Hi Jesus, just go to https://pdsp.unc.edu/databases/pdsp.php and enter "serotonin" into the "test ligand" field. submit your query, and you will get an overview of the affinity of serotonin for its receptors, incl. 5-HT2 and 1.

Thank so much PhD Buchborn

Difficult to find answers, but found some explanations:

From:

Int J Mol Sci. 2021 Aug; 22(16): 9015.

Published online 2021 Aug 20. doi: 10.3390/ijms22169015

PMCID: PMC8396477

PMID: 34445721

5-HT Receptors and the Development of New Antidepressants

Grzegorz Ślifirski, Marek Król,* and Jadwiga Turło

Philippe De Deurwaerdère, Academic Editor

....The serotonergic system affects various physiological functions, including psychoemotional expression, sensorimotor integration, and the regulation of the autonomic, cardiovascular, respiratory, and digestive systems. Within the CNS, 5-HT is involved in the regulation of higher mental functions and emotions, extrapyramidal motor functions, and cognitive functions (e.g., learning and memory).

At least 14 different serotonin receptors have been identified. These receptors can be divided into distinct families, which are labelled 1, 2, 3, 4, 5, 6, and 7, and the subtypes in each family are labelled with letters (e.g., a, b, c). Many of these receptors are thought to be involved in the pathogenesis of various CNS disorders [41].

3.1. The 5-HT1A Receptors

The 5-HT1A receptors are located primarily in the following populations: (i.) presynaptic neurons of the raphe nuclei of the midbrain and (ii.) postsynaptic neurons, mainly in the hippocampus, septum, amygdala, and corticolimbic regions [42]. Autoreceptors are located within the bodies and dendrites of serotonin neurons. Their activation inhibits neuronal discharges and reduces the release of serotonin [43]. Thus, 5-HT1A autoreceptors play an important role in the self-regulation of the serotonergic system; they partially inhibit the activity of adenylate cyclase [44] and activate G protein-dependent rectifying potassium channels (GIRK) with the use of the βγ subunit of G protein [45]. This causes membrane hyperpolarization, a reduction in neuronal excitability, and the inhibition of potential-dependent calcium channels, reducing the influx of calcium ions. The consequence is a reduction in the neural discharge rate. Given the significant influence of these neuronal discharges on the overall activity of the entire serotonergic system, it can be concluded that the reduction in the firing rate evoked by serotonin and other 5-HT1A agonists immediately translates into an overall reduction in 5-HT release in most areas of the brain, particularly in regions innervated by the dorsal raphe [20].

The activation of 5-HT1A autoreceptors by endogenous serotonin, therefore, plays an essential role in the physiological control of the activity of the 5-HT ascending neurons. The 5-HT neurons during waking periods show a slow and regular rate of discharge [36]. Under conditions of excessive excitatory input (e.g., stress), there is an increased release of serotonin in the vicinity of neuronal bodies. It activates 5-HT1A autoreceptors, which allow low and regular neuronal activity to be maintained [40]. Thus, 5-HT1A autoreceptors act as negative feedback physiological “safety valves” to maintain homeostasis.

The expression of 5-HT1A heteroreceptors, in turn, takes place in populations of non-serotonin receptors, mainly in the limbic system within: (i.) bodies and dendrites of glutamatergic neurons [43] or (ii.) axons of GABA-ergic [46], and (iii.) cholinergic neurons [47]. These receptors are involved in regulating the release of various neurotransmitters: acetylcholine in the medial septum [48], glutamate in the prefrontal cortex [49], and dopamine in the ventral tegmental area [50]. In most regions of the brain, the inhibition of adenylate cyclase occurs due to the activation of the Gαi protein. The GIRK channels in the hippocampus are activated by the βγ subunits of the Gαo isoform [51]. The 5-HT1A receptors in the cortex and hypothalamus bind to both the Gαi and Gαo subunits, while their preferential binding to the Gαi3 protein occurs within the raphe nucleus.

The differences in the properties of 5-HT1A auto- and hetero-receptors are manifested in their different functional selectivity [52]: 5-HT1A heteroreceptors stimulate [53], while 5-HT1A autoreceptors inhibit ERK1/2 transmission [54]. The 5-HT1A-biased agonism appears to result in the preferential activation of a specific signaling pathway without affecting or even blocking other pathways associated with this receptor subtype [55]. It has also been shown that there is an agonist-dependent modulation of G-protein coupling and a transduction of 5-HT1A receptors in rat dorsal raphe nucleus. Moreover, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a full 5-HT1A receptor agonist) compared with buspirone (a partial 5-HT1A receptor agonist) fails to modify forskolin-stimulated cAMP accumulation [56].

In general, 5-HT1A receptor-deficient mice show a shorter immobility time in the forced swim test than wild-type control animals [57]. The lack of functional 5-HT1A autoreceptors may, therefore, favor a less-depressed phenotype. The whole-life suppression of 5-HT1A heteroreceptor expression in adolescence results in a broad depression-like phenotype. In addition, the group showed physiological and cellular changes within medial prefrontal cortex–dorsal raphe proper circuitry: (i.) increased basal serotonin levels in the medial prefrontal cortex, which is hyporeactive to stress and (ii.) decreased basal serotonin levels and firing rates in a dorsal raphe hyperactivated by the same stressor [57].

Animal studies show that both the stimulation and blockade of 5-HT1A receptors can cause or accelerate the antidepressant effect [17]. It is difficult not to associate this with the above-described functional differences of 5-HT1A auto- and hetero-receptors and the phenomenon of the biased 5-HT1A agonism. Many studies have demonstrated the antidepressant effect of 8-OH-DPAT reversed by 5-HT1A receptor antagonists [58]. Moreover, 5-HT1A receptor-deficient mice showed no increase in adult neurogenesis in the hippocampus after chronic treatment with fluoxetine (SSRI) and not with imipramine (TCA) [59]. The preferential activation of postsynaptic 5-HT1A receptors by F15599 (Figure 2), a biased 5-HT1A agonist, resulted in an antidepressant-like effect [60]. Similar activity was shown by F13714, a non-selective agonist of 5-HT1A receptors, but it induced a deeper “serotonin syndrome”, hypothermia, and corticosterone release in rats. Elevated corticosterone levels accompany chronic stress in animals, leading to depression [61]. Moreover, the activation of 5-HT1A receptors in the prefrontal cortex (PFC) by F15599 produces strong antidepressant-like effects in the forced swim test (FST) in rats, with a distinctive bimodal dose–response pattern. These data suggest that F15599 may target specific 5-HT1A receptor subpopulations in the PFC, possibly located on the GABAergic and/or glutaminergic neurons [62].

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Figure 2

5-HT1A receptor agonists: 8-OH-DPAT, F15599, and F13714.

The previously described physiological function of 5-HT1A autoreceptors and their regulation of depressive behavior seem to be unfavorable in the context of the mechanism of action of antidepressants [20,63]. The negative feedback pathway through 5-HT1A autoreceptors may decrease the efficacy of the SSRI as the dose increases, thus creating a second, anomalous part of the dose–response curve. This effect may also be responsible for the so-called therapeutic window for such antidepressants [64]. The prolonged use of SSRIs translates into significantly higher levels of extracellular 5-HT than after a single administration [65]. The negative feedback loop is believed to be the cause of the slow and delayed clinical efficacy of antidepressant drugs [66]. Administration of antidepressants (tricyclic drugs, monoamine oxidase inhibitors, and SSRIs) significantly increases the level of extracellular 5-HT in the midbrain raphe [67]. This leads to: (i.) the activation of 5-HT1A receptors, (ii.) the reduction in 5-HT cell firing [68], and (iii.) the terminal release of 5-HT [69]. The inhibition of SSRIs in the negative feedback pathway clearly decreases with the duration of treatment. This is most likely due to the serotonin-induced desensitization of raphe 5-HT1A autoreceptors discussed earlier [70]. Thus, the desensitization of 5-HT1A autoreceptors may accelerate the onset and/or enhance the antidepressant effect [71]. Mice with higher levels of 5-HT1A autoreceptors showed a blunted physiological response to acute stress, increased behavioral despair, and no behavioral response to fluoxetine [72]. Moreover, mice with lower autoreceptor levels showed a strong behavioral response to fluoxetine after both chronic and subchronic administration [72]. Thus, lowering the level of 5-HT1A autoreceptors prior to antidepressant treatment may accelerate and increase the effectiveness of antidepressant therapy. Combining SSRI treatment with the 5-HT1A receptor antagonist pindolol significantly reduces the latency of the antidepressant response and improves the clinical response in previously untreated MDD patients (Table 1) [20,21,73]. The above data indicate that the stimulation of postsynaptic 5-HT1A receptors or the blockade of presynaptic 5-HT1A receptors results in antidepressant-like activity. (-)-pindolol may also stimulate somatodendritic 5-HT1A receptors. Then, its accelerating antidepressant effect might stem from the accelerated adaptive changes like autoreceptor desensitization in response to both serotonin and pindolol. This mechanism can also be achieved by initiating the treatment with high-dose SSRI when a patient is suicidal. The antidepressant action of pindolol may also be related to its agonistic activity at the β1-adrenoreceptor as this drug possesses the strongest intrinsic sympathicomimetic activity among other β-blockers [74].

Table 1

Clinical effects of augmentation of SERT inhibition with different activities towards 5-HT receptors.

Clinical InterventionMechanism of ActionEffectReferencesSSRI + pindololSERT inhibition + 5-HT1A agonismReduced latency of the antidepressant response and improved the clinical response in previously untreated MDD patients[21]SSRI + buspironeSERT inhibition + 5-HT1A partial agonismSymptom remission in patients unsuccessfully treated with SSRIs[75]SSRI + mirtazapineSERT inhibition + 5-HT2A antagonismAugmentation of the clinical response to SSRIs in treatment-resistant patients[76]VilazodoneSERT inhibition + 5-HT1A partial agonismIn contrast to prototypical SSRIs, vilazodone has not been associated with treatment-emergent sexual difficulties or dysfunction[27]VortioxetineSERT, 5-HT3 and 5-HT7 receptors inhibition, 5-HT1A agonismPotential rapid onset of action[77]

According to the neurotrophic hypothesis of depression, decreased neurotrophic support causes neuronal atrophy, which in turn reduces hippocampal neurogenesis and leads to depression. Clinical data support this theory: postmortem analysis has shown reduced volumes of the hippocampus and prefrontal cortex in depressed patients [78,79]. Persons diagnosed with MDD showed decreased levels of BDNF (brain-derived neurotrophic factor) and NGF (nerve growth factor) in the hippocampus. A deficit of these neurotrophins may promote neuronal loss [80,81]. This phenomenon was confirmed by in vivo studies [82,83,84,85], which showed that antidepressants reversed these changes [86]. Chronic treatment with 8-OH-DPAT, in turn reduced the feeding delay in the novelty-suppressed feeding test and increased adult hippocampal neurogenesis in wild-type mice, but showed no effect in the 5-HT1A receptor knockout group [59]. Thus, 5-HT1A receptors mediate the action of 8-OH-DPAT, from which it can be concluded that the postsynaptic 5-HT1A receptors mediate the antidepressant-like action of 8-OH-DPAT [87]. The specific deletion of the 5-HT1A heteroreceptors from mature granular cells in the dentate gyrus of the hippocampus has also been found to abolish the effects of SSRIs in various behavioral tests [88]. It also attenuated the effects of SSRIs on adult neurogenesis and the expression of hippocampal neurotrophic factors: BDNF and VEGF (vascular endothelial growth factor). Whole-life 5-HT1A heteroreceptor-knockout (but not autoreceptor-knockout) mice showed decreased mobility in the forced swim test [89]. Such a depression-like phenotype was not observed when the suppression of heteroreceptors was initiated in adulthood. Therefore, serotonergic signaling in the forebrain during development may stably influence the circuits underlying the behavioral response to the FST [89].

The STAR*D clinical trial shows that in patients unsuccessfully treated with SSRIs, the augmentation with buspirone resulted in symptom remission [75]. Buspirone (a partial agonist of the 5-HT1A receptor) enhances the desensitization of 5-HT1A autoreceptors, increasing the effectiveness of the SSRI treatment. Recently, a single transcription factor, Freud-1, has been found to be crucial for the expression of the 5-HT1A autoreceptor [90]. Mice with a conditional knockout of Freud-1 in serotonin neurons were shown to have elevated levels of 5-HT1A autoreceptors and exhibited the enhanced anxiety and depressive behavior in adulthood that was refractory to chronic SSRI treatment [90]. Interestingly, the double knockout of the Freud-1/5-HT1A gene did not produce such effects. In this case, the depressive-like behavior was even reduced [90]. The study suggests that targeting specific transcription factors may increase the response to antidepressant treatment. These reports indicated the need to search for compounds targeting only the population of 5-HT1A auto- or heteroreceptors.

The results of postmortem and neuroimaging studies suggest an increased density of 5-HT1A autoreceptors in patients with MDD compared to the control group [91,92,93]. Genetic studies have shown that individuals with an increased density or activity of 5-HT1A autoreceptors are more prone to mood disorders and respond poorly to antidepressant treatment [94,95]. However, the number and density of postsynaptic 5-HT1A receptors have been shown to be unaltered or reduced in depressed patients, and this alteration is not sensitive to antidepressant treatment [96]. Long-term antidepressant therapy causes the tonic activation of 5-HT1A receptors in the dorsal hippocampus [97], and activation of 5-HT1A receptors in the dentate gyrus increases hippocampal neurogenesis [98]. In light of the cited reports, the use of 5-HT1A agonists as antidepressants seems natural [99]. Some agents possessing such activity (e.g., buspirone and gepirone) show antidepressant efficacy in placebo-controlled trials, but their potency is lower than that of SSRIs. Most 5-HT1A agonists (especially azapirones, Figure 3) show the preferential activation of presynaptic 5-HT1A receptors. Moreover, these agents tend to have a reduced efficacy at postsynaptic 5-HT1A receptors. Thus, endogenous serotonin competes in the postsynaptic sites with an exogenous substance (with lower agonism), which causes a paradoxical reduction in the tone at the postsynaptic 5-HT1A receptors. Higher doses of 5-HT1A agonists (such as those used in experimental animals) are likely to result in the greater activation of postsynaptic 5-HT1A receptors, which may explain the positive results of efficacy studies in animal models. Conversely, the administration of the selective 5-HT1A receptor antagonist DU125530 with fluoxetine did not accelerate or increase the efficacy of fluoxetine in a double-blind, randomized, placebo-controlled clinical trial. DU125530 had similar binding to pre- and post-synaptic 5-HT1A receptors [100], and the blockade of postsynaptic 5-HT1A receptors likely offset the benefits of enhancing presynaptic serotonergic function [101]. This may show the importance of the activation of postsynaptic 5-HT1A receptors in the mechanism of antidepressant action.

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Figure 3

Azapirones: buspirone and gepirone.

Observations on the 5-HT1A receptor population contributed to a fruitful search for potential multimodal antidepressants that incorporate 5-HT1A receptor activity into their mechanism of action [102]. Recently developed compounds seem to overcome the aforementioned therapeutic problems of azapirones and other first-generation 5-HT1A agonists. Two new antidepressants, vilazodone [27,103] and vortioxetine [104,105], inhibit 5-HT reuptake and show the partial agonism at 5-HT1A receptors.

The 5-HT1A receptor ligands also possess their own potentially therapeutic activity. The 5-HT1A partial agonists show antianxiety [106,107], antidepressant [108], antiaggressive [109], anticraving [110], and anticataleptic properties [111]:

• Animal studies show that both the stimulation and blockade of 5-HT1A receptors can cause or accelerate the antidepressant effect. It is difficult not to associate this with the functional differences of 5-HT1A auto- and hetero-receptors and the phenomenon of a biased 5-HT1A agonism;
• A single transcription factor, Freud-1, has been found to be crucial for the expression of the 5-HT1A autoreceptor. Targeting it may increase the response to antidepressant treatment;
• Observations on the 5-HT1A receptor population contributed to a fruitful search for potential multimodal antidepressants (vilazodone and vortioxetine) that incorporate 5-HT1A receptor activity into their mechanism of action.

3.2. The 5-HT1B Receptors

The 5-HT1B receptors, like 5-HT1A receptors, are located pre- and post-synaptically and are also negatively coupled to adenylate cyclase. Their highest densities are in the striatum, pallidum, nucleus accumbens, substantia nigra, and ventral tegmental area. Lower levels of 5-HT1B receptors are found in the hippocampus, amygdala, and cingulate cortex [112].

Unlike somatodendritic 5-HT1A autoreceptors, 5-HT1B autoreceptors are located on serotonergic axons, where they regulate the synthesis and release of 5-HT locally. The 5-HT1B postsynaptic receptors are located mainly in the centers of motor control (such as the basal ganglia), where they control the synaptic transmission of other neurotransmitters [112]. Studies have shown that 5-HT1B receptors play a role in depression, anxiety, migraines, locomotor activity, aggressive behavior, and the potentiation of the action of other drugs [112,113,114].

Animal studies show that the involvement of 5-HT1B receptors in the pathophysiology of depression is partly related to their responsiveness to environmental stress as well as their exposure to antidepressants [115]. The 5-HT1B heteroreceptors are involved in hippocampal neurogenesis, which may explain their importance for the antidepressant-like effect [116]. Mice lacking 5-HT1B autoreceptors showed an increased mobility in the FST as well as an increased preference for lower-sucrose concentrations in the sucrose preference test compared to the control group. After SSRI administration, elevated levels of serotonin in the hippocampus were observed [117]. Moreover, two common genetic polymorphisms of 5-HT1B receptors, G861C [118] and C129T [119], were associated with MDD and affective disorders. The 5-HT1B receptor gene knockout mice showed increased aggression [120].

The p11 protein, which colocalizes with 5-HT1B and 5-HT4 receptors [121], plays a key role in modulating the function of the 5-HT1B receptor. Its dysregulation has been reported in preclinical models of depression and in postmortem samples from MDD patients [122]. The p11 protein improves 5-HT1B receptor function in various regions of the brain and contributes to an antidepressant-like effect in animal behavioral tests [123]. P11 knockout mice showed depression-like behavior and demonstrated a reduced responsiveness to 5-HT1B receptor agonists and tricyclic antidepressants [123].

Studies in the learned helplessness model showed that 5-HT1B receptors were upregulated in various regions of the brain following stress exposure. A reduced 5-HT1B autoreceptor function and, thus, increased serotonin release, has also been demonstrated after chronic antidepressant treatment [124]. Moreover, chronic treatment with SSRIs induced a negative regulation and/or desensitization of 5-HT1B autoreceptors [125] and facilitated the effect of SSRIs in serotonin neurotransmission [126]. Compounds exhibiting 5-HT1B antagonism, administered alone or with antidepressants, have been shown to be effective in preclinical models of depression [127]. The pretreatment with 5-HT1B receptor antagonists [128] or the genetic inactivation of the 5-HT1B receptor [129] increased the SSRI-induced effect in mice. Therefore, the blockade of 5-HT1B autoreceptors may promote the antidepressant effect. It has been suggested that the 5-HT1B receptor antagonists themselves may be attributed to an antidepressant-like effect. SB-616234-A, a 5-HT1B receptor antagonist, decreased immobility in a forced swim test in mice (Figure 4) [130]. The selective 5-HT1B receptor inverse agonist, SB236057A, increased, in turn, the extracellular concentration of serotonin in the dentate gyrus of a guinea pig. This effect was comparable to that of 14 days of paroxetine therapy [131]. The acute blockade of the 5-HT1B receptor might cause a rapid antidepressant effect [131]. It appears that the agonist activation of 5-HT1B heteroreceptors may also induce antidepressant-like effects [132]. CP94253, a selective 5-HT1B receptor agonist, showed an antidepressant-like activity in a forced swimming test in mice [133]. Anpirtoline, as a selective 5-HT1B receptor agonist, also reduced immobility in control mice but had no effect in 5-HT1B knockout mice [132]. The effect of this compound in the FST was, therefore, due to the activation of the 5-HT1B receptor. The above studies suggest that 5-HT1B receptors play a role in antidepressant-like activity. Ther stimulation of postsynaptic receptors and the inhibition of presynaptic 5-HT1B receptors may be beneficial in the treatment of depression [134].

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Figure 4

5-HT1B receptor ligands: anpirtoline, SB-616234-A, and SB236057A.

As with 5-HT1A receptors, acute SSRI therapy activates terminally localized 5-HT1B receptors, thus reducing 5-HT synthesis and release. The long-term administration of SSRIs desensitizes terminal 5-HT1B autoreceptors [135], suggesting that the plasticity of the autoregulatory function of both 5-HT1A and 5-HT1B receptors may be important with respect to the therapeutic profile of SSRIs. Again, as with 5-HT1A receptor antagonists, the administration of 5-HT1B receptor antagonists increases the neurochemical and behavioral effects of SSRIs [128,136]. Interestingly, the co-administration of the selective 5-HT1A antagonist WAY-100635 and the 5-HT1B receptor antagonist SB-224289 has an additive effect, enhancing the neurochemical effects of fluoxetine. This has led to the suggestion that the combination of the 5-HT1A and 5-HT1B receptor antagonism may increase CNS serotonin levels and, therefore, potentially be an effective treatment strategy for depression [20]:

• Animal studies show that the involvement of 5-HT1B receptors in the pathophysiology of depression is partly related to their responsiveness to environmental stress as well as an exposure to antidepressants;
• The p11 protein improves 5-HT1B receptor function in various regions of the brain and contributes to an antidepressant-like effect in animal behavioral tests;
• The 5-HT1B heteroreceptors are involved in hippocampal neurogenesis, which may explain their importance for the antidepressant-like effect. The stimulation of postsynaptic receptors and the inhibition of presynaptic 5-HT1B receptors may be beneficial in the treatment of depression.

3.3. The 5-HT1D, 5-HT1E, and 5-HT1F Receptors

The clinical significance of the remaining 5-HT1 receptors (5-HT1D, 5-HT1E, 5-HT1F) is less clear. There is limited preclinical evidence linking some of the receptors with depressive states. The sensitivity of postsynaptic 5-HT1D receptors in patients after treatment with SSRIs has been found to be impaired [137]. On the other hand, a postmortem study of untreated suicidal victims with a confirmed history of depression showed a much higher density of 5-HT1D receptors in the globus pallidus [138]. The observed high expression of the 5-HT1E receptor in the frontal cortex and hippocampus may indicate the relationship between 5-HT1E receptors and cognitive functions and memory [20,139].

3.4. The 5-HT2A Receptors

The 5-HT2A receptors, like the others of the 5-HT2 family, are preferentially coupled to the G protein of the Gq/11 type, so their activation increases the cellular level of inositol phosphate and, consequently, the cytosolic concentration of calcium ions. The 5-HT2A receptors are distributed postsynaptically and presynaptically throughout the brain at serotonergic terminals, with the greatest concentration in the neocortex [140,141,142]. Recent anatomical and functional studies suggest that 5-HT2A receptors are also present presynaptically as heteroreceptors, where they may enhance glutamatergic neurotransmission and participate in memory processes [143]. It has also been demonstrated that the 5-HT2A receptors of the cerebral cortex are located on GABAergic interneurons as well as glutamatergic projection neurons in the brains of humans and rodents [42,144].

Many antidepressants and antipsychotic drugs possess a relatively high binding to 5-HT2A receptors [145]. Although there is no direct correlation between the affinity of these drugs for 5-HT2A receptors and clinically effective doses, there is ample evidence that the 5-HT2A receptor plays a role in the pathomechanism of depression [20,146]. Some antidepressants mediate their action partly via the antagonism of 5-HT2A receptors [147]. In addition, chronic treatment with antidepressants, such as tricyclic antidepressants, monoamine oxidase inhibitors, mianserin, mirtazapine, or sertraline, decreased the number of 5-HT2A receptors in rodents [148]. Chronic electroconvulsive shock treatment resulted in the upregulation of cortical 5-HT2A receptors in rodents [149].

Several clinical trials have shown that atypical antipsychotics [150] and the antidepressant mirtazapine with an affinity for α2-adrenoceptors and 5-HT2A receptors [151] augment the clinical response to SSRIs in treatment-resistant patients [76]. A common feature of these substances is their ability, at clinical doses, to block responses to signals mediated by 5-HT2A receptors [152]. Such downregulation could, inter alia, explain why the side effects of SSRIs diminish after 2 or 3 weeks. The high co-expression of 5-HT1A and 5-HT2A receptors in the neocortex [153] may indicate that the blockade of 5-HT2A receptors enhances 5-HT1A receptor-mediated neurotransmission in the cortical and limbic regions, an activity associated with antidepressant efficacy. The chronic administration of 5-HT2A receptor antagonists has been shown to result in a paradoxically negative regulation of 5-HT2A receptors [154,155], which may be beneficial in the treatment of depression. Moreover, preclinical studies indicate that 5-HT2A antagonists have anxiolytic properties, as demonstrated by ritanserin, a 5-HT2A antagonist with anxiolytic effects in humans [156].

Another issue is the relationship between the 5-HT2A receptor and the noradrenergic system in relation to depression [157]. Studies have shown that the activation of 5-HT2A receptors as a result of treatment with SSRIs causes an increase in serotonin levels in GABA neurons. This inhibits the neuronal activity of norepinephrine through the prolonged release of GABA [158,159,160]. In turn, citalopram, in addition to reducing norepinephrine firing, also has the effect of lowering basal and evoked extracellular norepinephrine levels in the amygdala [161]. This may underlie SSRI ineffectiveness in resistant depression. The co-administration of an SSRI and a 5-HT2A receptor antagonist trazodone (as well as atypical antipsychotics, such as quetiapine, risperidone, olanzapine, and aripiprazole) reversed this inhibitory effect in noradrenergic neurons in rats and might be beneficial in the treatment of resistant depression [160,162,163,164]. Increasing evidence shows that 5-HT2A receptor antagonists display antidepressant effects. EMD 281014 (Figure 5), a 5-HT2A receptor antagonist, showed significant activity in the FST in congenital learned helpless rats [165]. A similar effect was shown by another 5-HT2A receptor antagonist, FG5893, which significantly shortened the immobility time in the FST [166]. The selective 5-HT2A receptor antagonist, M100907, enhanced the antidepressant-like behavioral effects of fluoxetine [167], suggesting that a selective 5-HT2A receptor blockade may complement the behavioral effects of serotonin transporter inhibition. In contrast, recent studies in rats have shown that the functional disturbance of the 5-HT2A receptor in the medial prefrontal cortex may contribute to postpartum mental disorders, including depression and psychosis [168]. In addition, prefrontal 5-HT2A receptors may both have beneficial and negative effects on cognition, which might explain the aggravation of cognitive deficits after the onset of SSRI treatment in depressed patients, as well as the limited efficacy of second-generation antipsychotics that act as 5-HT2A receptor antagonists against the strongly debilitating cognitive symptoms of schizophrenia and other psychiatric disorders [169]. A deficiency in 5-HT2A receptors has also been shown to alter the metabolic and transcriptional, but not behavioral, consequences of chronic unpredictable stress in mice [170]. The 5-HT2A blockade or SSRI-induced downregulation of 5-HT2A may lead to emotional blunting in patients. It is, therefore, very likely that 5-HT2A receptors may have different functions depending on the region of the brain:

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Figure 5

5-HT2A receptor antagonists: EMD 281014, FG5893 and M100907.

• Many antidepressants and antipsychotic drugs have relatively high binding to 5-HT2A receptors;
• The high co-expression of 5-HT1A and 5-HT2A receptors in the neocortex may indicate that the blockade of 5-HT2A receptors enhances 5-HT1A receptor-mediated neurotransmission in the cortical and limbic regions, an activity associated with antidepressant efficacy;
• Increasing evidence shows that 5-HT2A receptor antagonists display antidepressant effects. A selective 5-HT2A receptor blockade may complement the behavioral effects of serotonin

3.5. The 5-HT2B Receptors

The 5-HT2B receptor is expressed mainly in peripheral tissues, especially in the liver, kidneys, and heart, and its distribution in the brain is low [171]. In the central nervous system, the 5-HT2B receptor is present in septal nuclei, the dorsal hypothalamus, and the medial amygdala at levels similar to those found in the stomach [171]. The 5-HT2B receptor, mRNA, is found in the dorsal raphe nucleus, suggesting a potential autoreceptor role [172]. The 5-HT2B receptors are coupled to the Gq protein, which activates PLC (phospholipase C)/PKC (protein kinase C) and increases the concentration of calcium ions in the cytosol.

The knowledge about the function of the 5-HT2B receptor in the CNS is limited; however, there are reports of the antidepressant properties of selective 5-HT2B receptor agonists [173]. The presence of 5-HT2B receptors in the dorsal raphe and their stimulatory role in 5-HT release has been demonstrated [173]. The pharmacological or genetic inactivation of the 5-HT2B receptor abolished the effects of chronic treatment with SSRIs, and the stimulation of 5-HT2B receptors induced an SSRI-like response in behavioral and neurogenic tests. In turn, the genetic inactivation of 5-HT2B receptors in serotonergic neurons eliminated the neurogenic effects of fluoxetine [173]. It has recently been confirmed that 5-HT2B receptors directly and positively regulated the activity of serotonin neurons [174]. In addition, the stimulation of the 5-HT2B receptor via fluoxetine in astrocyte cell cultures resulted in the phosphorylation of extracellular signal-regulated kinases and the transactivation of the EGF (epidermal growth factor) receptor [175]. A reduced level of astroglial (but not neuronal) 5-HT2B receptors in a mouse model of Parkinson’s disease was also reported, which paralleled the development of the depression-like phenotype [176]. The stimulation of astroglial 5-HT2B receptors may, therefore, be beneficial in treating depressive disorders [177].

Considering the role of peripherally located 5-HT2B receptors, potential new antidepressants acting on 5-HT2B receptors may adversely affect the function of the respiratory and circulatory systems [17,20]:

• 5-HT2B receptors directly and positively regulate the activity of serotonin neurons;
• There are reports of the antidepressant properties of selective 5-HT2B receptor agonists;
• Potential new antidepressants acting on 5-HT2B receptors may adversely affect the function of the respiratory and circulatory systems.

3.6. The 5-HT2C Receptors

The 5-HT2C receptors are mainly located in the choroid plexuses, cerebral cortex, hippocampus, substantia nigra, and cerebellum. They bind preferentially with Gq/11 and increase the concentrations of inositol phosphates and cytosolic Ca2+. Like 5-HT2A receptors, they are involved in the regulation of mood, motor behavior, and appetite [178].

Several classes of antidepressants have an affinity for 5-HT2C receptors. Although these receptors are usually somatodendritic, in some regions they are also present on axon terminals [179]. The location of 5-HT2C receptors in relation to serotonergic and GABAergic neurons in the anterior raphe nuclei demonstrates complex systemic relationships in the brain. It has been shown that 5-HT2C receptors are preferentially located on GABAergic interneurons (and not on serotonergic neurons). This suggests that the stimulation of GABAergic interneurons by 5-HT2C receptors plays an important role in the suppression of serotonergic cell firing in the dorsal raphe and surrounding areas [180]. The immunoreactivity of the 5-HT2C receptor has also been described in GABAergic cells in the PFC [181] and in the dopaminergic and GABAergic neurons of the mesolimbic pathway [182].

A potent 5-HT2C receptor antagonist, S32006 (Figure 6), showed antidepressant activity in rodent behavioral tests and increased dopamine and norepinephrine levels in the frontal cortex [183]. This compound reduced immobility in the FST in mice, suppressed anhedonia in a chronic mild stress model, and increased cell proliferation and BDNF expression in the dentate gyri of rats [183]. In contrast, the inverse agonist of the 5-HT2C receptor, S32212, showed an antidepressant effect in the FST in rats after both acute and chronic treatment [184].

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Figure 6

5-HT2C receptor ligands: S32006, S32212, WAY-163909 and SB206553.

On the other hand, some studies report that 5-HT2C agonists have been shown to be active in animal models of depression, suggesting an antidepressant-like effect [185,186]. WAY-163909, a selective 5-HT2C receptor agonist, elicited a rapid antidepressant effect in a rat FST that was blocked by the 5-HT2C/2B receptor antagonist, SB206553 [186]. Moreover, after chronic treatment, WAY163909 reduced the hyperactivity associated with olfactory bulbectomy in rats [186,187]. It is possible that the mediated antidepressant effects of these compounds were due to the stimulation of 5-HT2C receptors and the resulting activation of postsynaptic serotonin receptors [188]. Other selective 5-HT2C receptor agonists have also been effective in animal models of depression and obsessive–compulsive disorder [189].

Preclinical data show that the antagonism of 5-HT2C receptors increases the neurochemical and behavioral effects of SSRIs. Examples include: the increase in the effect of SSRIs on extracellular 5-HT concentrations in the hippocampus and cortex [190,191], or a significant increase in the effect of SSRIs in behavioral models of depression by selective and non-selective 5-HT2C antagonists [190].

Additionally, 5-HT2C receptors have been shown to be involved in the anti-immobility effect of antidepressants in the FST, increasing the serotonin level in the synapse [192]. Few studies suggest that 5-HT2C receptor antagonists alone may also exhibit antidepressant-like properties. The inactivation of 5-HT2C receptors has been shown to potentiate SSRI-induced serotonin release in rodents [190]. However, 5-HT2C receptor antagonists administered separately had no effect on serotonin levels [191].

An altered editing of the mRNA-encoding 5-HT2C receptors has been reported in the PFC of depressed suicide victims [193]. The desensitization of these receptors has been observed in patients after chronic treatment with SSRIs [194].

The 5-HT2C receptors are also involved in the tonic modulation of dopaminergic activity [195]. The role of the dopaminergic system in schizophrenia, along with the antagonism of atypical antipsychotics towards the 5-HT2C receptors, has aroused interest in this receptor for the treatment of schizophrenia [196]. Conversely, the ineffectiveness of SSRIs in some patients may be due to the serotonin-related inhibition of the neuronal activity of dopamine in the ventral capping region via 5-HT2C receptors [157]. Escitalopram has been shown to reduce the stimulation of dopamine neurons by activating 5-HT2C receptors located on GABA neurons. Some studies indicate that the co-administration of SSRIs with 5-HT2C receptor antagonists (including atypical antipsychotics, such as aripiprazole) may eliminate the inhibitory effects on dopaminergic neurons in rat brains and restore the effect of the SSRI [163]. The aforementioned 5-HT2C receptor antagonist S32006, with a potential antidepressant- and anxiolytic-like effect, increased dopamine levels in the frontal cortex of rats and enhanced dopaminergic neuron firing [183]. The modulation of dopaminergic activity may, therefore, be beneficial in the development of antidepressants due to the above-mentioned activity of 5-HT2C receptor ligands. Recent studies demonstrate the contradictory effect of 5-HT2C receptors on the effects of SSRIs on motor function and affective behavior, highlighting the potential benefits of 5-HT2C receptor antagonists both for reducing SSRI motor side effects and enhancing the therapeutic antidepressant and anxiolytic effects [197].

Both 5-HT2C receptor agonists and antagonists exhibit antidepressant-like activity, and there is still a need to further define the role of this receptor subtype in depression:

• Several classes of antidepressants have an affinity for 5-HT2C receptors. Alterations in their functional status have been observed in depressive and anxiety states;
• Both 5-HT2C agonists and antagonists have been shown to be active in animal models of depression. Preclinical data show that the antagonism of 5-HT2C receptors increases the neurochemical and behavioral effects of SSRIs;
• There is still a need to further define the role of 5-HT2C receptor subtype in depression. ....