-HT2BR agents for treating different pathological conditions (Devroye et al., 2018; Maroteaux et al., 2017). Specifically, several findings reported herein permit identification of the DRN as a major site of action for the control exerted by 5-HT2BRs on both 5-HT and DA neuron activity. Although many contrasting results are observed between rats and mice, probably due to physiological differences between species and/or to brain developmenterelated factors, it appears that the 5-HT2BR represents a key player in the regulation of DA neuron activity. In particular, the data available in the literature demonstrate that 5-HT2BRs are able to regulate DA release, DA transmission, and DA-dependent behaviors. Additional experiments are warranted to determine the cellular localization of 5-HT2BRs in the rat brain as well as the cellular mechanisms underlying their impact on DA and 5-HT function. From a clinical point of view, the data reported here underline the therapeutic potential of 5-HT2BR antagonists for treating neuropsychiatric disorders related to DA neuron dysfunction. Specifically, the ability of 5-HT2BRs to afford a differential control on the DA network indicates that 5-HT2BR antagonists may represent a useful pharmacological tool for treating pathological conditions requiring an independent modulation of the activity of ascending DA pathways, such as schizophrenia (Devroye et al., 2018). Furthermore, the involvement of 5-HT2BRs in the regulation of psychostimulant drugeinduced neurochemical and behavioral responses buttresses the therapeutic potential of 5-HT2BR antagonists in drug addiction, a field which still demands efficacious pharmacological therapies (Howell & Cunningham, 2015). Finally, this chapter provides additional knowledge to the regulation of ascending DA pathways by the central 5-HT system and demonstrates the legitimacy of 5-HT2BRs among the key modulators of the activity of the central DA network.

Acknowledgments This work was supported by grants from the Institut National de la Sante´ et de la Recherche Me´dicale (INSERM) and Bordeaux University. Fig. 7.1 was adapted from Neuropharmacology, volume 119, Devroye et al., Opposite control of mesocortical and mesoaccumbal dopamine pathways by serotonin2B receptor blockade: Involvement of medial prefrontal cortex serotonin1A receptors, page 91e99, Copyright Elsevier, 2017. Table 7.1 was adapted from Pharmacology & Therapeutics, volume 181, Devroye et al., The central serotonin2B receptor as a new pharmacological target for the treatment of dopamine-related neuropsychiatric disorders: Rationale and current status of research, page 143e155, Copyright Elsevier, 2018.

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I. FUNCTIONAL ANATOMY OF THE SEROTONERGIC SYSTEM