Serotonin receptors in depression and anxiety: Insights from animal studies

Accepted Manuscript Serotonin receptors in depression and anxiety: Insights from animal studies

Elżbieta Żmudzka, Kinga Sałaciak, Jacek Sapa, Karolina Pytka PII: DOI: Reference:

S0024-3205(18)30504-6 doi:10.1016/j.lfs.2018.08.050 LFS 15897

To appear in:

Life Sciences

Received date: Revised date: Accepted date:

25 April 2018 13 August 2018 20 August 2018

Please cite this article as: Elżbieta Żmudzka, Kinga Sałaciak, Jacek Sapa, Karolina Pytka , Serotonin receptors in depression and anxiety: Insights from animal studies. Lfs (2018), doi:10.1016/j.lfs.2018.08.050

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ACCEPTED MANUSCRIPT Serotonin receptors in depression and anxiety: insights from animal studies Elżbieta Żmudzkaa, Kinga Sałaciaka, Jacek Sapaa, Karolina Pytkaa a

Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland Corresponding author: Karolina Pytka - Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland,

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phone: 48(12) 620 55 38, e-mail: [email protected]

Key words serotonin receptors; animal studies; antidepressant-like; anxiolytic-like; serotonin

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Word count: 8420 (without abstract and references) Table count: 10 Figure count: 2

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Abstract

Serotonin regulates many physiological processes including sleep, appetite, and mood. Thus, serotonergic system is an important target in the treatment of psychiatric disorders, such as

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major depression and anxiety. This natural neurotransmitter interacts with 7 families of its receptors (5-HT1-7), which cause a variety of pharmacological effects. Using genetically

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modified animals and selective or preferential agonists and antagonist, numerous studies demonstrated the involvement of almost all serotonin receptor subtypes in antidepressant- or

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anxiolytic-like effects. In this review, based on animal studies, we discuss the possible

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involvement of serotonin receptor subtypes in depression and anxiety.

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ACCEPTED MANUSCRIPT Introduction Serotonin plays a crucial role in the central nervous system as it acts as a neurotransmitter. This monoamine interacts with at least 14 different receptor subtypes in various brain regions and therefore participates in many physiological processes, including the regulation of emotion, circadian rhythm (sleep-wake) or cognition. Over four decades ago serotonin was first linked to depression. According to the serotonin hypothesis of depression postulated in

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1967 by Coppen [1], the deficit of serotonin in the brain was the cause of the illness. The evidence for the role of serotonin in depression was the efficacy of the drugs increasing brain serotonin levels, i.e., tricyclic antidepressants and monoaminoxidase inhibitors. Despite the therapeutic success, both groups of antidepressants possessed many side effects. The breakthrough was the development of selective serotonin reuptake inhibitors (SSRIs), a group of antidepressants with the much safer pharmacological profile.

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Although SSRIs launched the new era of antidepressants, still around one-third of patients do not respond to pharmacotherapy [2]. Thus, researchers are searching for more effective treatment strategies. One of them is combining serotonin transporter blockade (a well-known

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mechanism of action of SSRIs) with agonist/antagonist activity at various serotonin receptors. An excellent example of such a drug is vortioxetine. Vortioxetine is a 5-HT3, 5-

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HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and serotonin transporter inhibitor. The drug increases serotonergic, noradrenergic, dopaminergic, cholinergic, histaminergic, and glutamatergic neurotransmission in brain

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structures associated with the major depressive disorder, such as nucleus accumbens, dorsal raphe nucleus, ventral hippocampus and medial prefrontal cortex (reviewed in [3]).

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Vortioxetine as the only antidepressant has moderate procognitive properties, probably due to the blockade of 5-HT3 and 5-HT7 receptors and 5-HT1A receptor stimulation [4]. Moreover,

in [5]).

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the drug has beneficial effects on anxiety symptoms, functioning and quality of life (reviewed

Preclinical studies strongly suggest that blocking or stimulating individual serotonin receptor subtypes might accelerate the antidepressant-like response or cause the anxiolytic-like effect. Therefore, based on animal studies, in this review, we discuss the possible involvement of serotonin receptor subtypes in depression and anxiety. 5-HT1A receptors In the mammalian brain 5-HT1A receptors exist as two populations – autoreceptors and heteroreceptors. Autoreceptors reside on the soma and dendrites of serotonin neurons in the raphe nuclei, and their activation inhibits neuronal discharges and reduces the release of 2

ACCEPTED MANUSCRIPT serotonin [6]. The 5-HT1A autoreceptors partially inhibit adenyl cyclase [7]. They also activate G protein-gated inwardly rectifying potassium channels (GIRK) by G protein’s βγ subunit [8]. This hyperpolarizes the membrane, reduces neuronal excitability, and inhibits potential-dependent calcium channels, which decreases the amount of calcium influx [9]. Through these mechanisms, serotonin can quickly and effectively suppress neuronal transmission.

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Heteroreceptors are expressed on non-serotonergic neurons, mainly in the limbic system, such as body and dendrites of glutamatergic neurons [6], axons of GABAergic neurons [10] or cholinergic neurons [11]. Receptors located in the medial septum regulate the release of acetylcholine [12], in the prefrontal cortex - glutamate [13], and in the midbrain ventral tegmental area - dopamine [14]. Adenyl cyclase inhibition in most areas of the brain is the result of Gαi protein activation. The GIRK channels in the hippocampus are activated by the

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βγ subunits of Gαo isoform [15]. The 5-HT1A receptors in the raphe nuclei preferentially bind to Gαi3, whereas in the cortex and the hypothalamus, to both Gαi and Gαo subunits [16].

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Studies demonstrated that 5-HT1A receptors might show functional selectivity (biased agonism, reviewed in [17]), e.g., postsynaptic 5-HT1A heteroreceptors stimulate [18],

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whereas presynaptic inhibit ERK1/2 signaling [19]. Biased agonists preferentially activate specific signaling pathway without affecting or even blocking different pathways [20]. Valdizan and colleagues [21] reported an agonist-dependent modulation of G-protein

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coupling and transduction of 5-HT1A receptors in rat dorsal raphe nucleus. The authors showed that 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a full 5-HT1A receptor

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agonist) compared with buspirone (a partial 5-HT1A receptor agonist) failed to modify forskolin-stimulated cAMP accumulation [21].

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Depression

Animal studies demonstrated that both stimulation and blockade of 5-HT1A receptors might cause or accelerate antidepressant-like effect (Table 1). Researchers showed that 5-HT1A receptor-deficient mice were less immobile in the forced swim test than the wild-type controls [22], which suggests that the lack of functional 5-HT1A receptors favors a less depressed phenotype. Interestingly, Garcia-Garcia and colleagues [23] proved that the wholelife suppression of 5-HT1A heteroreceptor expression in adolescence resulted in a broad depression-like behavioral phenotype. Moreover, the group showed physiological and cellular changes within medial prefrontal cortex-dorsal raphe proper circuitry, i.e., increased basal serotonin in the medial prefrontal cortex that is hyporesponsive to stress and decreased 3

ACCEPTED MANUSCRIPT basal serotonin levels and firing rates in a dorsal raphe hyperactivated by the same stressor. Similarly, many studies showed the antidepressant-like activity of 8-OH-DPAT, a 5-HT1A receptor agonist, which was reversed by 5-HT1A receptor antagonists (reviewed in [24]). Santarelli and colleagues [25] proved that mice deficient for 5-HT1A receptors did not show an increase in adult hippocampal neurogenesis after chronic treatment with fluoxetine (SSRI) but not imipramine. According to the neurotrophic hypothesis of depression reduced

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neurotrophic support causes neuronal atrophy, which in turn decreases hippocampal neurogenesis and leads to depression. Clinical data supports this theory, as post-mortem analysis showed the reduced volume of the hippocampus and prefrontal cortex in depressed patients [26,27]. Moreover, individuals diagnosed with major depressive disorder showed decreased hippocampal levels of neurotrophins, such as BDNF and NGF [28,29], which might play a role in the neuronal loss. In vivo studies agree with the above findings [30–33].

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Studies show that antidepressants reverse these changes [34,35]. Interestingly, chronic treatment with 8-OH-DPAT mimicked the effects of antidepressants as it decreased latency to feed in the novelty suppressed feeding test and increased adult hippocampal neurogenesis

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in wild-type mice but showed no effect in 5-HT1A receptor knockouts [25]. Thus, 5-HT1A receptors mediated the effects of 8-OH-DPAT. Luscombe and colleagues [36] concluded that

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postsynaptic 5-HT1A receptors mediated the antidepressant-like effect of 8-OH-DPAT. In concordance, Samuels and colleagues [37] found that specific deletion of 5-HT1A heteroreceptors from mature granule cells in the dentate gyrus (hippocampus) abolished the

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effects of SSRIs in various behavioral tasks. Moreover, the authors showed that it attenuated the effects of SSRIs on adult neurogenesis and hippocampal neurotrophic factors expression

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(BDNF – brain-derived neurotrophic factor and VEGF – vascular endothelial growth factor). Richardson-Jones and colleagues [38] showed that whole-life 5-HT1A heteroreceptor (but

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not autoreceptor) knockout mice showed decreased mobility in the forced swim test in mice. The authors did not observe this depression-like phenotype when heteroreceptor suppression was initiated in adulthood. Richardson-Jones and colleagues [38] concluded that serotonergic signaling in the forebrain during development stably impacts the circuitry underlying the behavioral response to forced-swim stress. Similar to heteroreceptors, 5-HT1A autoreceptors also play an essential role in the regulation of depressive-like behaviors (reviewed in [39]). According to many animal studies, the desensitization of 5-HT1A autoreceptors can accelerate the onset and/or augment the antidepressant effect (reviewed in [40]). Richardson-Jones and colleagues [41] proved that mice with higher 5-HT1A autoreceptor level showed blunted physiological response to acute 4

ACCEPTED MANUSCRIPT stress, increased behavioral despair, and no behavioral response to the antidepressant. Moreover, mice with lower autoreceptor levels displayed a robust behavioral response to fluoxetine after both chronic and subchronic administration [41]. Thus, the authors concluded that reducing 5-HT1A autoreceptor levels prior antidepressant treatment might accelerate and increase the effectiveness of the antidepressant therapy. Clinical trials confirmed this theory. The STAR*D study proved that in patients unsuccessfully treated with SSRIs, the

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augmentation with buspirone resulted in symptom remission [42]. Buspirone as a 5-HT1A receptor agonist facilitated the desensitization of 5-HT1A autoreceptors, which increased the effectiveness of SSRI treatment.

Recently, Vahid-Ansari and colleagues [43] identified a single transcription factor, Freud-1, as crucial for 5-HT1A autoreceptor expression. The authors showed that mice with a conditional knock-out of Freud-1 in serotonin neurons, showed increased level of 5-HT1A

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autoreceptors and displayed increased anxiety- and depression-like behaviors in the adulthood, which were resistant to chronic SSRI treatment [43]. Interestingly, double Freud1/5-HT1A gene knockout did not cause such effects. Conversely, it reduced depressive-like

response to antidepressant treatment.

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behaviors [43]. The study suggests that targeting specific transcription factors might augment

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The general conclusion of the above findings is that there is a need for compounds targeting specific populations of 5-HT1A receptors – either autoreceptors or heteroreceptors. Studies by Assié and colleagues [44] partially addressed this issue. The authors demonstrated that

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preferential activation of postsynaptic 5-HT1A receptors by F15599 resulted in the antidepressant-like effect. Interestingly, the same activity presented F13714, 5-HT1A

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receptor agonist without postsynaptic selectivity, but it induced more profound ‘serotonin syndrome’, hypothermia, and corticosterone release in rats. Increased corticosterone levels

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accompany chronic stress in animals [45], which leads to depression. Thus, F13714 compared with F15599 is less likely to induce the stable antidepressant effect. In conclusion, based on the presented studies the stimulation of postsynaptic 5-HT1A receptors or blockade of presynaptic 5-HT1A receptors results in the antidepressant-like effect. Anxiety Most studies showed the anxiolytic-like effects of presynaptic 5-HT1A receptor agonists; however, some findings suggest the role of postsynaptic receptors (Table 1, reviewed in [46]). Recent studies by Garcia-Garcia and colleagues [47] demonstrated that activation of 5HT1A receptors in the dorsal part of the bed nucleus of the stria terminalis (a forebrain area 5

ACCEPTED MANUSCRIPT that receives serotonin innervation) was necessary for the anxiolytic-like effect observed following optogenetic stimulation of serotonin inputs into the dorsal part of the bed nucleus of the stria terminalis. The authors concluded that serotonin release in the dorsal part of the bed nucleus of the stria terminals modulated anxiety-like behavior via 5-HT1A receptors under naturalistic conditions. Genetic animals models indicated that anxiety-like behavior might be due to elimination or

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overexpression of 5-HT1A receptor function (reviewed in [48]). Consistent results regarding anxiety showed studies on 5-HT1A receptor knockout models. Three independent research groups demonstrated that 5-HT1A receptor knockout mice in three different genetic background, i.e., C57BL/6J, 129/Sv, Swiss-Webster, showed anxiety-like phenotype compared with wild-type controls (reviewed in [49]). Heisler and colleagues [22] found that both male and female mice (C57BL/6J background) showed the anxiety-like profile in the

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open field, elevated zero-maze, and novel object tests. Similarly, Parks and colleagues [50] demonstrated that their Swiss-Webster knockout line (males and females) were more anxious in the open field test. Ramboz and colleagues [51] observed similar behaviors in 129/Sv

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knockouts, i.e., increased anxiety in the open field and elevated plus maze test. Studies show that 5-HT1A receptors may influence anxiety-like behaviors between

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subpopulations and across developmental stages. Gross and colleagues [52] proved that the conditional expression of the 5-HT1A receptor in mouse forebrain during development (not in adulthood) restored normal anxiety-related behavior of 5-HT1A receptor knockout mice.

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The authors suggested that that normal anxiety-like behavior in the adult requires proper signaling by serotonin via forebrain 5-HT1A receptors during the early postnatal period [52].

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Another study by Richardson-Jones and colleagues [38] demonstrated that mice lacking 5HT1A autoreceptors (but not heteroreceptors) throughout life showed increased serotonergic

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tone and increased anxiety-like behaviors. Buspirone, which is a partial agonist of the presynaptic 5-HT1A receptor, is commonly used in the therapy of anxiety (reviewed in [53]). Other known azapirones, like ipsapirone or geopirone, also demonstrated anxiolytic-like activity in rodents [46]. As mentioned earlier, 5HT1A receptors couple with Gi protein to inhibit adenyl cyclase. However, in tissues such as hippocampus expressing adenyl cyclase II, activation of 5-HT1A receptors stimulate adenyl cyclase [54]. Interestingly, a study by Albert and colleagues [55] demonstrated stimulatory coupling of the 5-HT1A receptor to adenyl cyclase in the presence of adenyl cyclase II that becomes agonist-independent upon co-transfection with Gi2 in HEK-293 cells. The authors proved that coupling to adenyl cyclase II required Gβγ subunits and only partial 5-HT1A 6

ACCEPTED MANUSCRIPT receptor agonists, such as buspirone, inhibited this spontaneous process. Many research showed that cannabidiol, a Canabis sativa constituent without psychoactive effects of Δ9-tetrahydrocannabinol, exerted anxiolytic-like properties in animals, which may be due to its nonselective modulation of 5-HT1A receptors [56,57]. PRX00023, a selective 5HT1A receptor agonist, alleviated infantile anxiety-like behavior in rats bred by reducing ultrasonic vocalizations rate. The authors concluded that this effect was most likely

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modulated via targeting both pre- and postsynaptic 5-HT1A receptors, as most clinical and preclinical evidence suggested that both pre- and postsynaptic receptors contribute to anxiety and/or depression, with overall serotonergic tone as a background that determines the relative strength of 5-HT1A receptor activity [58]. Another 5-HT1A receptor ligand, S15535 influenced serotonin neurotransmission through the activation of 5-HT1A autoreceptors and blockade of postsynaptic 5-HT1A receptors [59]. The compound reduced dialysate

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concentration of serotonin in rats hippocampus and showed anxiolytic-like activity in animal models [60]. Cao and Rodgers [61] demonstrated opposite results showing anxiolytic-like properties of 5-HT1A receptor antagonist, p-MPPI in the elevated plus-maze test in mice.

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Similarly, another 5-HT1A receptor antagonist (S)-UH-301 demonstrated antianxiety-like profile in animals [62]. The comparative studies of agonist, partial agonist, and antagonist of

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5-HT1A receptors also supported the anxiolytic potential of 5-HT1A receptor blockade [63]. Partyka et al. [64] tested the series of 5-HT1A receptor pre- and postsynaptic partial agonists and postsynaptic antagonists and demonstrated anxiolytic-like activity of both types of

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ligands in the mouse four plate test. Moreover, SB649915, a 5-HT1A/1B receptor antagonist with additional serotonin reuptake inhibition properties, demonstrated anxiolytic-like profile

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in various animal models (reviewed in [65]). To sum up, the above studies suggest that the stimulation of presynaptic 5-HT1A receptors

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results in the anxiolytic-like effect, whereas the data on postsynaptic 5-HT1A receptors is inconclusive.

5-HT1B receptors

5-HT1B receptors are inhibitory G-protein coupled metabotropic receptors that decrease cyclic adenosine monophosphate (cAMP) level. Their highest density is in the striatum, pallidum, nucleus accumbens, substantia nigra and ventral tegmental area. Lower levels of 5HT1B receptors are in the hippocampus, amygdala and cingulate cortex (reviewed in [66]). 5HT1B receptors function both presynaptically as inhibitory autoreceptors located on terminals of serotonin neurons and postsynaptically as inhibitory heteroreceptors controlling the release of other neurotransmitters. Studies showed that 5-HT1B receptors play a role in 7

ACCEPTED MANUSCRIPT depression, anxiety, migraine, locomotor activity, aggressive behavior, and potentiation of other drug’s action (Table 2, reviewed in [66,67]). Depression Participation of 5-HT1B receptors in the pathophysiology of depression is partly related to their responsiveness to both environmental stress and antidepressant exposure (reviewed in [68]). 5-HT1B heteroreceptors participate in neurogenesis in the hippocampus, which may

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explain their role in antidepressant-like activity [69]. Another study showed that mice lacking autoreceptors exhibit antidepressant-like behavior in the forced swim and sucrose preference tests and increased serotonin level in hippocampus due to SSRI administration [70]. 5-HT1B receptors are additionally regulated by binding with p11 protein - a protein that improves the functioning of the receptor in different brain regions and contributes to antidepressant-like effect in behavioral tests in animals [71]. p11 knockout mice exhibited a depression-like

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behavior and displayed reduced responsiveness to 5-HT1B receptor agonists and tricyclic antidepressants (TCAs) [71]. Studies showed that there was an up-regulation of 5-HT1B receptors in different areas of the brain due to exposure to stress (LH model, learned

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helplessness model), as well as the reduced function of autoreceptors and thereby increased the release of serotonin after chronic antidepressant treatment (reviewed in [72,73]).

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Similarly, chronic treatment with SSRIs down-regulated and/or desensitized 5-HT1B autoreceptors [74] and facilitated the effect of SSRIs in serotonin neurotransmission [75]. Pretreatment with 5-HT1B receptor antagonists [76] or genetic inactivation of the 5-HT1B

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receptor [77] increased SSRI-induced effect in mice. The above studies suggest that blockade of 5-HT1B receptors might facilitate antidepressant-like effect. Moreover, some researchers

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imply that 5-HT1B receptor antagonists may possess antidepressant-like activity themselves. SB-616234-A, a 5-HT1B receptor antagonist, decreased immobility in the mouse forced

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swim test [78]. The selective 5-HT1B receptor inverse agonist, SB236057A, increased the extracellular serotonin level in the dentate gyrus in the guinea pig, which was comparable to the effect of 14 days of paroxetine treatment [79]. The study suggests that acute 5-HT1B receptor blockade might cause a rapid antidepressant effect [79]. On the other hand CP 94253, a selective 5-HT1B receptor agonist, also showed the antidepressant-like effect in forced swim test in mice [80]. Similarly, anpirtoline a selective 5-HT1B receptor agonist decreased immobility time in control mice, but it did not produce any effect in 5-HT1B receptor knockout mice [81]. Thus, that anti-immobility activity of this drug in the forced swim test is due to 5-HT1B receptor activation. The 5-HT1B receptor gene knockout mice showed increased aggression [82]. 8

ACCEPTED MANUSCRIPT The above studies suggest that 5-HT1B receptors play a role in antidepressant-like effect, i.e., the stimulation of postsynaptic and the blockade of presynaptic 5-HT1B receptors might be beneficial in depression. (Table 2). Anxiety The 5-HT1B receptor knockout mice demonstrated reduced anxiety and the hyperactivity (reviewed in [83]). Nautiyal and colleagues [84] showed that forebrain 5-HT1B

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heteroreceptors expressed during an early postnatal period contribute to the development of the neural systems underlying adult aggression. The group also proved that distinct heteroreceptors acting during adulthood are involved in mediating impulsivity [84]. Interestingly, mice lacking 5-HT1B autoreceptors presented decreased anxiety in the open field test [70]. Similarly, studies of Lin and Parsons [85] indicated that stimulation of 5HT1B receptors increased anxiety-like behavior in the elevated plus-maze test in rats,

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suggesting the role of this receptors subtype in the pathology and treatment of anxiety. Interestingly, in animal models of anxiety, both selective 5-HT1B receptor agonist (CP94253) and antagonists (SB216641) demonstrated anxiolytic-like activity [86]. The

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anxiolytic-like properties also showed non-selective 5-HT1B/1D receptor agonist GR127935 [86]. The observed antianxiety-like effect might be linked to the postsynaptic 5-HT1B

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receptors or/and 5-HT1B heteroreceptors [87]. Moreover, the tested agonist behaved like antidepressants, showing the anti-immobility effect in the forced swim test in mice [86]. All the above findings imply that 5-HT1B receptors participate in the anxiolytic-like effect

5-HT2A receptors

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(Table 2); however, given ambiguous results, its exact role is yet unclear.

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5-HT2A receptors are expressed mainly in the cerebral, piriform, and entorhinal cortices, claustrum, olfactory bulb, anterior olfactory nucleus, and the number of brainstem nuclei

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(reviewed in [88]). 5-HT2A receptors couple via Gq/11 to the IP3 (inositol triphosphate)/PKC (protein kinase C)/calcium pathway. They are known as postsynaptic and presynaptic receptors on serotonergic terminals, but recent anatomical and functional studies suggest that 5-HT2A receptors are also present presynaptically as heteroreceptors, where they can enhance glutamatergic neurotransmission and participate in memory processes [89]. Depression 5-HT2A receptors are involved in many central nervous system disorders, including depression (Table 3, reviewed in [90]). Some antidepressants mediate their action partly via modulation of 5-HT2A receptors [91]. The administration of antidepressants or 5-HT2 receptor antagonists resulted in the atypical downregulation of both 5-HT2A and 5-HT2C 9

ACCEPTED MANUSCRIPT receptor subtypes (reviewed in [92]). Furthermore, chronic treatment with antidepressants such as tricyclic antidepressants, monoamine oxidase inhibitors, mianserin, mirtazapine or sertraline downregulated 5-HT2A receptors in rodents [93–95]. Conversely, chronic electroconvulsive shock treatment upregulated cortical 5-HT2A receptors in rodents [96]. Another issue is the relation between 5-HT2A receptor and the noradrenergic system regarding depression (reviewed in [97]). Studies showed that increased serotonin level

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following activation of 5-HT2A receptors in GABA neurons (during SSRI treatment) inhibit the neuronal activity of noradrenaline through the extended release of GABA [98–100]. Interestingly, besides reducing noradrenaline firing, citalopram also diminish basal and evoked extracellular levels of noradrenaline in the amygdala [101]. This might underlie inefficiency of SSRIs in resistant depression. The co-administration of SSRI and 5-HT2A receptor antagonist (as well as atypical antipsychotic like quetiapine, risperidone, olanzapine

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or aripiprazole) reversed this inhibitory effect in rat’s noradrenergic neurons and might be advantageous in resistant depression [100,102–104].

There is a growing body of evidence that 5-HT2A receptor antagonists possess

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antidepressant-like effect. EMD 281014, a 5-HT2A receptor antagonist, showed significant activity in forced swim test in congenital learned helpless rats [105]. A similar effect showed

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another 5-HT2A receptor antagonist - FG5893, which significantly reduced the immobility time in the forced swim test [106]. Moreover, selective 5-HT2A receptor antagonist M100907, enhanced the antidepressant-like behavioral effect of fluoxetine [107], suggesting

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that selective blockade of 5-HT2A receptors may complement the behavioral effects of serotonin transporter inhibition.

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Conversely, recent studies in rats proved that functional disruption of the 5-HT2A receptor in the medial prefrontal cortex might contribute to postpartum mental disorders (e.g., depression

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and psychosis) [108]. Moreover, Jaggar and colleagues [109] demonstrated that 5-HT2A receptor deficiency altered the metabolic and transcriptional, but not the behavioral, consequences of chronic unpredictable stress in mice. Thus, most likely 5-HT2A receptors might have different functions depending on the brain region. Anxiety Studies showed that genetically modified mice with global disruption of 5-HT2A receptors demonstrated anxiolytic-like phenotype in three conflict paradigms: the dark-light choice test, the elevated plus-maze, and the novelty-suppressed feeding paradigm, without affecting depressive-like behavior [110]. The restoration of 5-HT2A receptor signaling in the cortex normalized conflict behavior in these tests, indicating an important role of cortical 5-HT2A 10

ACCEPTED MANUSCRIPT receptors in anxiety [110]. Moreover, Benekareddy et al. [111] proved that the enhanced prefrontal 5-HT2A receptor function in adult animals exposed to early stress might contribute to the vulnerability for anxiety and depressive-like behaviors observed in these animals. Thus, the above studies suggest that the blockade of 5-HT2A receptor in the central nervous system might be beneficial in the treatment of anxiety (Table 3). 5-HT2B receptors

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The 5-HT2B receptor is primarily expressed in peripheral tissues, especially in the liver, kidney and heart, and is not widely distributed in the mammalian brain [112,113]. In the central nervous system 5-HT2B receptor was found in septal nuclei, dorsal hypothalamus, and medial amygdala with the levels similar to those found in the stomach [114]. Interestingly, the 5-HT2B receptor mRNA was also found in the dorsal raphe nucleus, what may suggest its autoreceptor role (reviewed in [115]). The 5-HT2B receptors are coupled

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with Gq protein, which activates PLC (phospholipase C)/PKC, and causes an increase in cytosol calcium concentration. Depression

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Many studies indicated the essential role of 5-HT2B receptors in depression (Table 4). Pharmacological or genetic inactivation of the 5-HT2B receptor abolished the effects of

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chronic SSRI treatment [116]. Interestingly, stimulation of 5-HT2B receptors induced an SSRI-like response in behavioral and neurogenic assays [116]. The same study reported the presence of 5-HT2B receptors in dorsal raphe serotonin neurons and their stimulatory role on

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serotonin release [116] This agrees with the recent study of Belmer and colleagues [117] showing that genetical inactivation of 5-HT2B receptors in serotonergic neurons eliminated

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the neurogenic effects of fluoxetine. The study proves that 5-HT2B receptors directly and positively regulate serotonin neurons activity [117]. Moreover, in cultured astrocytes

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fluoxetine-mediated 5-HT2B receptor stimulation resulted in extracellular signal-regulated kinases phosphorylation and epidermal growth factor receptor transactivation [118]. Interestingly, scientists described a reduced level of astroglial (but not neuronal) 5-HT2B receptors in a mouse model of Parkinson's disease, which paralleled the development of depressive-like phenotype [119]. The studies suggest that the stimulation of astroglial 5HT2B receptors might be beneficial in depressive disorders. However, taking into consideration the role of 5-HT2B receptors in the periphery, potential new compounds targeting 5-HT2B receptors may negatively influence the cardiovascular system. Anxiety There is little preclinical data on the role of 5-HT2B receptors in anxiety (Table 4). Some 11

ACCEPTED MANUSCRIPT behavioral studies showed that BW723C86, a 5-HT2B receptor agonist, exerted the anxiolytic-like effect in rat social interaction test, Vogel drinking test, and Geller-Seifter conflict test but showed no activity in the elevated plus-maze test [120,121]. The observed antianxiety-like activity was mediated by the 5-HT2B receptor, as SB200646A, a 5-HT2C/2B receptor antagonist, blocked this effect [122]. Thus, some evidence suggests that 5-HT2B receptor agonists might have anxiolytic-like properties, but to prove this, scientists should

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perform more studies. 5-HT2C receptors

The 5-HT2C receptor is the second subtype often linked with depression (Table 5) [123]. This receptor couples preferentially to Gq/11 and increases inositol phosphates and cytosolic Ca2+ concentrations. 5-HT2C receptors were identified in the hippocampus, amygdala, anterior olfactory and endopiriform nuclei, cingulate and piriform cortex, thalamic nuclei,

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and the substantia nigra [88]. Chronic treatment with classical antidepressants downregulated 5-HT2C receptor function [124]. Not surprisingly, scientists concluded that antagonists of this receptor might be beneficial in depression. The 5-HT2C receptors

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blockade might also result in anxiolytic-like effect (reviewed in [125]). Depression

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Numerous findings connect the antidepressant-like activity with the 5-HT2C receptor (Table 5). Behavioral studies with rats isolation rearing indicated increased 5-HT2C receptor responsiveness, suggesting their involvement in depression and anxiety [126]. Experiments

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showed that 5-HT2C receptors were involved in the anti-immobility effect of antidepressants increasing the serotonin level in the synapse [127].

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Few studies suggested that 5-HT2C receptor antagonists alone may also exhibit antidepressant-like properties. S-32006 - the potent 5-HT2C receptor antagonist - showed

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antidepressant-like activity in behavioral tests in rodents and increased levels of dopamine and noradrenaline in the frontal cortex [128]. The compound decreased immobility in the forced swim test in mice, suppressed anhedonia in a chronic mild stress model, and increased cell proliferation and BDNF expression in rat dentate gyrus [128]. An inverse agonist of the 5-HT2C receptor, S32212, exhibited antidepressant-like activity in the forced swim test in rats, after both acute and chronic treatment [129]. Moreover, chronic treatment with SSRIs caused 5-HT2C receptor desensitization [130]. Cremers et al. [131] showed that inactivation of 5-HT2C receptors potentiated SSRI-induced serotonin release in rodents. 5-HT2C antagonists administered alone did not affect the serotonin level [132]. Similarly, studies suggest that the lack of SSRIs’ efficacy in some patients might due to the 12

ACCEPTED MANUSCRIPT serotonin-related inhibition of neuronal dopamine activity in the ventral tegmental area via 5HT2C receptors (reviewed in [97]). Dremencov et al. [133] showed that escitalopram by activating 5-HT2C receptors on GABA neurons decreased the firing of dopamine neurons. Some studies indicated that co-administration of SSRI with the 5-HT2C receptor antagonists (including atypical antipsychotics like aripiprazole) might eliminate the inhibitory effect on dopamine neurons in rat brain and restore the action of SSRI [103]. Thus, blockade of 5-

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HT2C receptors might be beneficial in treatment-resistant depression. Interestingly, a novel 5-HT2C receptor antagonist, S32006, with potential antidepressant- and anxiolytic-like activity, increased dopamine level in the frontal cortex in rats and enhanced the firing of dopaminergic neurons [128].

In contrast, some studies demonstrated that 5-HT2C receptor agonists showed activity in animal

models

of

depression,

suggesting

antidepressant-like

activity

[134,135].

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WAY163909, selective 5-HT2C receptor agonist produced a rapid antidepressant-like effect in the rat forced swim test, which was blocked by 5-HT2C/2B receptor antagonist, SB206553 [135]. Moreover, WAY163909 also reduced the hyperactivity associated with olfactory

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bulbectomy in rats after chronic treatment [135,136]. It is possible that the antidepressant-like effect mediated by these compounds was a result of 5-HT2C receptor stimulation and

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consequent activation of postsynaptic serotonin receptors (reviewed in [137]). Similarly, other selective 5-HT2C receptors agonists were effective in animal models of depression and obsessive-compulsive disorder [138,139]. Other research group confirmed the potential of 5-

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HT2C receptor agonists in the treatment of obsessive-compulsive disorder [140]. In conclusion, both agonists and antagonists of the 5-HT2C receptor show antidepressant-like

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effects. Therefore, we need more region-specific studies to define the exact role of this

Anxiety

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receptor subtype in depression.

The 5-HT2C receptor is also involved in anxiolytic-like response in rodents (Table 5) [141]. Studies showed that acute administration of SSRIs might induce anxiety probably due to 5HT1A autoreceptors and 5-HT2C heteroreceptors activation [142,143]. According to the recent development of Marcinkiewicz and colleagues [144], serotonin release from the dorsal raphe nucleus can lead to fear and anxiety behaviors through the activation of 5-HT2C receptors in the bed nucleus of the stria terminalis, which may underlie the negative effects of acute SSRIs administration. Interestingly, the desensitization of the 5-HT2C receptor might restrain anxiety in mice lacking the serotonin transporters [145]. Additionally, some 5HT2C/2B receptor antagonists, SB200646A or S32006, demonstrated also anxiolytic-like 13

ACCEPTED MANUSCRIPT effects in conflict and social interaction models of anxiety in rats [122,128,146]. Similarly, another mixed 5-HT2C/2B receptor antagonist, SB206553 or selective 5-HT2C receptor antagonist SB242084 possessed anxiolytic-like activity in rodents behavioral test [147,148]. Furthermore, S32212, which is an inverse agonist of the 5-HT2C receptor showed antianxiety actions in the Vogel conflict test [129]. Another inverse agonist of the 5-HT2C receptor, SB243213 was active in social interaction and Geller-Seifter conflict test showing an

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improved anxiolytic profile in comparison to benzodiazepines [149]. Conversely, in the panic model of anxiety using aversive brain stimulation into the dorsolateral periaqueductal gray matter in rats, the selective 5-HT2C receptor activation reduced elicited symptoms similar to clonazepam or fluoxetine [139]. The study demonstrates the potential antipanic properties of selective 5-HT2C receptor agonists. It is in agreement with the hypothesis that serotonin may induce a dual action on the neural

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mechanism of anxiety by influencing different brain regions in opposite ways (reviewed in [150]).

To sum up, both stimulation and blockade of the 5-HT2C receptor can induce the anxiolytic-

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like response. Thus, to know the exact role of this receptor subtype in anxiety, we should investigate the effects of 5-HT2C activation in specific regions of the brain.

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5-HT3 receptors

5-HT3 receptors belong to the superfamily of ligand-gated ion channels, which resemble historical M receptors (reviewed in [151]). They cause a rapid depolarization of neurons by

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opening non-selective cation channels (Na+, Ca2+ influx, K+ efflux). In the central nervous system, they are most often located in the dorsal vagal complex (nucleus tractus solitarius,

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area postrema, and dorsal motor nucleus of the vagus nerve), where they are involved in the initiation and coordination of the vomiting reflex [88]. Higher levels are in the hippocampus,

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amygdala, and superficial layers of the cerebral cortex [88]. There are some differences in 5HT3 receptor distribution between species. In rats, higher levels are expressed in the cortex, hippocampus, and amygdala, but in mice, a relatively lower expression is observed in the hippocampus and amygdala [152,153]. Depression There are numerous animal studies concerning 5-HT3 antagonists and their antidepressantlike effects in various animal models (Table 6, reviewed in [154]). Systemic administration of tropisetron (5-HT3 receptor antagonist) prevented restraint stress-induced dopamine release in the nucleus accumbens and prefrontal cortex in rats, which indicate that 5-HT3 receptors mediate stress-dependent activation of dopaminergic neurotransmission [151,155]. The 14

ACCEPTED MANUSCRIPT compound exerted the antidepressant-like effect in the rat forced swim test, and its effect was abolished after pretreatment with mCPGB – a potent high-affinity 5-HT3 receptor agonist [156,157]. Interestingly, structurally different antidepressants, i.e., tricyclic antidepressants, SSRIs, noradrenergic reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants, showed functional antagonism at 5-HT3 receptor [158]. Moreover, some reports suggest that the antidepressant-like effects of SSRIs are partially mediated by the

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blockade of 5-HT3 receptors [159]. Vortioxetine, which is a relatively new multimodal antidepressant, is among others 5-HT3 receptor antagonist (reviewed in [160]). The exact mechanism of antidepressant-like effect of 5-HT3 receptor antagonists is not clear, although various experiments on rodents show that this effect should be attributed to postsynaptic rather than presynaptic 5-HT3 receptor antagonism. Ramamoorthy et al. [161] showed that presynaptic and somatodendritic 5-HT3 receptor blockade reduced serotonin levels.

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Importantly, studies suggest that 5-HT3 receptor blockade might underlie vortioxetine’s faster onset of action [162]. Recently some novel 5-HT3 receptor antagonists showed antidepressant-like and/or antianxiety-like activity in animal models of depression, which

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might be due to the modulation of the hypothalamic-pituitary-adrenal axis, interaction with the serotonergic system or antioxidative properties [163–168]. In the chronic unpredictable

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stress model in mice, the administration of ondansetron reversed depressive-like behavior influencing the hypothalamic-pituitary-adrenal axis [169]. Furthermore, in streptozotocininduced diabetic mice, the drug also demonstrated antidepressant- and anxiolytic-like

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properties probably via modulation of the serotonergic system [170]. Behavioral studies with ondansetron (and tropisetron) also suggested the interaction of 5-HT3 and NMDA receptors

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as well as the involvement of nitric oxide-cyclic guanosine monophosphate pathway in the observed antidepressant-like effects [171,172]. Moreover, ondansetron reversed depression

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and anxiety-like behavior in streptozotocin-induced diabetic mice [170]. Studies on genetically modified animals support the role of 5-HT3 receptors in the antidepressant-like effect. Martin and colleagues [173] demonstrated that 5-HT3 receptor knockout mice showed the antidepressant-like phenotype. Moreover, using in vitro electrophysiology, the authors showed that a low-dose citalopram treatment triggered 5HT1A receptor desensitization only in the dorsal raphe nucleus of 5-HT3 knockout mice, while a high dose desensitized 5-HT1A autoreceptor function equally in 5-HT3 knockout and wild types [173]. Thus, the lower doses of citalopram might be effective when 5-HT3 receptors are inactivated. In conclusion, studies proved the blockade of 5-HT3 receptor induces the antidepressant-like 15

ACCEPTED MANUSCRIPT effect. Anxiety Many preclinical data indicated the 5-HT3 receptor as a potential target in the treatment of anxiety (Table 6, reviewed in [174]). Behavioral studies demonstrated that 5-HT3 receptor antagonists were effective in rodent anxiety models, e.g., social interaction test in rats or light/dark exploration test in mice, secondary to the limbic hyperactivity response blockade

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(reviewed in [175]). The atypical 5-HT3 receptor antagonist, VA21B7, demonstrated anxiolytic-like activity in the elevated plus maze and punished-drinking in rats [176]. Following 5-HT3 receptor antagonists, WAY100289 and BRL46470A also showed anxiolytic-like activity in animal models: light/dark box test, acoustic startle response paradigm, elevated X-maze and social interaction test [177,178]. Similarly, studies with selective 5-HT3 receptor antagonists, i.e., ondansetron, tropisetron or zacopride demonstrated

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their anxiolytic-like effects in the popular rodent models of anxiety (light/dark box, elevated plus maze and social interaction tests) [179–181]. However, there is research in which ondansetron did not present any anxiolytic-like effect in the elevated plus maze in mice

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[182]. The lack of effect might be because ondansetron was administered chronically (21 days) at subchronic doses.

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Studies on genetically modified mice further support the role of 5-HT3 receptor blockade. Martin and colleagues [173] demonstrated that 5-HT3 receptor knockout mice showed the anxiolytic-like phenotype. Similar results obtained Kelley and colleagues [183] who showed

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that 5-HT3A receptor knockout mice exhibited anxiolytic-like behavior in the elevated plus maze, light/dark box, and novelty interaction tests. This suggests the role of the 5-HT3A

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receptor subunit in the anxiolytic-like effect. Authors speculated that the lack of 5-HT3A receptor subunit might have functionally disabled or significantly altered the 5-HT3 cation

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channel, which resulted in changes similar to 5-HT3 receptor pharmacological blockade. Additionally, a study by Bhatnagar and colleagues [184] suggested that 5-HT3 receptors differentially regulate depressive- and anxiety-like behaviors in males and females. Compared with their wild-type littermates, 5-HT3 receptor knockout females showed increased depressive- and decreased anxiety-like phenotype. On the other hand, males did not show any differences in the forced swim test, whereas demonstrated increased anxiety-like behaviors in the defensive withdrawal test. Same authors in other studies showed sex differences in hypothalamic-pituitary-adrenal responses to novel restraint in chronically stressed 5-HT3 receptor knockout mice, which were partly related to 5-HT3A receptor function [185,186]. Compared with wild-type rodents 5-HT3 receptor-deficient mice 16

ACCEPTED MANUSCRIPT displayed lower adrenocorticotropin responses to restraint or lipopolysaccharide, lower vasopressin mRNA in the paraventricular nucleus of the hypothalamus and higher corticotropin-releasing hormone mRNA in the central amygdala. The above studies suggest the potential interaction between the 5-HT3A receptor and corticotrophin-releasing hormone in the amygdala. Still, some new 5-HT3 receptor antagonists are designed, synthesized and successfully tested

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in rodent models of anxiety, which further supports the potential role of the 5-HT3 receptor blockade in anxiolytic-like effect [187,188]. 5-HT4 receptors

The serotonergic 5-HT4 receptor plays a significant role in heart, gastrointestinal tract, adrenal gland, urinary bladder, but also in the central nervous system. In the brain, the receptor is mainly expressed in the hypothalamus, hippocampus, nucleus accumbens, the

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ventral pallidum, amygdala, the basal ganglia, olfactory bulbs, frontal cortex, septal area, substantia nigra, and fundus striatus (reviewed in [189]). The 5-HT4 receptor is a Gs-coupled receptor which activates the adenylate cyclase/protein kinase and increases the intracellular

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level of cAMP. Depression

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Some reports link the 5-HT4 receptor with depression (Table 7, reviewed in [190]). The 5HT4 receptors signaling can modulate the function of the hippocampal dentate gyrus by increasing neurogenesis and neurotrophic factors expression, which can contribute to the

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antidepressant effect of serotonin-enhancing drugs (reviewed in [191]). In preclinical models of depression, i.e., olfactory bulbectomized and glucocorticoid heterozygous receptor mice,

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the expression of 5-HT4 receptors was increased in the ventral hippocampus or striatum, respectively [192], whereas in the Flinders-sensitive line rat model of depression

[193].

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downregulation of 5-HT4 receptors was observed in the ventral and dorsal hippocampus

Pharmacological studies indicated that chronic treatment with 5-HT4 receptor agonists did not induce desensitization of receptors in the medial prefrontal cortex whereas activation of receptors by selective 5-HT4 receptor agonists enhanced the electrical activity of serotonin neurons in dorsal raphe nuclei [194]. Amigo et al. [195] demonstrated that 5-HT4 receptor knockout mice might trigger some adaptive changes resulting in depression- and anxiety-like behavior. Moreover, the knockout mice did not respond to the antidepressant action of fluoxetine in the olfactory bulbectomized model of depression and anxiety [195]. These findings are in agreement with another research showing reduced immobility of rats in the 17

ACCEPTED MANUSCRIPT forced swim test after acute administration of partial 5-HT4 receptor agonist [196]. Chronic treatment with fluoxetine and venlafaxine (but not reboxetine) decreased the density of 5HT4 receptor in rat brain [197]. Altgough 5-HT4 receptor antagonist, SB 204070A, had no independent effect and did not affect the decreased immobility in the forced swim test in naive rats [198], another receptor antagonist, GR 125487, prevented the effects of fluoxetine in the corticosterone-induced model of depression in mice [199]. Thus, the study suggests

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that the antidepressant-like effect of fluoxetine is mediated through the activation of 5-HT4 receptors.

In agreement with these findings are reports concerning RS 67333 (5-HT4 receptor agonist). RS 67333 proved to be active after acute and chronic treatment in various animal models of depression, and it showed even faster antidepressant-like effect than classical antidepressants [196,200]. Moreover, the activation of 5-HT4 receptors caused an increase in cAMP, protein

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kinase A activation, phopsphorylation of cAMP responsive element binding protein (CREB), and transcription of BDNF [200]. What is even more interesting, an increase in BDNF levels was noticeable after only three days of treatment with RS 67333 [200]. All mentioned

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changes are associated with antidepressant response.

The neurogenesis in the adult mammalian brain takes place in the subventricular zone of the

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lateral ventricle and the subgranular zone of the denate gyrus [201]. Most antidepressants, administered chronically, stimulate adult hippocampal neurogenesis. Not only do antidepressants increase the proliferation of newborn cells, but also the survival and

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maturation of the young neurons [25,34,189]. Interestingly, the 5-HT4 receptor agonists induce neurogenesis in the hippocampus in adult rodents faster than traditional

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antidepressants [200,202]. Pascual-Brazo and others [200] showed that 3-day treatment with RS 67333 enhanced neurogenesis in the subgranular zone of the denate gyrus of the

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hippocampus, and the observed effect was similar to 2-week treatment with antidepressants (e.g., SSRIs). Furthermore, GR 125487 was reported to partially block the neurogenic effects of chronic fluoxetine administration [199]. The 5-HT4 receptor agonist may also play a role in cognitive deficits associated with major depressive disorder. Using RS 67333 in chronic neuroendocrine animal models of depression/anxiety Darcet et al. [203] resulted in the restoration of induced learning and memory impairments. In conclusion, the above studies indicate that the stimulation of 5-HT4 receptor might cause antidepressant-like effect in rodents. Anxiety Studies into the role of 5-HT4 receptors in anxiety show conflicting results (Table 7). Kennett 18

ACCEPTED MANUSCRIPT and colleagues [204] demonstrated a modest anxiolytic-like effect of two selective 5-HT4 receptor antagonists, SB204070A and SB207266A, in behavioral tests in rats. Conversely, Mendez-David and colleagues [205] showed that the activation of 5-HT4 receptors might be involved in the anxiolytic-like activity of fluoxetine in the elevated plus-maze test and the open field test in mice. Studies on L-lysine (alone or in combination with L-arginine) showed that pretreatment with this aminoacid/aminoacids reduced anxiety in stressed rats and

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suggested that L-lysine acts like a partial 5-HT4 receptor antagonist [206,207]. We need more studies to find out the role of the 5-HT4 receptor in anxiety, as both stimulation and blockade might cause the anxiolytic-like effect. 5-HT5A receptors

There were two 5-HT5 receptor subtypes identified in the mouse and rat brain: 5-HT5A and 5-HT5B [208,209]. Studies of Grailhe et al. [210] indicated that human 5-HT5B gene does

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not encode a functional protein and 5-HT5B receptor is absent in human probably due to evolutionary changes. Thus, in this review, we discussed only the 5-HT5A receptor subtype. The 5-HT5A receptor is coupled to Gi protein in various cell systems [211].

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Immunohistochemical studies in rat brain reported that the 5-HT5A receptor is expressed mainly in the raphe nuclei, including the dorsal raphe nucleus and median raphe nucleus,

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cerebral cortex, hippocampus, amygdala, and hypothalamus [212]. As the receptor is widely expressed in the dorsal raphe nucleus in rat brain, it suggests that 5-HT5A receptor might serve an autoreceptor function [212]. The function of the 5-HT5A receptor is poorly

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characterized, due to the lack of highly selective pharmacological tools. Phenotyping studies on the 5-HT5A receptor knockout mice brought the first information concerning the potential

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role of the 5-HT5A receptor in brain function. The 5-HT5A receptor knockout mice showed increased exploration in a novel environment, without modifying anxiety-related behaviors

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[213]. This together with the receptor widespread localization pattern and its autoreceptor function, suggests that the 5-HT5A receptor is involved in mood, affective disorder, and cognitive function (Table 8) [214]. Depression Some data suggest the involvement of 5-HT5A receptors in depression (Table 8). Studies showed that 5-HT5A receptor antagonists might induce acetylcholine release in the medial prefrontal cortex and activate brain regions like some antidepressants [215]. Among two 5HT5A receptors antagonists, tested in animals tests of anxiety and depression, one of them, A-843277 demonstrated antidepressant-like properties in the forced swim test [215]. Anxiety 19

ACCEPTED MANUSCRIPT There are very few behavioral studies on the 5-HT5A receptor and its role in anxiety (Table 8). One group demonstrated the anxiolytic-like activity of selective 5-HT5A receptor antagonist, SB-699551-A, in ultrasonic vocalization test in rodents [215]. We need more studies to determine the potential role of the 5-HT5A receptor in anxiety. 5-HT6 receptors The 5-HT6 receptor is widely distributed in rat’s serotonergic brain regions such as olfactory

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tubercle, striatum, nucleus accumbens, cerebral cortex and hippocampus [216,217]. It is probably a postsynaptic receptor since its activity was found rather in serotonin projection fields than in serotonin-containing body cells regions [217]. The receptor is coupled to Gs protein and activates the adenylate cyclase/protein kinase. Studies showed that many nonselective compounds like some tricyclic antidepressants possess high affinity towards 5-HT6 receptor [218]. It suggests that this receptor plays some role in mediating antidepressant

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effect of these drugs. Besides the possible role in antidepressant-like effect, 5-HT6 receptors might also influence the animal’s anxiety-like behaviors (Table 9, reviewed in [219]). Depression

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Preclinical studies suggest the role of 5-HT6 receptors in depression (Table 9). Dawson and Li [220] using in vivo microdialysis showed that 5-HT6 receptor antagonist did not augment

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the antidepressant treatment by desipramine, venlafaxine or fluoxetine in the frontal cortex of rats. Studies of Yau et colleagues [221] showed that endogenous corticosterone synthesis blockade was followed by up-regulation of 5-HT6 as well as 5-HT7 receptors mRNA in the

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hippocampus, which could increase sensitivity to the antidepressant ligands and be used in the treatment-resistant depression. There are studies showing the increased BDNF mRNA

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expression in the hippocampus after the administration of LY586713, a 5-HT6 receptor agonist (reviewed in [222]). Pereira et colleagues [223] demonstrated reduced immobility of

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mice in the forced swim test after administration of WAY208466 – a selective, potent 5-HT6 receptor agonist.

Interestingly, some 5-HT6 receptor antagonists showed antidepressant-like activity in rat forced swim test [224,225] and other behavioral tests [226]. The partial agonist of the 5-HT6 receptor, EMD-386088 also demonstrated antidepressant-like effects after acute and chronic treatment in rats, probably since it stimulated the receptor directly [227]. The data concerning the role of the 5-HT6 receptor is ambiguous, as both blockade and stimulation of the receptor might result in the antidepressant-like effect. Anxiety As mentioned earlier, 5-HT6 receptors are also involved in anxiety-like behaviors (Table 9). 20

ACCEPTED MANUSCRIPT Transgenic 5-HT6 receptor knockout mice showed increased anxiety behavior characterized by elevated stretched attend posture and reduced investigation of foreign objects [228]. Studies demonstrated that administration of 5-HT6 specific antisense oligonucleotides inhibited the conditioned fear stress-induced increase in serotonin release from the prefrontal cortex in rats, suggesting anxiolytic-like response [229]. Conversely, Hamon et colleagues [230] demonstrated that chronic infusion of antisense

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oligonucleotide down-regulated the 5-HT6 receptor expression in the rat nucleus accumbens and induced anxiogenic behavior in the elevated plus maze test and social interaction test. Similar conclusions were drawn by the team of Otano and colleagues [231], who confirmed the role of 5-HT6 receptors in anxiety-related neurobiological mechanisms. The 5-HT6 receptor activation by selective agonists enhanced the extracellular level of GABA, which could be useful in the treatment of some anxiety disorders [232]. EMD-386088, a partial 5-

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HT6 receptor agonist showed anxiolytic-like activity in the rat elevated plus-maze test and the Vogel conflict test [233]. Some 5-HT6 receptor antagonists also demonstrated antianxiety effects in behavioral experiments in animals [225,226].

role depends on the brain region.

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5-HT7 receptors

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Since both activation and blockade of the 5-HT6 receptor causes anxiolytic-like effect, its

The 5-HT7 receptor is one of the youngest members of the serotonin receptor family, which is connected to Gs protein. It can occur in several different isoforms with various number of

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amino acids in carboxyl terminal tails, depending on the species [234]. The widespread distribution of 5-HT7 receptors in limbic and thalamocortical regions of the brain suggests

Depression

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their potential role in depression and anxiety (Table 10, reviewed in [235,236]).

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Behavioral studies using 5-HT7 receptor knockout mice demonstrated antidepressant-like activity in the forced swim test and the tail suspension test [237,238]. The administration of a selective 5-HT7 receptor antagonist, SB-269970, also exhibited the anti-immobility effect in the above tests [238,239]. Moreover, intrahippocampal administration of SB-269970 induced antidepressant-like activity in the rat forced swim test [240]. Bonaventure et al. [241] demonstrated that co-administration of citalopram and SB-269970 increased the activity of serotonin neurons in rats and potentiated the antidepressant-like effect in the tail suspension test. Similarly, SB-269970 enhanced the anti-immobility effect of antidepressants (citalopram, imipramine, desipramine, and moclobemide) in the forced swim test in mice [242]. Moreover, Mnie-Filali and colleagues [243] showed that the administration of SB21

ACCEPTED MANUSCRIPT 269970 for only one week resulted in behavioral, electrophysiological, and neuroanatomical changes that usually occur after prolonged treatment with SSRIs. Therefore, the researchers concluded that 5-HT7 receptor antagonists might represent a new class of antidepressants with faster therapeutic effects. Other 5-HT7 receptor antagonists also showed antidepressantlike effects, e.g., JNJ-18038683, was effective in the tail suspension test in mice [244]. Moreover, the compound potentiated the serotonin transmission, REM suppression and

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antidepressant-like behavior induced by citalopram in rodents [244]. The above studies clearly show the involvement of the 5-HT7 receptor in the antidepressant-like effect (Table 10). Furthermore, the research suggests that the blockade of the 5-HT7 receptor might not only induce but also accelerate the antidepressant effect. Anxiety

The 5-HT7 receptor mRNA expression increased after acute, but not chronic, stress in the rat

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hippocampus, which suggested their role in stress regulation [245]. The study by Clemett et al. [246] demonstrated no significant effect in the elevated plus-maze test in rats treated with 5HT7 receptor antisense oligonucleotides. Similarly, both wild-type and 5-HT7 receptor

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knockout mice showed no difference in the same model of anxiety behavior [237]. On the other hand, Wesołowska and colleagues [239] demonstrated anxiolytic-like activity of

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selective 5-HT7 receptor antagonist, SB-269970 in the Vogel drinking test and the elevated plus-maze test in rats, as well as in the four plate test in mice. Moreover, intrahippocampal administration of SB-269970 induced an antianxiety-like effect in the Vogel conflict test in

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rats [240]. Simultaneously, one of the 5-HT7 receptor agonists, LP-211, demonstrated anxiolytic-like activity in the dark/light test in mice [247]. Another study suggested the

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involvement of 5-HT7 receptors in the mouse behavioral model of obsessive-compulsive disorder [248]. In the marble burying test both pharmacological blockade and inactivation of

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5-HT7 receptors resulted in reduced number of buried marbles [248]. Thus, the blockade of the 5-HT7 receptor might be beneficial in anxiety (Table 10). Examples of compounds targeting serotonin receptors for potential use in the treatment of depression and anxiety Since serotonin receptors play a role in the antidepressant- and anxiolytic-like effects, the compounds that target their specific subtypes may be of potential use in the treatment of depression and anxiety. The example of such compound is MIN-117, which is an antidepressant drug candidate under development by Minerva Neurosciences for the clinical treatment of major depressive disorder with comorbid anxiety [249]. MIN-117, currently in phase II clinical trials, is a 5-HT1A and 5-HT2A receptor antagonist and inhibitor of 22

ACCEPTED MANUSCRIPT serotonin and dopamine reuptake, with the affinity for the α1A- and α1B-adrenergic receptors [249]. Another example is FKB01MD, which is a serotonin reuptake inhibitor, 5-HT1A and 5HT1D receptor agonist, and 5-HT2 receptor antagonist. The compound is currently under development by Fabre-Kramer for the treatment of major depressive disorder [250]. FKB01MD shows strong antidepressant activity and is currently in phase II clinical trials

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[250]. Our group also demonstrated compounds targeting serotonin receptors with potent antidepressant- and anxiolytic-like activity [251–256]. Among all tested compounds HBK15, a 5-HT1A, 5-HT3, 5-HT7 and D2 antagonist, showed the most robust antidepressant- and anxiolytic-like effect. In the mouse model of corticosterone-induced depression, the compound reversed depressive-like behaviors after only single administration [257].

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Moreover, a single administration of HBK-15 was enough to regulate decreased BDNF level in the hippocampus in corticosterone-treated mice [257]. Except for ketamine (anesthetic drug) which is sometimes used off-label to treat depression, no other commonly used

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antidepressant shows such an effect. The activity of HBK-15 was confirmed in other tests and models of depression and anxiety [45,257,258]. Interestingly, in preclinical studies, HBK-15

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showed procognitive properties and ameliorated scopolamine-induced memory impairment in the step-through passive-avoidance test [258]. Unlike many antidepressants the compound did not decrease the seizure threshold in seizure tests in mice [259], which is beneficial.

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Furthermore, despite α1-adrenolytic properties HBK-15 at antidepressant-like doses did not

Conclusions

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affect blood pressure or ECG after a single [260] or chronic administration [261].

In this review, we presented the involvement of almost all serotonin receptors subtypes in

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antidepressant- and anxiolytic-like effects in rodents. The stimulation of postsynaptic 5HT1A, postsynaptic 5-HT1B, 5-HT2B, and 5-HT4 receptors or blockade of presynaptic 5HT1A, presynaptic 5-HT1B, 5-HT2A, 5-HT3, 5-HT5A, and 5-HT7 might result in antidepressant-like effect (Fig. 1). For 5-HT2C and 5-HT6 subtypes the data is ambiguous (Fig. 1), as both agonists and antagonists induce antidepressant-like activity. Similarly, to induce the anxiolytic-like effect we should stimulate 5-HT2B or block 5-HT2A, 5-HT3, and 5-HT5A receptors (Fig. 2). In the case of 5-HT1A, 5-HT1B, 5-HT2C, 5-HT4, 5-HT6, and 5HT7 receptors it is not clear whether stimulation or blockade results in anxiolytic-like effect (Fig. 2). Although we should be cautious while extrapolating the results from animal studies to humans, the results from preclinical experiments clearly show that most serotonin receptor 23

ACCEPTED MANUSCRIPT subtypes participate in depressive and anxiety-like processes. Despite numerous studies on serotonin receptors, the exact role of each subtype in depression and anxiety is yet to be determined. We still have little knowledge on serotonin receptors subpopulations and their signaling pathways to fully understand their role in mood disorders and anxiety. Thus, to better understand the basis of divergent and convergent actions of agonists vs. antagonists we need to gain knowledge on the region-specific actions of serotonin. This work was supported by Jagiellonian University grants number

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Funding:

K/DSC/004285. Conflict of interest The authors declare no conflict of interest. References

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ACCEPTED MANUSCRIPT Figure legends Figure 1. The involvement of serotonin receptor subtypes in antidepressant-like effect in rodents

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Figure 2. The involvement of serotonin receptor subtypes in anxiolytic-like effect in rodents

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ACCEPTED MANUSCRIPT Tables Table 1 Preclinical data on the role of serotonin 5-HT1A receptor in depression and anxiety. Manipulation

Test

Result

T P

DEPRESSION

I R

KNOCK-OUT

C S U

Reference

5-HT1A receptor (C57BL/6J)

Tail suspension test

Decreased immobility in mice

[22]

5-HT1A receptor + fluoxetine (129SvEv)

Novelty suppressed feeding test

No effect in mice

[25]

Decreased mobility in mice

[38]

No effect (mice)

[43]

Increased immobility in mice in the adulthood, which was not reversed by SSRI treatment

[43]

5-HT1A heteroreceptor throughout Forced swim test life (mixed: 129S6/Sv; C57B6; CBA)

D E

Tail suspension test Transcription factor Freud-1 repressing the 5-HT1A autoreceptor’s gene (C57BL/6N)

M

N A

PT

Forced swim test

E C

Novelty suppressed feeding test

Decrease in the latency to feed in mice in the adulthood, [43] which was not reversed by SSRI treatment

Novelty suppressed feeding test

Decrease in latency to feed in mice

[25]

8-OH-DPAT, Ipsapirone

Forced swim test

Decreased immobility in mice

[36]

Gepirone, Buspirone

Forced swim test

No effect (mice)

[36]

AGONIST 8-OH-DPAT

AC

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ACCEPTED MANUSCRIPT 8-OH-DPAT + ipsapirone, gepirone, Forced swim test buspirone

Increased immobility in mice

[36] [44]

F15599 (agonist of postsynaptic receptor)

Forced swim test

Decreased immobility in rats

F13714 (agonist of presynaptic receptor)

Forced swim test

Decreased immobility in rats

T P

I R

ANXIETY

C S U

KNOCK-OUT

Decrease in the percentage of entries into open arms and [22] time spent in open arms in mice

Elevated zero maze

N A

5-HT1A receptor (C57BL/6J) Novel object 5-HT1A receptor (C57BL/6J, SwissOpen field test Webster, 129SV, respectively) 5-HT1A receptor (129SV)

5-HT1A autoreceptor (mixed: 129S6/Sv; C57B6; CBA)

D E

A

M

Increased number of entries into the area of novel object [22] in mice Decrease in time spent in the center and in the open arms [22,50,51] in mice

Elevated plus maze

Decrease in the percentage of entries into open arms and [51] time spent in open arms in mice

Open field test

Decreased total exploration and percentage exploration of the center in mice

[38]

Light/dark exploration test

Decreased total exploration and entries into light compartment in mice

[38]

Open field test

Adult mice showed decreased time spent in the center, which was not reversed by SSRI treatment

[43]

Elevated plus maze

Adult mice showed decreased time spent in open arms, which was not reversed by SSRI treatment

[43]

T P E

C C

Transcription factor Freud-1 repressing the 5-HT1A autoreceptor’s gene (C57BL/6N)

[44]

AGONIST

45

ACCEPTED MANUSCRIPT

Cannabidiol

Cannabidiol (pretreatment with mCPP)

PRX-00023

Elevated plus maze

No significant effect in the percentage of entries into open arms and time spent in open arms in rats; after acute restraint stress: increase the above-mentioned parameters

Marble burying test

Reduced number of buried marbles in mice

Open field test

No significant effect in mice

Ultrasonic vocalization test

Reduction of ultrasonic vocalizations in rats

Ultrasonic vocalization test

Reduced fear-induced ultrasonic vocalization in rats

Elevated plus maze S15535 (full agonist of presynaptic receptors, partial of postsynaptic)

D E

Geller-Seifter test

PT

Vogel test

E C

LY293284

AC

LY315712 (partial agonist)

T P

I R

SC

U N

A M

[56]

[57] [57] [58] [59]

No effect in rats (in high doses reduced both percent time in open arms and total entries)

[59]

Increase in the punished responses in rats

[59]

Increase in the punished licks in rats

[60]

Social interaction test

Increase in the social interaction between rats

[60]

Elevated plus-maze test

Reduction of the percentage of entries into open arms and time spent in open arms in mice

[63]

Elevated plus-maze test

No significant effect in mice

[63]

Increase in the number of punished crossings in mice

[64]

Compound 9 (full agonist), Four plate test Compound 12 (agonist of presynaptic receptors, partial agonist

46

ACCEPTED MANUSCRIPT of postsynaptic receptors) ANTAGONIST pMPPI

Elevated plus-maze test

Increase in the percentage of entries into open arms and time spent in open arms in mice

Light/dark exploration test

Increase in the time mice spent in white area

Elevated plus-maze test

Increase in the percentage of entries into open arms and time spent in open arms in rats

Elevated plus-maze test

Increase in the percentage of entries into open arms and time spent in open arms in mice

[63]

Increase in the number of punished crossings in mice

[64]

Reduction of ultrasonic vocalizations in rats

[65]

Increase in the social interaction between rats

[65]

UH-301

LY297996

Compound 14 (presynaptic receptor Four plate test agonist)

D E

Ultrasonic vocalization test SB-649915

PT

Social interaction test

T P

I R

SC

U N

A M

[61] [62] [62]

E C

8-OH-DPAT: 8-hydroxy-2-(di-n-propylamino)tetralin; mCPP: meta-chlorophenylpiperazine; pMPPI: 4-(2'-methoxyphenyl)-1-(2'-(N-(2''pyridinyl)-4-iodobenzamido)ethyl)piperazine; SSRI: selective serotonin reuptake inhibitor.

AC

47

ACCEPTED MANUSCRIPT Table 2 Preclinical data on the role of serotonin 5-HT1B receptor in depression and anxiety. Manipulation

Test

Result

Reference

DEPRESSION

T P

KNOCK-OUT 5-HT1B autoreceptor (C57BL/6129/Sv)

I R

Forced swim test

Decreased immobility in mice

Sucrose preference test

Increased preference to sucrose consumption in mice

SC

U N

AGONIST CP94253

Forced swim test

Anpirtoline

Forced swim test

A M

[70] [70]

Decreased immobility in mice

[80]

Decreased immobility in mice

[80]

Anpirtoline + pretreatment with 5,7 Forced swim test DHT

Decreased immobility in mice

[81]

Anpirtoline + pretreatment with pCPA

Decreased immobility in mice

[81]

Devoid the activity of antidepressants (no significant changes in mobility of mice)

[81]

Decreased immobility in mice

[78]

D E

T P E

Forced swim test

C C

ANTAGONIST

A

GR127935 + paroxetine, citalopram Forced swim test SB-616234-A

Forced swim test

ANXIETY AGONIST

48

ACCEPTED MANUSCRIPT

Vogel test

Increase in the punished drinking in rats

[86,87]

Elevated plus-maze test

Increase in the percentage of entries into open arms and time spent in open arms in rats

[86]

Four plate test

Increase in the number of punished crossings in mice

[86]

Open-field test

Increase in the exploratory activity- walking in rats

[86]

Vogel test

Increase in the punished drinking in rats

[86,87]

Increase in the percentage of entries into open arms and time spent in open arms in rats

[86]

Increase in the number of punished crossings in mice

[86]

CP94253

T P

I R

C S U

ANTAGONIST

Elevated plus-maze test

SB216641, GR127935

D E

Four plate test

M

N A

T P E

5,7 DHT: 5,7-Dihydroxytryptamine; pCPA: para-chlorophenylalanine.

C C

A

49

ACCEPTED MANUSCRIPT Table 3 Preclinical data on the role of serotonin 5-HT2A receptor in depression and anxiety. Manipulation

Test

Result

Reference

DEPRESSION

T P

ANTAGONIST

I R

EMD281014

Forced swim test

Decreased immobility in rats

FG5893

Forced swim test

Decreased immobility in rats

SC

U N

The differential reinforcement of Enhanced the effect of fluoxetine (increased the low rate 72-s schedule of reinforcement, decreased the response rate in rats) reinforcement ANXIETY

M100907 + fluoxetine

KNOCK-OUT

5-HT2A receptor (129S6/SvEv)

D E

[105] [106] [107]

A M

Dark-light choice test

Increase in the time mice spent in white area

[110]

Elevated plus-maze

Increase in the percentage of entries into open arms and time spent in open arms in mice

[110]

Decreased latency to approach the food pellet in mice

[110]

C C

T P E

Novelty-suppressed feeding

A

50

ACCEPTED MANUSCRIPT Table 4 Preclinical data on the role of serotonin 5-HT2B receptor in depression and anxiety. Manipulation

Test

Result

Reference

DEPRESSION

T P

KNOCK-OUT 5-HT2B receptor (129S2/SvPas) + Fluoxetine

I R

Novelty-suppressed feeding test

No effect in latency to feed in mice

Novelty-suppressed feeding test

Reduced latency to feed in mice

[119]

Sucrose consumption test

Increased preference to sucrose consumption in mice

U N

[119]

Reduced latency to feed in mice

[116]

No effect in latency to feed in mice

[116]

Social interaction test

Increase in the social interaction between rats

[120]

Elevated x-maze test

No significant effect in the percentage of time and the [120] number of entries into open arms in rats

Geller-Seifter test

Increase in the punished responding in rats

5-HT2B receptor (129S2/SvPas)

AGONIST

Novelty-suppressed feeding test

BW723C86

D E

ANTAGONIST

T P E

Novelty-suppressed feeding test

RS127445 + fluoxetine

C C

AGONIST

A BW723C86

A M

SC

[116]

ANXIETY

[120]

51

ACCEPTED MANUSCRIPT

Vogel test

Increase in the punished drinking in rats

[121]

T P

I R

C S U

N A

D E

M

T P E

C C

A

52

ACCEPTED MANUSCRIPT Table 5 Preclinical data on the role of serotonin 5-HT2C receptor in depression and anxiety. Manipulation

Test

Result

Reference

DEPRESSION

T P

AGONIST RO60-0175 + paroxetine, citalopram, fluvoxamine, imipramine (subactive Forced swim test doses) RO60-0175 + paroxetine, citalopram, Forced swim test fluvoxamine, imipramine (active doses) WAY-161503, RO60-0175, RO60Forced swim test 0332

[127]

Anti-immobility effect deprivation of antidepressants in mice

[127]

C S U

N A

Decreased immobility in rats

[134]

Decreased immobility in rats

[135,136]

Olfactory bulbectomy

Decreased hyperactivity induced by olfactory bulbectomy in rats

[135]

Learned helplessness model

Decreased escape latency and escape failures in rats

[136]

Forced swim test

D E

WAY-163909

I R

Enhanced anti-immobility effect of antidepressants in mice

T P E

M

RO60-0175

C C

A

Prevention from stress-induced anhedonia in rats Unpredictable chronic mild stress measured as percentage change in ventral tegmentum self-stimulated thresholds

[138]

Forced swim test

[129]

Decreased immobility in rats

S32212 (inverse agonist) Sucrose consumption test

Reduction in sucrose intake in rats

[129]

ANTAGONIST

53

ACCEPTED MANUSCRIPT

Forced swim test

Decreased immobility in rats

[128]

Sucrose consumption test

Reduction in sucrose intake in rats

[128]

S32006

T P

ANXIETY

I R

AGONIST Vogel test

Increase in the punished drinking in rats

[129]

Social interaction test

Increase in the social interaction between rats

[129]

C S U

S32212 (inverse agonist)

N A

Geller-Seifter test

Increase in the punished responding in rats

[149]

Increase in the punished responding in rats

[122]

Increase in the punished drinking in rats

[128]

Social interaction test

Increase in the social interaction between rats

[128]

Social interaction test

Increase in the social interaction between rats

[146]

SB206553

Geller-Seifter test

Increase in punished responding in rats

[147]

SB-242084

Elevated plus-maze test

Increase in the percentage of time and the number of entries into open arms in rats

[148]

SB243213 (inverse agonist) ANTAGONIST

D E

Geller-Seifter test

SB200646A

T P E

Vogel test S32006

A

C C

SB200646A + pretreatment with mCPP, SB206553

M

54

ACCEPTED MANUSCRIPT

Geller-Seifter test

Increase in the punished responding in rats

[148]

mCPP: meta-chlorophenylpiperazine.

T P

I R

C S U

N A

D E

M

T P E

C C

A

55

ACCEPTED MANUSCRIPT Table 6 Preclinical data on the role of serotonin 5-HT3 receptor in depression and anxiety. Manipulation

Test

Result

Reference

DEPRESSION

T P

ANTAGONIST

I R

Forced swim test

Decreased immobility in mice

Tail suspension test

Decreased immobility in mice

Ondansetron + fluoxetine

Forced swim test

Enhanced anti-immobility effect of antidepressants (decreased immobility in mice)

[161]

Tropisetron

Forced swim test

Decreased immobility in rats

[157]

Ondansetron

D E

KNOCK-OUT

SC

U N

Elevated plus-maze test

Increase in the percentage of time and the number of entries into open arms in mice

[173,183]

Social interaction test

Increase in the social interaction in mice

[173]

Light/dark exploration test

Increase in the time mice spent in white area

[183]

Social interaction test

Increase in the social interaction between rats

[175]

E C

AC

[161]

ANXIETY

PT

5-HT3 receptor (C57BL/6J)

A M

[161]

ANTAGONIST GR38032F, ICS205-930, Zacopride

56

ACCEPTED MANUSCRIPT GR38032F, ICS205-930, BRL43694, Light/dark exploration test Zacopride, MDL72222

Increase in the time spent in white area in mice

[175]

Elevated plus-maze test

Increase in the percentage of time and the number of entries into open arms in rats

[176]

Light/dark exploration test

Increase in the time spent in white area in mice

[175]

Vogel test

Increase in the punished drinking in rats

[176]

WAY100289, Zacopride, Ondansetron, ICS-205930

Light/dark exploration test

Increase in the time spent in white area in mice

[177]

WAY100289

Acoustic startle paradigm

VA21B7, Granisetron, Tropisetron

VA21B7, Ondansetron, Granisetron, Tropisetron

I R

C S U

N A

Reduction of the potentiated startle response and in higher dose also reduction normal acoustic startle (rats)

[177]

Increase in the social interaction between rats

[178]

Elevated x-maze test

Increase in the percentage of time and the number of entries into open arms in rats

[178]

Light/dark exploration test

Increase in the time mice spent in white area

[181]

Social interaction test

D E

BRL46470A, Ondansetron

T P E

BRL4670A

T P

M

C C

A

57

ACCEPTED MANUSCRIPT Table 7 Preclinical data on the role of serotonin 5-HT4 receptor in depression and anxiety. Manipulation

Test

Result

Reference

DEPRESSION

T P

KNOCK-OUT

5-HT4 receptor (129SvTer)

No difference between wild-type and knock-out mice

Sucrose intake test

Reduced sucrose intake in mice

Nesting test

Reduced nesting behavior in mice

Forced swim test

RS67333 (corticosterone model of depression)

D E

T P E

Tail suspension test

ANTAGONIST

C C

SB20470A + fluoxetine

Forced swim test

A

SC

U N

AGONIST RS67333

I R

Forced swim test

GR12547 + fluoxetine (pretreatment Tail suspension test with corticosterone)

A M

[195] [195] [195]

Decreased immobility in rats

[196]

Decreased immobility in mice

[199]

Decreased immobility in rats

[198]

Increase in the immobility in mice compared with fluoxetine

[199]

ANXIETY KNOCK-OUT 5-HT4 receptor (129SvTer)

Open field test

Reduced central activity in mice

[195]

58

ACCEPTED MANUSCRIPT AGONIST Open field test

Increase in time mice spent in the center and in the open [199] arms

Elevated plus maze

Increase in percentage of the time spent in open arms and the percentage of entries into open arms in mice

Social interaction test

Increased time of social interaction in rats

Elevated x-maze test

Increase in the percentage of the time spent in open arms [204] in rats

RS67333, Fluoxetine

T P

I R

ANTAGONIST

C S U

SB204070A, SB207266A

L–Lysine (partial antagonist) (alone Elevated plus maze or with combination with L-arginine)

D E

[199]

[204]

M

N A

Increase in the percentage of the time spent in open arms [207] and the percentage of entries into open arms in rats

T P E

C C

A

59

ACCEPTED MANUSCRIPT Table 8 Preclinical data on the role of serotonin 5-HT5 receptor in depression and anxiety. Manipulation

Test

Result

Reference

DEPRESSION

T P

ANTAGONIST Forced swim test

A-843277

[215]

C S U

[215]

ANXIETY ANTAGONIST

N A

Ultrasonic vocalization test

SB-699551-A

D E

I R

Decreased immobility in rats

Reduction of ultrasonic vocalizations in rats

M

T P E

C C

A

60

ACCEPTED MANUSCRIPT Table 9 Preclinical data on the role of serotonin 5-HT6 receptor in depression and anxiety. Manipulation

Test

Result

Reference

DEPRESSION

T P

AGONIST

I R

WAY-208466

Forced swim test

Decreased immobility in mice

EMD 386088 (partial agonist)

Forced swim test

Decreased immobility in rats

SC

U N

ANTAGONIST Forced swim test SB-399885 Tail suspension test SB-399855 + imipramine, desipramine, bupropion, moclobemide (ineffective doses)

D E

T P E

Forced swim test

C C

AGONIST

A

A M

[223] [227]

Decreased immobility in mice and rats

[226]

Decreased immobility in mice

[226]

Decreased immobility in mice

[262]

ANXIETY

Elevated plus maze

Increase in the percentage of the time spent in open arms [233] and the percentage of entries into open arms in rats

Vogel drinking test

Increase in the number of accepted shocks in rats

EMD 386088 (partial agonist)

[233]

ANTAGONIST

61

ACCEPTED MANUSCRIPT

SB399885

Vogel drinking test

Increase in the number of accepted shocks in rats

[226]

Elevated plus maze

Increase in percentage of the time rats spent in open arms and the percentage of entries

[226]

Four-plate test

Increase in number of punished crossings in mice

T P

I R

[226]

C S U

N A

D E

M

T P E

C C

A

62

ACCEPTED MANUSCRIPT Table 10 Preclinical data on the role of serotonin 5-HT7 receptor in depression and anxiety. Manipulation

Test

Result

Reference

DEPRESSION

T P

KNOCK-OUT

I R

Forced swim test

Decreased immobility in mice

Tail suspension test

Decreased immobility in mice

5-HT7 receptor (C57BL/6J)

SC

U N

ANTAGONIST Forced swim test

SB-269970 + citalopram/ imipramine/ desipramine/ moclobemide JNJ-18038683

[239]

Decreased immobility in mice

[239]

Olfactory bulbectomy

Decreased hyperactivity induced by olfactory bulbectomy in rats

[243]

Tail suspension test

Enhanced anti-immobility effect of citalopram (decreased immobility in mice)

[241]

Forced swim test

Enhanced anti-immobility effect of antidepressants (decreased immobility in mice)

[242]

Tail suspension test

Decreased immobility in mice

[244]

Tail suspension test

Enhanced anti-immobility effect of citalopram (decreased immobility in mice)

[244]

D E

SB-269970 + citalopram

T P E

C C

A

JNJ-18038683 + citalopram

[238]

Decreased immobility in mice

Tail suspension test

SB-269970

A M

[238]

ANXIETY

63

ACCEPTED MANUSCRIPT KNOCK-OUT Elevated plus maze

No difference between knock-outs and wild-type mice in [237] time spent in open arms and open arms entries

Marble burying test

Reduction of buried marble in mice

Dark/light test

Increase in the time mice spent in bright light

5-HT7 receptor (C57BL/6J)

T P

I R

AGONIST LP-211

C S U

ANTAGONIST

N A

Vogel drinking test Elevated plus maze

D E

SB-269970 Four plate test

T P E

Marble burying test

Increase in the number of accepted shocks in rats

M

[248]

[247]

[239]

Increase in the percentage of the time spent in open arms [239] and the percentage of entries into open arms in rats Increase in the number of punished crossings in mice

[239]

Reduction of buried marble in mice

[248]

C C

A

64

Figure 1

Figure 2