The Implication of 5-HT Receptor Family Members in Aggression, Depression and Suicide: Similarity and Difference

Being different multifactorial forms of psychopathology, aggression, depression and suicidal behavior, which is considered to be violent aggression directed against the self, have principal neurobiological links: preclinical and clinical evidence associates depression, aggression and suicidal behavior with dysregulation in central serotonergic (5-HT) neurotransmission. The implication of different types of 5-HT receptors in the genetic and epigenetic mechanisms of aggression, depression and suicidality has been well recognized. In this review, we consider and compare the orchestra of 5-HT receptors involved in these severe psychopathologies. Specifically, it concentrates on the role of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3 and 5-HT7 receptors in the mechanisms underlying the predisposition to aggression, depression and suicidal behavior. The review provides converging lines of evidence that: (1) depression-related 5-HT receptors include those receptors with pro-depressive properties (5-HT2A, 5-HT3 and 5-HT7) as well as those providing an antidepressant effect (5-HT1A, 5-HT1B, 5-HT2C subtypes). (2) Aggression-related 5-HT receptors are identical to depression-related 5-HT receptors with the exception of 5-HT7 receptors. Activation of 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C receptors attenuate aggressiveness, whereas agonists of 5-HT3 intensify aggressive behavior.


Introduction
Aggression, depression and suicide are the global burden of human society. Each year, almost one million people die of suicide [1,2]. Major Depressive Disorder (MDD) is one of the most frequent psychiatric disorders affecting 5-12% of men and 10-25% of women [3]. Acts of violence and aggression account for 1.43 million deaths worldwide annually [4].
Polyfunctionality of the brain 5-HT is due to impressive variety of 5-HT receptors. Currently, 14 types of 5-HT receptors have been cloned and identified including both metabotropic G-protein-coupled and inotropic (5-HT 3 ) receptors. Distinct types of 5-HT receptors are targets for approximately 40% of approved medicines [24]. Available 5-HT

The 5-HT 1A Receptor
The 5-HT 1A receptor attracts special attention due to its key role in the autoregulation of the brain 5-HT system functional activity. The net effect of 5-HT 1A signaling is to reduce neuronal firing rate and protein kinase activation [26]. However, according to its localization, the 5-HT 1A receptor exerts different effects on the functional states of the 5-HT system. 5-HT 1A receptors are found on 5-HT cell bodies and dendrites, mainly in the midbrain raphe nucleus region (presynaptically located autoreceptors) and on terminal targets of 5-HT release (postsynaptic 5-HT 1A receptors). Presynaptic 5-HT 1A receptors inhibit neuronal spike activity in dorsal raphe nucleus and 5-HT release into the synaptic cleft [27][28][29]. Negative feedback control of functional activity of 5-HT neurons by presynaptic 5-HT 1A receptors was considered as a key mechanism in the autoregulation of the brain 5-HT system. Postsynaptic 5-HT 1A receptors mediate the action of serotonin on neurons and also could regulate 5-HT system functional activity via complex feedback neural networks [30,31]. Thus, the 5-HT 1A receptors are a powerful regulator of both preand postsynaptic 5-HT neurotransmission involved in mechanisms of sleep, stress response, appetite, sexual motivation, aggressive behavior, depression and anxiety.

The 5-HT 1A Receptor in Aggressive Behavior
An inhibitory effect of 5-HT 1A receptor agonists on aggressive and social behavior was shown in different animal models [16,[32][33][34][35][36][37]. Considerable differences in 5-HT 1A receptors were found between rats selectively bred for high levels of aggressive reaction towards man or for its absence [16,38]. Genetically defined aggressiveness was shown to be associated with decreased expression of 5-HT 1A receptor mRNA in the midbrain, decreased 5-HT 1A receptor density in hypothalamus, frontal cortex and amygdala and decreased functional activity of 5-HT 1A receptors. Notably, the greatest difference between aggressive and tame rats was found in the structures of cortico-limbic circuitry (frontal cortex, amygdala, and hypothalamus) representing neuroanatomical substrates for the origins and expression of impulsive aggressive behavior [4,[39][40][41][42]. The frontal cortex-amygdala network supports affective control [43] and regulates aggressive impulses originating in the amygdala [42,44,45]. These data suggested an important role of 5-HT 1A receptors in the suppression of impulsive aggressive behavior, and are consistent with the studies carried out in man. There was a significant negative correlation found between lifetime aggression and binding potential of 5-HT 1A receptors measured by positron emission tomography (PET) [46] and by the response to 5-HT 1A receptor agonist, ipsapirone [47].
Positive correlation of reduced 5-HT 1A receptor binding in the temporal cortex with aggressive behavior in Alzheimer disease was described by Lai and co-authors [48], who suggested that the 5-HT 1A receptor B max represented the best predictor for aggression.
Taken together, the evidence reviewed above suggests that 5-HT 1A receptors contribute to prefrontal cortex-limbic system circuits and may fulfill a significant role in the expression of impulsive aggression. Hereditary high or low aggressiveness may be defined, at least partly, by the expression and density of 5-HT 1A receptors in the prefrontal cortex and limbic system.

The 5-HT 1A Receptor and Suicide
In contrast to numerous animal models of depressive and, especially, aggressive behavior, no convincing animal model of suicide has been produced to date [72]. The data concerning the implication of 5-HT receptors in suicidal behavior were obtained using postmortem brain tissue studies, genetic association of 5-HT receptor polymorphism, and using PET in patients with a history of suicide attempts or suicidal intentions.
Higher 5-HT 1A binding potential of 5-HT 1A autoreceptors was shown in raphe nuclei of individuals with depression who attempted suicide [66,73] and in the raphe 5-HT 1A receptor density of individuals who committed suicide [74,75]. No changes in 5-HT 1A receptor density in the prefrontal cortex of suicide victims were revealed [74]. At the same

The 5-HT 1B Receptor in Aggressive Behavior
Several lines of evidence indicate the essential role of the 5-HT 1B receptor in the modulation of aggressive behavior: (1) lacking 5-HT 1B receptor knockout mice demonstrate enhanced aggressive behavior and reduced anxiety [84,85]. (2) Alcohol-heightened aggression [86] and socially provoked aggressive behavior [87] are highly sensitive to the inhibitory effect of 5-HT 1B agonists. Microinjection of the 5-HT 1B agonist, CP-94,253, into the dorsal raphe reduced both aggressive and motor behaviors in mice with alcoholescalated aggression. However, infusion of the 5-HT 1B agonist into the medial prefrontal cortex after alcohol drinking increased aggressive behavior [88,89]. (3) Repeatedly observed aggression increased aggressiveness in rats [90,91]. These changes in aggressive behavior were accompanied by decreased 5-HT 1B receptor density in the striatal brain regions and increased 5-HT 1B receptor density in the basolateral amygdala suggesting a modulatory role of 5-HT 1B receptors in the mechanism of learned aggression. (4) The SNP rs6296 in the 5-HT 1B gene was associated with childhood aggressive behavior but not with adulthood anger and hostility [18].

The 5-HT 1B Receptor in Depressive Behavior and Suicide
A review of the literature, albeit fraught with inconsistent results, provides strong evidence in support of the involvement of 5-HT 1B receptors in the pathophysiology of depression and in the action of classical antidepressants, SSRIs. Behavioral antidepressantlike effects similar to those induced by SSRIs have been produced by agonists of 5-HT 1B receptors [3,52,81,92,93]. Furthermore, 5-HT 1B receptor knockout or pharmacological blockade of 5-HT 1B receptors abolished the antidepressant effect of SSRIs [92], suggesting significant contribution of the 5-HT 1B receptors in the mechanisms of SSRIs action.
Overexpression of encoding 5-HT 1B receptor gene in the caudal dorsal raphe nucleus increased swimming in the swimming forced test and reduced conditioned freezing [94]. At the same time, decreased anxiety along with an antidepressant-like effect in the forced swim and sucrose preference test were displayed by mice lacking 5-HT 1B autoreceptors [95]. The antidepressant-like effect was produced by the 5-HT 1B receptor agonist anpirtoline [92]. Reduced 5-HT 1B receptor binding in ventral striatal/ventral pallidal brain regions has been reported in MDD [82,96]. Importantly, the firing of 5-HT neurons in the dorsal raphe nucleus is controlled by both 5-HT 1A and 5-HT 1B receptors. However, in contrast to the inhibitory influence of 5-HT 1A receptors, excitatory control of the 5-HT neurons firing through 5-HT 1B autoreceptors was revealed [97].
Attempts to find evidence for the implication of 5-HT 1B receptor genetic polymorphism in the susceptibility to suicide were unsuccessful [98][99][100][101][102][103], suggesting that 5-HT 1B polymorphism is unlikely to play a major role in the genetic predisposition to suicide attempts. However, in one more recent study, an association was shown between a few 5-HT 1B polymorphisms, MDD, suicide and aggression [104].

The 5-HT 2 Receptor Family
Serotonin 2A (5-HT 2A ), 5-HT 2B and 5-HT 2C receptors are members of the superfamily of 7-transmembrane-spanning (7-TMS) receptors. These receptors share about 46-50% overall sequence identity and couple preferentially to G q/11 to increase inositol phosphates and cytosolic Ca 2+ [105]. The 5-HT 2A receptors are predominantly cortical, and in subcortical structures their expression is considerably lower [106,107]. Cortical 5-HT 2A signaling can initiate a negative feedback mechanism through cortical glutamatergic and GABAergic interneurons that inhibits the firing of 5-HT neurons in the dorsal raphe nuclei [31]. At the membrane level, activation of 5-HT 2A receptors produced membrane depolarization and the closing of potassium channels that increased the excitability of host neuron [108].
One remarkable characteristic of 5-HT 2A and 5-HT 2C receptors is constitutive activity [109] revealed by the presence of receptor signaling in the absence of any ligand [110]. Constitutive activity of 5-HT 2A and 5-HT 2C receptors can impact and significantly change the therapeutic response of these receptors [109].
Widely presented in astrocytes, 5-HT 2B receptors play a key role in astrocyte response to antidepressant treatment. Upon stimulation, 5-HT 2B receptors activate MEPK/EKT and PI3K/AKT signal pathways via EGF receptor transactivation that leads to changes in the expression of multiple genes and affects astrocytic functions including, possibly, gliotransmitter secretion [111]. More intriguingly still, 5-HT 2B receptors are expressed in the 5-HT neurons and, acting as somatodendritic autoreceptors, regulate their excitability together with 5-HT 1A receptors [112]. Stimulation of the 5-HT 2B receptor is associated with an increase in cyclic GMP through the dual activation of constitutive and inducible Nitric Oxide Synthase [113,114].
Initially erroneously identified as 5-HT 1C receptors [115], 5-HT 2C receptors are found widely distributed throughout the brain [105]. The primary transcript of the 5-HT 2C receptor is subjected to multiple RNA editing. Fully edited variants (VSV and VGV) of 5-HT 2C receptors have reduced G-protein coupling and 40-fold decreased serotonergic potency [116]. Within the brain, 5-HT 2C receptors modulate the mesolimbic dopaminergic function exerting a tonic inhibitory influence over dopamine neurotransmission [117,118]. High levels of 5-HT 2C receptors were detected on parvalbumin GABAergic neurons in the prelimbic prefrontal cortex and to a lesser degree on pyramidal glutamatergic neurons [117]. There are some pharmacological data indicating a link between aggressive behavior and 5-HT 2A receptor activity. In animals, 5-HT 2A agonists, such as DOI, reduced aggressive behavior in flies, amphibians, mice and rats [34]. However, accumulated data also revealed a pro-aggressive effect of the 5-HT 2A agonist DOI [119,120], whereas 5-HT 2A antagonists effectively suppressed aggressive behavior [119,121,122].
In humans, a number of atypical antipsychotics, which act as antagonists of 5-HT 2A receptors, had antiaggressive effects in clinical trials reviewed by Comai and co-authors [123]. A number of polymorphisms associated with impulsivity, aggression and violence were reported [124][125][126].
Some conflicting results were obtained in PET studies. Compared with the low-IA (impulsive aggression) group, cortical 5-HT 2A receptors in the high-IA group were modestly lowered [127]. No differences between cortical 5-HT 2A receptor levels in highand low-aggressive participants was found [128]. 5-HT 2A receptor binding was increased in the hippocampus [129] and diminished in cortical areas and basal ganglia [130] of subjects with borderline personality disorder (BPD) characterized by impulsive aggression. In contrast, Rosell and co-authors [131] demonstrated positive association of cortical 5-HT 2A receptor binding in physically aggressive BPD subjects. Positive correlation of prefrontal 5-HT 2A receptor binding with lifetime history of aggression was found in a postmortem study of suicide victims [132] The 5-HT 2A receptor is the primary site of the action of 5-HTergic hallucinogens, such as LSD, psilocybin, mescaline, currently recognized as fast acting antidepressants [133]. Depressive-like behavior was not affected in mice with global knockout of 5-HT 2A receptor [134]. However, in response to chronic corticosterone exposure, Htr2a −/− mice displayed a more pronounced anxiodepressive-like phenotype than wild-type mice [135].
Selective 5-HT 2A antagonists generate antidepressant-like effects, inhibiting 5-HT reuptake and modulating the release of other neurotransmitters in the prefrontal cortex [52,136,137]. Numerous open-label and placebo-controlled studies have suggested that some antidepressants and atypical antipsychotic drugs known to block 5-HT 2A receptors augment the clinical response to SSRIs in treatment-resistant patients [59,136].
Committed suicide depressive patients show increased expression of 5-HT 2A receptors in the prefrontal cortex and both lower expression and reduced 5-HT 2A receptor binding affinity in the hippocampus compared with matched controls [138]. In fact, results of studies on 5-HT 2A binding have been equivocal depending on the character of suicide, brain region and diagnosis, as reviewed by Stockmeier [139]. Deliberate self-harm patients had a significantly reduced 5-HT 2A frontal binding index. The reduction was more pronounced among self-injury patient than among self-poisoning patients [140]. In the recent study by Underwood and co-authors [141], the 5-HT 2A binding was greater in the prefrontal cortex of MDD suicides with alcoholism and childhood adversity. Evidence from direct in vivo functional imaging with either PET or Single-Photon Emission Computed Tomography demonstrated contradicting results with lower [142][143][144], unchanged [145,146] and higher [147] levels of 5-HT 2A binding in MDD patients.
Despite the huge amount of studies, the contribution of 5-HT 2A polymorphisms to depressive disorders in humans is not fully understood. The number of meta-analyses did not show any significant association between polymorphisms in the Htr2a gene and depressive disorders [148][149][150]. However, recent gene-based analysis does suggest an association of the Htr2a gene with antidepressant treatment response in depressed patients [151,152].
The majority of studies devoted to finding a link between 5-HT 2A receptor polymorphisms and suicidal risk failed to find any association [153][154][155][156][157]. At the same time, in a number of studies, an association between the Htr2a gene variants and suicidal behavior in subjects with stressful life events [158,159], such as sexual and physical child abuse, was found [160].

The 5-HT 2B Receptor in Aggressive and Depressive Behavior
It has been generally assumed that 5-HT 2B receptor dysfunction or deficiency resulted in increased impulsivity and aggression. High impulsivity was found in 5-HT 2B mutant (Htr2b −/− ) mice [161]. Among the QTLs underlying behaviors associated with intermale aggression in mice, the strongest candidate within the narrow QTL interval on chromosome 1 for both attack and latency variables is Htr2b gene [162].
Humans with specific 5-HT 2B receptor stop codon (Htr2b Q20*), that led to loss of receptor expression, are predisposed to severe impulsivity and aggressive behavior towards themselves and others [163][164][165]. Genomic-wide association studies and experiments on 5-HT knockout mice implicate the 5-HT 2B receptor as a major locus associated with cannabis-induced aggression both in mice and humans [166].
A lack of SSRI effects was observed in Htr2b −/− [167] and Htr2b 5-HTKO mice [112,168]. In contrast, agonist-induced stimulation of 5-HT 2B receptors mimicked behavioral and neurogenic SSRI actions [167]. Of interest was that non-stressed 5-HT 2B knockout mice displayed an antidepressant-like phenotype that was reversed to depressive-like after four weeks of social isolation [169]. There is much evidence that astroglial, rather than neuronal 5-HT 2B receptor expression changes are associated with depressive behaviors [111]. Recently it was found that down-regulation of astrocytic 5-HT 2B receptors may underlie depressivelike behavior induced by sleep deprivation, while restoration of receptor levels augments the antidepressant action [170]. Based on the existent literature data, we suggested a hypothetical mechanism of 5-HT 2B receptors implicated in the mechanisms of depression ( Figure 1).
Humans with specific 5-HT2B receptor stop codon (Htr2b Q20*), that led to loss of receptor expression, are predisposed to severe impulsivity and aggressive behavior towards themselves and others [163][164][165]. Genomic-wide association studies and experiments on 5-HT knockout mice implicate the 5-HT2B receptor as a major locus associated with cannabis-induced aggression both in mice and humans [166].
A lack of SSRI effects was observed in Htr2b −/− [167] and Htr2b 5-HTKO mice [112,168]. In contrast, agonist-induced stimulation of 5-HT2B receptors mimicked behavioral and neurogenic SSRI actions [167]. Of interest was that non-stressed 5-HT2B knockout mice displayed an antidepressant-like phenotype that was reversed to depressive-like after four weeks of social isolation [169]. There is much evidence that astroglial, rather than neuronal 5-HT2B receptor expression changes are associated with depressive behaviors [111]. Recently it was found that down-regulation of astrocytic 5-HT2B receptors may underlie depressive-like behavior induced by sleep deprivation, while restoration of receptor levels augments the antidepressant action [170]. Based on the existent literature data, we suggested a hypothetical mechanism of 5-HT2B receptors implicated in the mechanisms of depression ( Figure 1).   The role of 5-HT 2C receptors in aggressive behavior has long remained elusive due to the lack of selective ligands [9]. To our knowledge, the first evidence of the implication of 5-HT 2C receptors in aggressive behavior was obtained in our experiments on rats selected for many generations for high or low impulsive aggressiveness [171]. Significant difference between highly aggressive and nonaggressive rats in the expression and functional response of 5-HT 2C receptors was shown. The level of 5-HT 2C receptor mRNA in the frontal cortex and hippocampus and functional response to 5-HT 2C receptor agonist was lower in aggressive rats than in nonaggressive animals, suggesting an inhibitory role of 5-HT 2C receptors in genetically-defined aggressiveness.
There are a few currently available data in support of the antiaggressive role of 5-HT 2C receptors: (1) the activation of 5-HT 2C receptors enhanced the display of defeat submissive and defensive behavior in golden hamsters [172]. (2) 5-HT 2C receptor agonist/alpha 2 receptor antagonist S32212 suppressed aggressive behavior in mice [173]. (3) Mice expressing only the VGV isoform of 5-HT 2C receptors displayed a high level of conspecific aggression [174]. (4) The association between Htr2c gene polymorphism and criminal behavior in humans was demonstrated [175]. (5) Recently, a novel 5-HT 2C agonist, lorcaserin, has been demonstrated to have antiaggressive properties in human subjects with impulsive aggressive behavior. Lorcaserin attenuated provoked, but not unprovoked, aggression in impulsively aggressive individuals indicating that 5-HT 2C receptor may be a putative target for the treatment of impulsive aggressive behavior in human subjects [176].

5-HT 2C Receptor, Depressive Behavior and Suicide
Htr2c −/− mice do not exhibit depressive-like behavior in a TST paradigm [177]. However, 5-HT 2C knockout enhanced fluoxetine effects on immobility in the TST [177]. Recently, Demireva and co-authors demonstrated that 5-HT 2C receptor blockade led to augmentation of therapeutic antidepressant and anxiolytic effects of SSRIs [178]. Indeed, tricyclic antidepressants and SSRIs act as antagonists of 5-HT 2C receptors, and when administered chronically, can lead to 5-HT 2C receptor downregulation [179][180][181][182][183]. 5-HT 2C receptor antagonists not only possess antidepressant and anxiolytic properties in diverse rodent models [184], but are also introduced as antidepressant drugs in clinics. One of them, agomelatine, has long been registered for the treatment of MDD [185]. On the other hand, 5-HT 2C agonists also have antidepressant activity in various models of depressive-like behavior [186][187][188]. At least one of the explanations of paradoxical antidepressant-like effects of both agonists and antagonists of 5-HT 2C , as well as 5-HT 2A receptors, is an impact of the constitutive activity of these receptors [109,110]. Constitutive activity of 5-HT 2A and 5-HT 2C receptors is identified by receptor signaling in the absence of any ligand and it can change the response to drugs.
The sum of data indicates the opposite roles of 5-HT 2A/2C and 5-HT 2B receptors in the regulation of affective behavior. The 5-HT 2B receptors play an inhibitory role in both aggressive and depressive-like behavior, acting through direct modulation of serotonergic neurotransmission as well as astrocytic functions. Under stressful conditions, the 5-HT 2B receptors are downregulated, in contrast to 5-HT 2A and 5-HT 2C receptors that are upregulated and sensitized in response to stress. In turn, sensitized 5-HT 2A and 5-HT 2C receptors indirectly inhibit serotonergic neurotransmission and provoke depressive-like behavior ( Figure 2). At the same time, 5-HT 2A/2C receptors play an opposite role in the regulation of impulsivity. neurotransmission as well as astrocytic functions. Under stressful conditions, the 5-HT2 receptors are downregulated, in contrast to 5-HT2A and 5-HT2C receptors that are upregu lated and sensitized in response to stress. In turn, sensitized 5-HT2A and 5-HT2C receptor indirectly inhibit serotonergic neurotransmission and provoke depressive-like behavio (Figure 2). At the same time, 5-HT2A/2C receptors play an opposite role in the regulation o impulsivity.

The 5-HT 3 Receptor
The 5-HT 3 receptor is the only known exception among G-protein-coupled receptors in the 5-HT receptor family. Unlike all the others 5-HT receptors, the 5-HT 3 receptor is a ligand-gated ion channel. It belongs to the Cys-loop receptor family of pentametric neurotransmitter-gated ion channels permeable to Ca 2+ , Na + and K + , and plays a key role in fast synaptic transmission. The 5-HT 3 receptor expressing neurons are mainly GABA cells in the neocortex, olfactory cortex, hippocampus and amygdala [207]. It was suggested that the activation of 5-HT 3 receptors inhibits pyramidal neurons in the medial prefrontal cortex via GABAergic interneurons [208]. In addition, 5-HT 3 receptors control dopamine and acetylcholine release, and this interrelation can be an important mechanism the 5-HT 3 receptor ligands effects [60].
The most well established physiological roles of the 5-HT 3 receptor are to regulate gastrointestinal motility and coordinate emesis and vomiting [60,209]. Thus, 5-HT 3 agonists cause unpleasant effects of nausea, vomiting and anxiety, and have not been used clinically owing to their emetogenic and anxiogenic properties [210]. Additionally, it was shown that central 5-HT 3 receptors play an important role in thermoregulation [211,212].
Meanwhile, 5-HT 3 antagonists produced distinct antiemetic activity for chemotherapyinduced vomiting and different kinds of chronic neuropathic nausea and vomiting [213]. Antagonists of 5-HT 3 receptors do not modify any aspects of normal behavior in animals or induce pronounced changes in physiological functions in healthy subjects [213]. The efficacy was shown mainly in pathological models of behavior [214]. Positive anti-inflammatory and immunomodulatory effects of 5-HT 3 antagonists (seemingly related to substance P-mediated inflammation and hyperalgesia) have also been observed [210].
These data showed the implication of the 5-HT 3 receptor in the regulation of aggressiveness and suggested the 5-HT 3 receptor as a pro-aggressive factor [218,219]. However, this suggestion met some controversies: (1) isolation-induced aggressive behavior is accompanied by down-regulated hypothalamic 5-HT 3 protein level. (2) Intrahypothalamic infusion of ondansetron increased isolation-induced aggression, whereas 5-HT 3 receptor agonist SR57227A decreased aggression levels [220]; and 5-HT 3 antagonist zacopride failed to attenuate isolation-induced aggression [122]. It therefore seems that the antiaggressive effect of the 5-HT 3 receptor antagonists is dependent upon the phenotype. Tropisetron inhibited expression of aggression in an impulsive-aggressive phenotype High-Aggression group of golden hamsters, while enhancing aggressive behavior in Low-Aggressive animals [219]. The aggression-reducing effect of 5-HT 3 receptor antagonists was found in the offensive response of adolescent cocaine-treated hamsters [217] and alcohol heightened aggression [215]. Taken together these data show 5-HT 3 receptor antagonists to be a promising antiaggression substance, although this effect depends on the genetic background of the animal and on the kind of aggression in question.

The 5-HT 3 Receptor in Depression
Accumulated evidence that is well covered in comprehensive reviews [60,214,221,222] suggested 5-HT 3 receptor antagonists as possible antidepressant drug targets. Indeed, 5-HT 3 receptor antagonists inhibit the binding of 5-HT to postsynaptic 5-HT 3 receptors and increase their availability to other receptors like 5-HT 1A , 5-HT 1B and 5-HT 2A receptors, thereby producing an antidepressant effect [222]. Antidepressant-like effects of 5-HT 3 receptor antagonists ondansetron, zacopride, ICS 205-930 [181,223,224] and tropisetron [225] were demonstrated on mice and rats in various behavioral models of depression.

The 5-HT 3 Receptor in Suicidal Behavior
In contrast to numerous data demonstrating the link between the 5-HT 3 receptor, aggression and depression, investigations in to the involvement of the 5-HT 3 receptor in suicidal behavior are scarce. The few currently available studies give a reason to believe that 5-HT 3 receptors are not involved in the predisposition to suicide. In particular, no differences in number and affinity of 5-HT 3 receptors in the cortex of suicide victims were shown [226]. The data concerning 5-HT 3A and 5-HT 3B receptor polymorphisms also suggest that 5-HT 3 receptors may not play a major role in the susceptibility to suicidal behavior in schizophrenia patients [227].

The 5-HT 7 Receptor
The 5-HT 7 receptor is one of the most recently described G-protein-coupled 5-HT receptors. This receptor exhibits a high percentage of homology with the 5-HT 1A receptor and exerts its effects on neurons via the same second messenger as the 5-HT 1A receptor-adenylyl cyclase. However, the 5-HT 7 receptor activates adenylyl cyclase, whereas the 5-HT 1A receptor inhibits it.

The 5-HT 7 Receptor in Aggression
In contrast with very consistent lines of evidence that the 5-HT 7 receptor contributes to modulatory mechanisms of depression, efforts to evaluate the implication of the 5-HT 7 receptor in the control of aggressive behavior have been negative. To our knowledge, there are no studies establishing a link between the 5-HT 7 receptor and aggression. Administration of different doses of selective 5-HT 7 receptor antagonist SB269970 to mice did not produce any significant effect on isolation-induced aggressive behavior [228]. In our experiments (unpublished data), no effect on intermale aggression in mice was found of intracerebroventricularly administered 5-HT 7 receptor agonist, LP 44.
Remarkable coincidence of the effects of antidepressant treatment, 5-HT 7 knockout and pharmacological blockade of 5-HT 7 receptors indicates that 5-HT 7 receptor facilitates the mechanisms provoking depression and suggest that 5-HT 7 antagonists might have therapeutic value as novel antidepressant drugs [235,241,242]. Moreover, a novel antipsychotic drug lurasidone which is notable for high affinity for 5-HT 7 receptor is approved for the treatment of schizophrenia and patients with major depressive episodes associ-ated with bipolar depression in a number of countries including UK, USA, Canada and Australia [243].
Recently, a novel role of 5-HT 7 receptors in the functionality of the 5-HT system was revealed. The idea that G-protein-coupled receptors (GPCRs) can function as dimers is now generally accepted [244][245][246]. Moreover, a growing body of evidence points to the functional importance of oligomers for receptor trafficking, receptor activation and Gprotein coupling in native tissues [246]. The clinical significance of GPCR oligomerization has also become more evident during recent years, leading to identification of oligomeric complexes as novel therapeutic targets [247,248].
Convincing evidence indicating that G-protein-coupled 5-HT receptors can interact with each other forming protein-protein complexes has been obtained. It was found that 5-HT 1A receptors form heterodimers with 5-HT 7 receptors (5-HT 1A -5-HT 7 ) [249,250]. Functionally, heterodimerization inhibits the binding of 5-HT 1A receptors to the G i -protein, reducing the 5-HT 1A receptor-mediated potassium channel activation, and facilitates the internalization of 5-HT 1A receptors without affecting the 5-HT 7 receptor-mediated signaling [250]. Thus, the formation of the 5-HT 1A -5-HT 7 receptor complex enhances the desensitization of 5-HT 1A receptors with unchanged 5-HT 7 receptor functional activity. Although the evidence for the physiological significance of 5-HT 1A -5-HT 7 dimers has been obtained mainly from cell culture experiments, taking into account the acknowledged role of 5-HT 1A receptors in autoregulation of the brain 5-HT system, these data suggest 5-HT 7 receptors to be important regulators of 5-HT 1A activity.
The possible role of 5-HT 1A /5-HT 7 heterodimers in the development of pathophysiological processes in the central nervous system and in the effect of antidepressant treatment is of particular interest. We suggested that the higher sensitivity of presynaptic 5-HT 1A receptors to prolonged 5-HTstimulation compared to postsynaptic 5-HT 1A receptors is based on the larger density of 5-HT 1A /5-HT 7 heterodimers on the presynaptic membrane [251]. According to this hypothesis, the ratio of 5-HT 1A /5-HT 1A homodimers and 5-HT 1A /5-HT 7 heterodimers on pre-and postsynaptic terminals is not the same: 5-HT 1A /5-HT 7 heterodimeric complexes predominate on presynaptic terminals ( Figure 3). SSRIs increase the level of 5-HT in the synaptic cleft, which enhances the internalization of 5-HT 1A /5-HT 7 receptor complexes. This leads to inhibition of the 5-HT 1A autoreceptor activity resulting in the increase in 5-HT system functional activity. Therefore, the formation of the 5-HT 1A /5-HT 7 heterodimeric complex may play a significant role both in the development of depression and in the mechanism of its treatment. We also suggested that under depression, the ratio of 5-HT 1A /5-HT 1A homo-to 5-HT 1A /5-HT 7 heterodimers in presynaptic neurons may shift towards 5-HT 1A /5-HT 1A homodimers, leading to a delay in 5-HT 1A autoreceptor internalization following SSRI treatment which could result in antidepressant resistance. If this hypothesis is correct, then artificial increase in 5-HT 7 receptor expression in the raphe nuclei area should lead to a shift in the ratios of 5-HT 1A /5-HT 1A homodimers and 5-HT 1A /5-HT 7 heterodimers towards 5-HT 1A /5-HT 7 heterodimers, enhance 5-HT 1A autoreceptor internalization and thus result in an antidepressant effect. Recently we verified this hypothesis, and showed that 5-HT 7 receptor overexpression in the raphe nuclei area of the midbrain of both "nondepressive" C57Bl/6J mice and ASC mice with genetic predisposition to depressive-like behavior produced an antidepressant effect [252].
Meanwhile, despite comprehensive evidence on the implication of the 5-HT 7 receptor in mood disturbances and MDD, there is no data on its role in the mechanisms underlying suicidal behavior.

Discussion
Deepening acquaintance with functional characteristics and the nature of the participation of individual 5-HT receptors in the regulation of pathological behavior is important not only for our understanding of the mechanisms regulating pathological aggressiveness, depression, and suicide, but also for creating new, more effective antidepressant and antiaggressive pharmacological medicines. Over the past decade, a number of attempts have been made to enhance antidepressant effects by combining drugs that increase serotonergic activity. The combined drug approach is based on the utilization of different pathways enhancing 5-HT signaling-increased 5-HT synthesis, inhibited 5-HT reuptake and catabolism, and increased receptor activity-as well as on the implementation of specific receptor agonists, or blockade with antagonists.
A successful example of this novel approach is the unique multimodal 5-HTergic drug vortioxetine, which combines a 5-HT reuptake inhibitor activity with agonistic 5-HT1A receptor activity and antagonistic 5-HT3 and 5-HT7 receptor activity. Preclinical and clinical trials have shown high efficacy of vortioxetine in MDD [253][254][255]. Vortioxetine was the first antidepressant to demonstrate clinical efficacy in improving cognition regardless of the effect on affective symptomatology [256,257]. Another advantage of vortioxetine over currently utilized antidepressants is a favorable effect in elderly patients [258]. Despite a large number of studies supporting vortioxetine, its place among antide-

Discussion
Deepening acquaintance with functional characteristics and the nature of the participation of individual 5-HT receptors in the regulation of pathological behavior is important not only for our understanding of the mechanisms regulating pathological aggressiveness, depression, and suicide, but also for creating new, more effective antidepressant and antiaggressive pharmacological medicines. Over the past decade, a number of attempts have been made to enhance antidepressant effects by combining drugs that increase serotonergic activity. The combined drug approach is based on the utilization of different pathways enhancing 5-HT signaling-increased 5-HT synthesis, inhibited 5-HT reuptake and catabolism, and increased receptor activity-as well as on the implementation of specific receptor agonists, or blockade with antagonists.
A successful example of this novel approach is the unique multimodal 5-HTergic drug vortioxetine, which combines a 5-HT reuptake inhibitor activity with agonistic 5-HT 1A receptor activity and antagonistic 5-HT 3 and 5-HT 7 receptor activity. Preclinical and clinical trials have shown high efficacy of vortioxetine in MDD [253][254][255]. Vortioxetine was the first antidepressant to demonstrate clinical efficacy in improving cognition regardless of the effect on affective symptomatology [256,257]. Another advantage of vortioxetine over currently utilized antidepressants is a favorable effect in elderly patients [258]. Despite a large number of studies supporting vortioxetine, its place among antidepressants remains unclear due to the insufficient number of studies devoted to comparison with currently used antidepressants, primarily with the drugs from the SSRI group [259].
The similar effect of SSRIs and some 5-HT receptors on depressive and aggressive behavior, i.e., suppressive effect of 5-HT 1A receptors and facilitative 5-HT 3 receptors (in absence of a significant effect of the 5-HT 7 receptor on aggressiveness), suggests that vortioxetine should also have antiaggressive agent properties. Indeed, preliminary results support this assumption although so far obtained only for a very small number of patients [260].
Two main limitations of the multimodal drug approach are (1) potential danger of unwanted side-effects caused by increased action of a particular drug, e.g., hallucinogenic effects of 5-HT 2A receptor activation, emesis and vomiting produced by activation of 5-HT 3 receptors; (2) the danger of the Serotonin Syndrome (SS) development-toxic symptoms produced from too much 5-HT in the central and peripheral nervous system [261,262].
Nevertheless, the key role of 5-HT in the regulation of behavior and mechanisms underlying a wide range of neuro-and psychopathologies, on the one hand, and the polyfunctionality and diversity of 5-HT receptors on the other hand, open broad prospects for the creation of new effective combined 5-HTergic drugs. As an example, an antidepressant drug litoxetine was developed, combining SERT inhibition and 5-HT 3 antagonism to prevent SSRI-induced gastrointestinal side effects [263]. However, our growing knowledge of the role of 5-HT also highlights the necessity for a detailed investigation into the functional characteristics of all 5-HT receptor types as well as their cross-talk and roles in the regulation of numerous types of behavior.

Conclusions
Aggression, depression, and suicide are multifactorial behavioral conditions controlled by an ensemble of 5-HT receptor types exerting reciprocal suppressive or facilitative influence.
Currently, the brain 5-HT system is the main target for antidepressant drugs: almost all clinically effective antidepressants act via 5-HTergic neurons (the only exception being bupropion) [23]. Available 5-HT receptor density data suggest that the antidepressant effect of SSRIs is only observable when inhibitory and excitatory 5-HT receptors are balanced [25].
This review examines the evidence for the contribution of seven types of 5-HT receptors to the regulation of aggressive, depressive and suicidal behavior in an attempt to identify similarities and differences in the 5-HT receptor ensemble underlying these psychopathologies.
Comparison of aggressive and depressive behavior reveals significant similarities in the 5-HT receptors set and in the character of their modulating effect suggesting that impulsive violent aggressive behavior and depression share common genetic and epigenetic mechanisms. Along with 5-HT 1A , 5-HT 1B , and 5-HT 2B receptors, the activation of which produces antidepressant effects and suppresses (decreases) aggressiveness, 5-HT 3 receptor agonists enhance both aggressiveness and depressive-like behavior ( Table 1). The differences might be found in the effect of 5-HT 7 receptor agonists, which enhance depression and, apparently, do not play a significant role in the regulation of aggressive behavior.
Paradoxically, an antidepressant effect may be produced by both agonists and antagonists of 5-HT 1B , 5-HT 2A and 5-HT 2C receptors (Table 1), suggesting posttranslational modification due to the regional differences. Additionally, for these receptor subtypes, biased agonism was demonstrated. This phenomenon results in activation of different signal pathways depending on ligand [24,[264][265][266]. At the same time, for 5-HT 2C receptors, mRNA-editing resulting in the translation of various isoforms of receptor was shown [267][268][269]. These features could also explain the paradoxically antidepressant effect induced by both agonist and antagonist of these receptors. Moreover, this rather disappointing situation of combined effects may be associated with the constitutive features of these types of 5-HT receptors, which are active even in the absence of a ligand. This may determine the unusual response of 5-HT 2A / 2C receptors to antagonists [270]. Table 1. Summarized effects of 5-HT receptors on aggression and depression. Activating effect is shown by up arrow; suppressing effect is shown by down arrow; bidirectional effect is shown by double arrow; no effect is shown by straight line.

Receptor
Aggression Depression

5-HT 1A
Int. J. Mol. Sci. 2022, 23, 8814 Table 1. Summarized effects of 5-HT receptors on aggression and depression. Activa shown by up arrow; suppressing effect is shown by down arrow; bidirectional effect double arrow; no effect is shown by straight line.

5-HT7
Paradoxically, an antidepressant effect may be produced by both agonists nists of 5-HT1B, 5-HT2A and 5-HT2C receptors (Table 1), suggesting posttranslation tion due to the regional differences. Additionally, for these receptor subtypes, bias was demonstrated. This phenomenon results in activation of different signal pa pending on ligand [24,[264][265][266]. At the same time, for 5-HT2C receptors, mRNA-ed ing in the translation of various isoforms of receptor was shown [267][268][269]. Th could also explain the paradoxically antidepressant effect induced by both agonis onist of these receptors. Moreover, this rather disappointing situation of combined be associated with the constitutive features of these types of 5-HT receptors, whic even in the absence of a ligand. This may determine the unusual response of 5-H tors to antagonists [270].
The investigation of the individual roles of different 5-HT receptors in the m underlying suicide is complicated-not only by the great diversity of suicidal be cide ideation, suicidal attempt, completed suicide, depressive or violent suicid most importantly, by the lack of experimental animal model of suicide [72]. Neve available data indicate the involvement of at least some of the 5-HT receptors in nisms of suicide. This applies in particular to the main autoregulator of the brai tem-the 5-HT1A receptor. An increase in the 5-HT1A autoreceptor density in the r area of individuals who attempted suicide [66,73] and who committed suicide [74 Indeed, 5-HT1A receptors in the in raphe nuclei act as somatodendritic autorecep increase in their activity leads to a decrease in 5-HT signaling in the brain that is in ment with the prevailing ideas about the role of 5-HT deficiency in psychopath changes in 5-HT1A receptor density in the prefrontal cortex of suicide victims w [74]. However, a decrease in activity of cortical 5-HT1A receptor downstream effe cide victims was shown [77]. Recently, the association of suicide with the disruptio 5-HT1A receptor functioning in MDD patients was demonstrated [78]. Another 5likely to be involved in mechanisms underlying suicide is the 5-HT2A receptor. receptor level in the frontal cortex is reported to be increased in suicide victims the 5-HT2A receptor binding index in the frontal cortex of deliberate self-harm p decreased. An explanation of this discrepancy can be found in the study of And co-authors [142], who showed that the nature of changes in 5-HT2A receptors clos on the type of suicide-depressive or violent. Table 1. Summarized effects of 5-HT receptors on aggression and depression. Activating effect is shown by up arrow; suppressing effect is shown by down arrow; bidirectional effect is shown by double arrow; no effect is shown by straight line.

Receptor
Aggression Depression

5-HT7
Paradoxically, an antidepressant effect may be produced by both agonists and antagonists of 5-HT1B, 5-HT2A and 5-HT2C receptors (Table 1), suggesting posttranslational modification due to the regional differences. Additionally, for these receptor subtypes, biased agonism was demonstrated. This phenomenon results in activation of different signal pathways depending on ligand [24,[264][265][266]. At the same time, for 5-HT2C receptors, mRNA-editing resulting in the translation of various isoforms of receptor was shown [267][268][269]. These features could also explain the paradoxically antidepressant effect induced by both agonist and antagonist of these receptors. Moreover, this rather disappointing situation of combined effects may be associated with the constitutive features of these types of 5-HT receptors, which are active even in the absence of a ligand. This may determine the unusual response of 5-HT2A/2C receptors to antagonists [270].
The investigation of the individual roles of different 5-HT receptors in the mechanisms underlying suicide is complicated-not only by the great diversity of suicidal behavior (suicide ideation, suicidal attempt, completed suicide, depressive or violent suicide), but also, most importantly, by the lack of experimental animal model of suicide [72]. Nevertheless, the available data indicate the involvement of at least some of the 5-HT receptors in the mechanisms of suicide. This applies in particular to the main autoregulator of the brain 5-HT system-the 5-HT1A receptor. An increase in the 5-HT1A autoreceptor density in the raphe nuclei area of individuals who attempted suicide [66,73] and who committed suicide [74] was found. Indeed, 5-HT1A receptors in the in raphe nuclei act as somatodendritic autoreceptors, and an increase in their activity leads to a decrease in 5-HT signaling in the brain that is in good agreement with the prevailing ideas about the role of 5-HT deficiency in psychopathologies. No changes in 5-HT1A receptor density in the prefrontal cortex of suicide victims were revealed [74]. However, a decrease in activity of cortical 5-HT1A receptor downstream effectors in suicide victims was shown [77]. Recently, the association of suicide with the disruption of cortical 5-HT1A receptor functioning in MDD patients was demonstrated [78]. Another 5-HT receptor likely to be involved in mechanisms underlying suicide is the 5-HT2A receptor. The 5-HT2A receptor level in the frontal cortex is reported to be increased in suicide victims [21,141] but the 5-HT2A receptor binding index in the frontal cortex of deliberate self-harm patients was decreased. An explanation of this discrepancy can be found in the study of Andenaert with co-authors [142], who showed that the nature of changes in 5-HT2A receptors closely depends on the type of suicide-depressive or violent.

5-HT 1B
Int. J. Mol. Sci. 2022, 23, 8814 Table 1. Summarized effects of 5-HT receptors on aggression and depression. Activa shown by up arrow; suppressing effect is shown by down arrow; bidirectional effect double arrow; no effect is shown by straight line.

Receptor
Aggression Depression

5-HT7
Paradoxically, an antidepressant effect may be produced by both agonists nists of 5-HT1B, 5-HT2A and 5-HT2C receptors (Table 1), suggesting posttranslation tion due to the regional differences. Additionally, for these receptor subtypes, bias was demonstrated. This phenomenon results in activation of different signal p pending on ligand [24,[264][265][266]. At the same time, for 5-HT2C receptors, mRNA-ed ing in the translation of various isoforms of receptor was shown [267][268][269]. Th could also explain the paradoxically antidepressant effect induced by both agonis onist of these receptors. Moreover, this rather disappointing situation of combined be associated with the constitutive features of these types of 5-HT receptors, whi even in the absence of a ligand. This may determine the unusual response of 5-H tors to antagonists [270].
The investigation of the individual roles of different 5-HT receptors in the m underlying suicide is complicated-not only by the great diversity of suicidal be cide ideation, suicidal attempt, completed suicide, depressive or violent suicid most importantly, by the lack of experimental animal model of suicide [72]. Neve available data indicate the involvement of at least some of the 5-HT receptors in nisms of suicide. This applies in particular to the main autoregulator of the brai tem-the 5-HT1A receptor. An increase in the 5-HT1A autoreceptor density in the area of individuals who attempted suicide [66,73] and who committed suicide [74 Indeed, 5-HT1A receptors in the in raphe nuclei act as somatodendritic autorecep increase in their activity leads to a decrease in 5-HT signaling in the brain that is in ment with the prevailing ideas about the role of 5-HT deficiency in psychopath changes in 5-HT1A receptor density in the prefrontal cortex of suicide victims w [74]. However, a decrease in activity of cortical 5-HT1A receptor downstream effe cide victims was shown [77]. Recently, the association of suicide with the disruptio 5-HT1A receptor functioning in MDD patients was demonstrated [78]. Another 5likely to be involved in mechanisms underlying suicide is the 5-HT2A receptor. receptor level in the frontal cortex is reported to be increased in suicide victims the 5-HT2A receptor binding index in the frontal cortex of deliberate self-harm p decreased. An explanation of this discrepancy can be found in the study of And co-authors [142], who showed that the nature of changes in 5-HT2A receptors clos on the type of suicide-depressive or violent.  Table 1. Summarized effects of 5-HT receptors on a shown by up arrow; suppressing effect is shown by double arrow; no effect is shown by straight line.

5-HT7
Paradoxically, an antidepressant effect may nists of 5-HT1B, 5-HT2A and 5-HT2C receptors (Tabl tion due to the regional differences. Additionally, was demonstrated. This phenomenon results in pending on ligand [24,[264][265][266]. At the same time, ing in the translation of various isoforms of rece could also explain the paradoxically antidepressan onist of these receptors. Moreover, this rather disap be associated with the constitutive features of thes even in the absence of a ligand. This may determi tors to antagonists [270].
The investigation of the individual roles of d underlying suicide is complicated-not only by t cide ideation, suicidal attempt, completed suicid most importantly, by the lack of experimental anim available data indicate the involvement of at leas nisms of suicide. This applies in particular to the tem-the 5-HT1A receptor. An increase in the 5-HT area of individuals who attempted suicide [66,73] a Indeed, 5-HT1A receptors in the in raphe nuclei ac increase in their activity leads to a decrease in 5-HT ment with the prevailing ideas about the role of changes in 5-HT1A receptor density in the prefron [74]. However, a decrease in activity of cortical 5cide victims was shown [77]. Recently, the associat 5-HT1A receptor functioning in MDD patients was likely to be involved in mechanisms underlying receptor level in the frontal cortex is reported to the 5-HT2A receptor binding index in the frontal decreased. An explanation of this discrepancy ca co-authors [142], who showed that the nature of c on the type of suicide-depressive or violent.  Table 1. Summarized effects of 5-HT receptors on aggression and depression. Activating effect is shown by up arrow; suppressing effect is shown by down arrow; bidirectional effect is shown by double arrow; no effect is shown by straight line.

eceptor Aggression Depression
Paradoxically, an antidepressant effect may be produced by both agonists and antagonists of 5-HT1B, 5-HT2A and 5-HT2C receptors (Table 1), suggesting posttranslational modification due to the regional differences. Additionally, for these receptor subtypes, biased agonism was demonstrated. This phenomenon results in activation of different signal pathways depending on ligand [24,[264][265][266]. At the same time, for 5-HT2C receptors, mRNA-editing resulting in the translation of various isoforms of receptor was shown [267][268][269]. These features could also explain the paradoxically antidepressant effect induced by both agonist and antagonist of these receptors. Moreover, this rather disappointing situation of combined effects may be associated with the constitutive features of these types of 5-HT receptors, which are active even in the absence of a ligand. This may determine the unusual response of 5-HT2A/2C receptors to antagonists [270].
The investigation of the individual roles of different 5-HT receptors in the mechanisms underlying suicide is complicated-not only by the great diversity of suicidal behavior (suicide ideation, suicidal attempt, completed suicide, depressive or violent suicide), but also, most importantly, by the lack of experimental animal model of suicide [72]. Nevertheless, the available data indicate the involvement of at least some of the 5-HT receptors in the mechanisms of suicide. This applies in particular to the main autoregulator of the brain 5-HT system-the 5-HT1A receptor. An increase in the 5-HT1A autoreceptor density in the raphe nuclei area of individuals who attempted suicide [66,73] and who committed suicide [74] was found. Indeed, 5-HT1A receptors in the in raphe nuclei act as somatodendritic autoreceptors, and an increase in their activity leads to a decrease in 5-HT signaling in the brain that is in good agreement with the prevailing ideas about the role of 5-HT deficiency in psychopathologies. No changes in 5-HT1A receptor density in the prefrontal cortex of suicide victims were revealed [74]. However, a decrease in activity of cortical 5-HT1A receptor downstream effectors in suicide victims was shown [77]. Recently, the association of suicide with the disruption of cortical 5-HT1A receptor functioning in MDD patients was demonstrated [78]. Another 5-HT receptor likely to be involved in mechanisms underlying suicide is the 5-HT2A receptor. The 5-HT2A receptor level in the frontal cortex is reported to be increased in suicide victims [21,141] but the 5-HT2A receptor binding index in the frontal cortex of deliberate self-harm patients was decreased. An explanation of this discrepancy can be found in the study of Andenaert with co-authors [142], who showed that the nature of changes in 5-HT2A receptors closely depends on the type of suicide-depressive or violent.  Table 1. Summarized effects of 5-HT receptors on aggression and depression. Activating effect is shown by up arrow; suppressing effect is shown by down arrow; bidirectional effect is shown by double arrow; no effect is shown by straight line.

5-HT7
Paradoxically, an antidepressant effect may be produced by both agonists and antagonists of 5-HT1B, 5-HT2A and 5-HT2C receptors (Table 1), suggesting posttranslational modification due to the regional differences. Additionally, for these receptor subtypes, biased agonism was demonstrated. This phenomenon results in activation of different signal pathways depending on ligand [24,[264][265][266]. At the same time, for 5-HT2C receptors, mRNA-editing resulting in the translation of various isoforms of receptor was shown [267][268][269]. These features could also explain the paradoxically antidepressant effect induced by both agonist and antagonist of these receptors. Moreover, this rather disappointing situation of combined effects may be associated with the constitutive features of these types of 5-HT receptors, which are active even in the absence of a ligand. This may determine the unusual response of 5-HT2A/2C receptors to antagonists [270].
The investigation of the individual roles of different 5-HT receptors in the mechanisms underlying suicide is complicated-not only by the great diversity of suicidal behavior (suicide ideation, suicidal attempt, completed suicide, depressive or violent suicide), but also, most importantly, by the lack of experimental animal model of suicide [72]. Nevertheless, the available data indicate the involvement of at least some of the 5-HT receptors in the mechanisms of suicide. This applies in particular to the main autoregulator of the brain 5-HT system-the 5-HT1A receptor. An increase in the 5-HT1A autoreceptor density in the raphe nuclei area of individuals who attempted suicide [66,73] and who committed suicide [74] was found. Indeed, 5-HT1A receptors in the in raphe nuclei act as somatodendritic autoreceptors, and an increase in their activity leads to a decrease in 5-HT signaling in the brain that is in good agreement with the prevailing ideas about the role of 5-HT deficiency in psychopathologies. No changes in 5-HT1A receptor density in the prefrontal cortex of suicide victims were revealed [74]. However, a decrease in activity of cortical 5-HT1A receptor downstream effectors in suicide victims was shown [77]. Recently, the association of suicide with the disruption of cortical 5-HT1A receptor functioning in MDD patients was demonstrated [78]. Another 5-HT receptor likely to be involved in mechanisms underlying suicide is the 5-HT2A receptor. The 5-HT2A receptor level in the frontal cortex is reported to be increased in suicide victims [21,141] but the 5-HT2A receptor binding index in the frontal cortex of deliberate self-harm patients was decreased. An explanation of this discrepancy can be found in the study of Andenaert with co-authors [142], who showed that the nature of changes in 5-HT2A receptors closely depends on the type of suicide-depressive or violent.

5-HT 2B
Int. J. Mol. Sci. 2022, 23, 8814 Table 1. Summarized effects of 5-HT receptors on aggression and depression. Activa shown by up arrow; suppressing effect is shown by down arrow; bidirectional effect double arrow; no effect is shown by straight line.

Receptor
Aggression Depression

5-HT7
Paradoxically, an antidepressant effect may be produced by both agonists nists of 5-HT1B, 5-HT2A and 5-HT2C receptors (Table 1), suggesting posttranslation tion due to the regional differences. Additionally, for these receptor subtypes, bias was demonstrated. This phenomenon results in activation of different signal p pending on ligand [24,[264][265][266]. At the same time, for 5-HT2C receptors, mRNA-ed ing in the translation of various isoforms of receptor was shown [267][268][269]. Th could also explain the paradoxically antidepressant effect induced by both agonis onist of these receptors. Moreover, this rather disappointing situation of combined be associated with the constitutive features of these types of 5-HT receptors, whi even in the absence of a ligand. This may determine the unusual response of 5-H tors to antagonists [270].
The investigation of the individual roles of different 5-HT receptors in the m underlying suicide is complicated-not only by the great diversity of suicidal be cide ideation, suicidal attempt, completed suicide, depressive or violent suicid most importantly, by the lack of experimental animal model of suicide [72]. Neve available data indicate the involvement of at least some of the 5-HT receptors in nisms of suicide. This applies in particular to the main autoregulator of the brai tem-the 5-HT1A receptor. An increase in the 5-HT1A autoreceptor density in the area of individuals who attempted suicide [66,73] and who committed suicide [74 Indeed, receptors in the in raphe nuclei act as somatodendritic autorecep increase in their activity leads to a decrease in 5-HT signaling in the brain that is in ment with the prevailing ideas about the role of 5-HT deficiency in psychopath changes in 5-HT1A receptor density in the prefrontal cortex of suicide victims w [74]. However, a decrease in activity of cortical 5-HT1A receptor downstream effe cide victims was shown [77]. Recently, the association of suicide with the disruptio 5-HT1A receptor functioning in MDD patients was demonstrated [78]. Another 5likely to be involved in mechanisms underlying suicide is the 5-HT2A receptor. receptor level in the frontal cortex is reported to be increased in suicide victims the 5-HT2A receptor binding index in the frontal cortex of deliberate self-harm p decreased. An explanation of this discrepancy can be found in the study of And co-authors [142], who showed that the nature of changes in 5-HT2A receptors clos on the type of suicide-depressive or violent.  Table 1. Summarized effects of 5-HT receptors on a shown by up arrow; suppressing effect is shown by double arrow; no effect is shown by straight line.

5-HT7
Paradoxically, an antidepressant effect may nists of 5-HT1B, 5-HT2A and 5-HT2C receptors (Tabl tion due to the regional differences. Additionally, was demonstrated. This phenomenon results in pending on ligand [24,[264][265][266]. At the same time, ing in the translation of various isoforms of rece could also explain the paradoxically antidepressan onist of these receptors. Moreover, this rather disap be associated with the constitutive features of thes even in the absence of a ligand. This may determi tors to antagonists [270].
The investigation of the individual roles of d underlying suicide is complicated-not only by t cide ideation, suicidal attempt, completed suicid most importantly, by the lack of experimental anim available data indicate the involvement of at leas nisms of suicide. This applies in particular to the tem-the 5-HT1A receptor. An increase in the 5-HT area of individuals who attempted suicide [66,73] a Indeed, 5-HT1A receptors in the in raphe nuclei ac increase in their activity leads to a decrease in 5-HT ment with the prevailing ideas about the role of changes in  receptor density in the prefron [74]. However, a decrease in activity of cortical 5cide victims was shown [77]. Recently, the associat 5-HT1A receptor functioning in MDD patients was likely to be involved in mechanisms underlying receptor level in the frontal cortex is reported to the 5-HT2A receptor binding index in the frontal decreased. An explanation of this discrepancy ca co-authors [142], who showed that the nature of c on the type of suicide-depressive or violent.

5-HT 2C
Int. J. Mol. Sci. 2022, 23, 8814 Table 1. Summarized effects of 5-HT receptors on aggression and depression. Activa shown by up arrow; suppressing effect is shown by down arrow; bidirectional effect double arrow; no effect is shown by straight line.

Receptor
Aggression Depression

5-HT7
Paradoxically, an antidepressant effect may be produced by both agonists nists of 5-HT1B, 5-HT2A and 5-HT2C receptors (Table 1), suggesting posttranslation tion due to the regional differences. Additionally, for these receptor subtypes, bias was demonstrated. This phenomenon results in activation of different signal pa pending on ligand [24,[264][265][266]. At the same time, for 5-HT2C receptors, mRNA-ed ing in the translation of various isoforms of receptor was shown [267][268][269]. Th could also explain the paradoxically antidepressant effect induced by both agonis onist of these receptors. Moreover, this rather disappointing situation of combined be associated with the constitutive features of these types of 5-HT receptors, whic even in the absence of a ligand. This may determine the unusual response of 5-H tors to antagonists [270].
The investigation of the individual roles of different 5-HT receptors in the m underlying suicide is complicated-not only by the great diversity of suicidal be cide ideation, suicidal attempt, completed suicide, depressive or violent suicid most importantly, by the lack of experimental animal model of suicide [72]. Neve available data indicate the involvement of at least some of the 5-HT receptors in nisms of suicide. This applies in particular to the main autoregulator of the brai tem-the 5-HT1A receptor. An increase in the 5-HT1A autoreceptor density in the r area of individuals who attempted suicide [66,73] and who committed suicide [74 Indeed, receptors in the in raphe nuclei act as somatodendritic autorecep increase in their activity leads to a decrease in 5-HT signaling in the brain that is in ment with the prevailing ideas about the role of 5-HT deficiency in psychopath changes in 5-HT1A receptor density in the prefrontal cortex of suicide victims w [74]. However, a decrease in activity of cortical 5-HT1A receptor downstream effe cide victims was shown [77]. Recently, the association of suicide with the disruptio 5-HT1A receptor functioning in MDD patients was demonstrated [78]. Another 5likely to be involved in mechanisms underlying suicide is the 5-HT2A receptor. receptor level in the frontal cortex is reported to be increased in suicide victims the 5-HT2A receptor binding index in the frontal cortex of deliberate self-harm p  Table 1. Summarized effects of 5-HT receptors on aggression and depression. Activating effect is shown by up arrow; suppressing effect is shown by down arrow; bidirectional effect is shown by double arrow; no effect is shown by straight line.

5-HT7
Paradoxically, an antidepressant effect may be produced by both agonists and antagonists of 5-HT1B, 5-HT2A and 5-HT2C receptors (Table 1), suggesting posttranslational modification due to the regional differences. Additionally, for these receptor subtypes, biased agonism was demonstrated. This phenomenon results in activation of different signal pathways depending on ligand [24,[264][265][266]. At the same time, for 5-HT2C receptors, mRNA-editing resulting in the translation of various isoforms of receptor was shown [267][268][269]. These features could also explain the paradoxically antidepressant effect induced by both agonist and antagonist of these receptors. Moreover, this rather disappointing situation of combined effects may be associated with the constitutive features of these types of 5-HT receptors, which are active even in the absence of a ligand. This may determine the unusual response of 5-HT2A/2C receptors to antagonists [270].
The investigation of the individual roles of different 5-HT receptors in the mechanisms underlying suicide is complicated-not only by the great diversity of suicidal behavior (suicide ideation, suicidal attempt, completed suicide, depressive or violent suicide), but also, most importantly, by the lack of experimental animal model of suicide [72]. Nevertheless, the available data indicate the involvement of at least some of the 5-HT receptors in the mechanisms of suicide. This applies in particular to the main autoregulator of the brain 5-HT system-the 5-HT1A receptor. An increase in the 5-HT1A autoreceptor density in the raphe nuclei area of individuals who attempted suicide [66,73] and who committed suicide [74] was found. Indeed, 5-HT1A receptors in the in raphe nuclei act as somatodendritic autoreceptors, and an increase in their activity leads to a decrease in 5-HT signaling in the brain that is in good agreement with the prevailing ideas about the role of 5-HT deficiency in psychopathologies. No changes in 5-HT1A receptor density in the prefrontal cortex of suicide victims were revealed [74]. However, a decrease in activity of cortical 5-HT1A receptor downstream effectors in suicide victims was shown [77]. Recently, the association of suicide with the disruption of cortical 5-HT1A receptor functioning in MDD patients was demonstrated [78]. Another 5-HT receptor likely to be involved in mechanisms underlying suicide is the 5-HT2A receptor. The 5-HT2A receptor level in the frontal cortex is reported to be increased in suicide victims [21,141] but the 5-HT2A receptor binding index in the frontal cortex of deliberate self-harm patients was

5-HT 3
Int. J. Mol. Sci. 2022, 23, 8814 Table 1. Summarized effects of 5-HT receptors on aggression and depression. Activ shown by up arrow; suppressing effect is shown by down arrow; bidirectional effec double arrow; no effect is shown by straight line.

5-HT7
Paradoxically, an antidepressant effect may be produced by both agonists nists of 5-HT1B, 5-HT2A and 5-HT2C receptors (Table 1), suggesting posttranslation tion due to the regional differences. Additionally, for these receptor subtypes, bia was demonstrated. This phenomenon results in activation of different signal p pending on ligand [24,[264][265][266]. At the same time, for 5-HT2C receptors, mRNA-e ing in the translation of various isoforms of receptor was shown [267][268][269]. Th could also explain the paradoxically antidepressant effect induced by both agoni onist of these receptors. Moreover, this rather disappointing situation of combined be associated with the constitutive features of these types of 5-HT receptors, whi even in the absence of a ligand. This may determine the unusual response of 5-H tors to antagonists [270].
The investigation of the individual roles of different 5-HT receptors in the underlying suicide is complicated-not only by the great diversity of suicidal b cide ideation, suicidal attempt, completed suicide, depressive or violent suicid most importantly, by the lack of experimental animal model of suicide [72]. Nev available data indicate the involvement of at least some of the 5-HT receptors in nisms of suicide. This applies in particular to the main autoregulator of the bra tem-the 5-HT1A receptor. An increase in the 5-HT1A autoreceptor density in the area of individuals who attempted suicide [66,73] and who committed suicide [74 Indeed, 5-HT1A receptors in the in raphe nuclei act as somatodendritic autorecep increase in their activity leads to a decrease in 5-HT signaling in the brain that is in ment with the prevailing ideas about the role of 5-HT deficiency in psychopat changes in 5-HT1A receptor density in the prefrontal cortex of suicide victims w [74]. However, a decrease in activity of cortical 5-HT1A receptor downstream eff cide victims was shown [77]. Recently, the association of suicide with the disrupti 5-HT1A receptor functioning in MDD patients was demonstrated [78]. Another 5 likely to be involved in mechanisms underlying suicide is the 5-HT2A receptor receptor level in the frontal cortex is reported to be increased in suicide victims the 5-HT2A receptor binding index in the frontal cortex of deliberate self-harm decreased. An explanation of this discrepancy can be found in the study of An co-authors [142], who showed that the nature of changes in 5-HT2A receptors clos on the type of suicide-depressive or violent.  Table 1. Summarized effects of 5-HT receptors on aggression and depression. Activating effect is shown by up arrow; suppressing effect is shown by down arrow; bidirectional effect is shown by double arrow; no effect is shown by straight line.

5-HT7
Paradoxically, an antidepressant effect may be produced by both agonists and antagonists of 5-HT1B, 5-HT2A and 5-HT2C receptors (Table 1), suggesting posttranslational modification due to the regional differences. Additionally, for these receptor subtypes, biased agonism was demonstrated. This phenomenon results in activation of different signal pathways depending on ligand [24,[264][265][266]. At the same time, for 5-HT2C receptors, mRNA-editing resulting in the translation of various isoforms of receptor was shown [267][268][269]. These features could also explain the paradoxically antidepressant effect induced by both agonist and antagonist of these receptors. Moreover, this rather disappointing situation of combined effects may be associated with the constitutive features of these types of 5-HT receptors, which are active even in the absence of a ligand. This may determine the unusual response of 5-HT2A/2C receptors to antagonists [270].
The investigation of the individual roles of different 5-HT receptors in the mechanisms underlying suicide is complicated-not only by the great diversity of suicidal behavior (suicide ideation, suicidal attempt, completed suicide, depressive or violent suicide), but also, most importantly, by the lack of experimental animal model of suicide [72]. Nevertheless, the available data indicate the involvement of at least some of the 5-HT receptors in the mechanisms of suicide. This applies in particular to the main autoregulator of the brain 5-HT system-the 5-HT1A receptor. An increase in the 5-HT1A autoreceptor density in the raphe nuclei area of individuals who attempted suicide [66,73] and who committed suicide [74] was found. Indeed, 5-HT1A receptors in the in raphe nuclei act as somatodendritic autoreceptors, and an increase in their activity leads to a decrease in 5-HT signaling in the brain that is in good agreement with the prevailing ideas about the role of 5-HT deficiency in psychopathologies. No changes in 5-HT1A receptor density in the prefrontal cortex of suicide victims were revealed [74]. However, a decrease in activity of cortical 5-HT1A receptor downstream effectors in suicide victims was shown [77]. Recently, the association of suicide with the disruption of cortical 5-HT1A receptor functioning in MDD patients was demonstrated [78]. Another 5-HT receptor likely to be involved in mechanisms underlying suicide is the 5-HT2A receptor. The 5-HT2A receptor level in the frontal cortex is reported to be increased in suicide victims [21,141] but the 5-HT2A receptor binding index in the frontal cortex of deliberate self-harm patients was decreased. An explanation of this discrepancy can be found in the study of Andenaert with co-authors [142], who showed that the nature of changes in 5-HT2A receptors closely depends on the type of suicide-depressive or violent.

5-HT 7
Int. J. Mol. Sci. 2022, 23, 8814 Table 1. Summarized effects of 5-HT receptors on aggression and depression. Activ shown by up arrow; suppressing effect is shown by down arrow; bidirectional effe double arrow; no effect is shown by straight line.

Receptor
Aggression Depression

5-HT7
Paradoxically, an antidepressant effect may be produced by both agonist nists of 5-HT1B, 5-HT2A and 5-HT2C receptors (Table 1), suggesting posttranslatio tion due to the regional differences. Additionally, for these receptor subtypes, bi was demonstrated. This phenomenon results in activation of different signal pending on ligand [24,[264][265][266]. At the same time, for 5-HT2C receptors, mRNA-e ing in the translation of various isoforms of receptor was shown [267][268][269]. T could also explain the paradoxically antidepressant effect induced by both agon onist of these receptors. Moreover, this rather disappointing situation of combine be associated with the constitutive features of these types of 5-HT receptors, wh even in the absence of a ligand. This may determine the unusual response of 5-H tors to antagonists [270].
The investigation of the individual roles of different 5-HT receptors in the underlying suicide is complicated-not only by the great diversity of suicidal b cide ideation, suicidal attempt, completed suicide, depressive or violent suici most importantly, by the lack of experimental animal model of suicide [72]. Nev available data indicate the involvement of at least some of the 5-HT receptors nisms of suicide. This applies in particular to the main autoregulator of the br tem-the 5-HT1A receptor. An increase in the 5-HT1A autoreceptor density in the area of individuals who attempted suicide [66,73] and who committed suicide [7 Indeed, 5-HT1A receptors in the in raphe nuclei act as somatodendritic autorece increase in their activity leads to a decrease in 5-HT signaling in the brain that is i ment with the prevailing ideas about the role of 5-HT deficiency in psychopa changes in 5-HT1A receptor density in the prefrontal cortex of suicide victims w [74]. However, a decrease in activity of cortical 5-HT1A receptor downstream ef cide victims was shown [77]. Recently, the association of suicide with the disrupt 5-HT1A receptor functioning in MDD patients was demonstrated [78]. Another 5 likely to be involved in mechanisms underlying suicide is the 5-HT2A recepto receptor level in the frontal cortex is reported to be increased in suicide victim the 5-HT2A receptor binding index in the frontal cortex of deliberate self-harm decreased. An explanation of this discrepancy can be found in the study of An co-authors [142], who showed that the nature of changes in 5-HT2A receptors clo on the type of suicide-depressive or violent.  Table 1. Summarized effects of 5-HT receptors on ag shown by up arrow; suppressing effect is shown by double arrow; no effect is shown by straight line.

5-HT7
Paradoxically, an antidepressant effect may nists of 5-HT1B, 5-HT2A and 5-HT2C receptors (Tabl tion due to the regional differences. Additionally, f was demonstrated. This phenomenon results in a pending on ligand [24,[264][265][266]. At the same time, ing in the translation of various isoforms of rece could also explain the paradoxically antidepressan onist of these receptors. Moreover, this rather disap be associated with the constitutive features of thes even in the absence of a ligand. This may determin tors to antagonists [270].
The investigation of the individual roles of d underlying suicide is complicated-not only by th cide ideation, suicidal attempt, completed suicid most importantly, by the lack of experimental anim available data indicate the involvement of at least nisms of suicide. This applies in particular to the tem-the 5-HT1A receptor. An increase in the 5-HT area of individuals who attempted suicide [66,73] a Indeed, 5-HT1A receptors in the in raphe nuclei ac increase in their activity leads to a decrease in 5-HT ment with the prevailing ideas about the role of changes in 5-HT1A receptor density in the prefron [74]. However, a decrease in activity of cortical 5- The investigation of the individual roles of different 5-HT receptors in the mechanisms underlying suicide is complicated-not only by the great diversity of suicidal behavior (suicide ideation, suicidal attempt, completed suicide, depressive or violent suicide), but also, most importantly, by the lack of experimental animal model of suicide [72]. Nevertheless, the available data indicate the involvement of at least some of the 5-HT receptors in the mechanisms of suicide. This applies in particular to the main autoregulator of the brain 5-HT system-the 5-HT 1A receptor. An increase in the 5-HT 1A autoreceptor density in the raphe nuclei area of individuals who attempted suicide [66,73] and who committed suicide [74] was found. Indeed, 5-HT 1A receptors in the in raphe nuclei act as somatodendritic autoreceptors, and an increase in their activity leads to a decrease in 5-HT signaling in the brain that is in good agreement with the prevailing ideas about the role of 5-HT deficiency in psychopathologies. No changes in 5-HT 1A receptor density in the prefrontal cortex of suicide victims were revealed [74]. However, a decrease in activity of cortical 5-HT 1A receptor downstream effectors in suicide victims was shown [77]. Recently, the association of suicide with the disruption of cortical 5-HT 1A receptor functioning in MDD patients was demonstrated [78]. Another 5-HT receptor likely to be involved in mechanisms underlying suicide is the 5-HT 2A receptor. The 5-HT 2A receptor level in the frontal cortex is reported to be increased in suicide victims [21,141] but the 5-HT 2A receptor binding index in the frontal cortex of deliberate self-harm patients was decreased. An explanation of this discrepancy can be found in the study of Andenaert with co-authors [142], who showed that the nature of changes in 5-HT 2A receptors closely depends on the type of suicide-depressive or violent.

Conflicts of Interest:
The authors declare no conflict of interest.