Open access peer-reviewed chapter

Association of 5-HT1A Receptors with Affective Disorders

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Cesar Soria-Fregozo, Maria Isabel Perez-Vega, Juan Francisco Rodríguez-Landa, León Jesús Germán-Ponciano, Rosa Isela García- Ríos and Armando Mora-Perez

Submitted: 14 October 2016 Reviewed: 04 April 2017 Published: 26 July 2017

DOI: 10.5772/intechopen.68975

From the Edited Volume

Serotonin - A Chemical Messenger Between All Types of Living Cells

Edited by Kaneez Fatima Shad

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Abstract

Serotonin or 5-hydroxytryptamine (5-HT) is synthesized in both the brain and peripheral system, which exert their actions at a wide family of receptors classified as 5-HT1 to 5-HT7. Pharmacological, behavioral, and clinical studies involve particularly to the 5-HT1A receptors (5-HT1A-R) - auto-receptors (presynaptic) and heteroreceptors (postsynaptic) - in the control of motivated behavior, and consequently in the physiopathology of affective disorders and in the action mechanism of antidepressant drugs. In this way, some research support that 5-HT1A-R participates in the delayed effect of different types of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), and tricyclic drugs, principally. The therapeutic effect of serotonergic drugs as the SSRIs, starting with the binding to auto-receptors, which produces increases of 5-HT in the synaptic cleft as consequence of blockade of serotonin reuptake. While these molecular events occur initially, in the long-term are produced plastic changes at neuronal level, as well as down-regulation of the 5-HT1A-R, which is associated with the therapeutic effects of antidepressant drugs. The purpose of this chapter is to analyze and discuss the current information about of 5-HT1A-R-mediated signaling cascades, the intracellular signaling of 5-HT1A-R, in addition to their expression and pharmacology that are important to treatment of affective disorders symptoms.

Keywords

  • 5-HT1A receptors
  • affective disorders serotonin

1. Introduction

5-Hydroxytryptamine (5-HT) regulates many important physiological processes, including body temperature, sleep, appetite, pain, motor activity, and affective disorders. One type of 5-HTergic functions is performed by the release of 5-HT into targeted areas and its action via at least 16 different pre-and postsynaptic 5-HT receptor (5-HTR) [1]. 5-HTRs are subdivided into seven groups—from 5-HT1-R to 5-HT7-R—according to their distribution, molecular structure, cell response, and function. Except for the 5-HT3-Rs, which are ligand-gated ion channels, all other 5-HTR are G-protein-coupled receptors that influence different transduction pathways (Table 1). 5-HT1A-R auto-receptors located on the soma of 5-HTergic neurons are key components of the negative feedback loop that inhibits neuronal signaling and 5-HT release [2], while 5-HT1A-R heteroreceptors located on postsynaptic 5-HTergic and non-5-HTergic neurons [3, 4], particularly those in the limbic system, are involved in emotional states.

Receptor familySubtypeMechanismCellular response
5-HT11A, 1B, 1D, 1E, 1FAdenylate cyclaseInhibitory
5-HT22A, 2B, 2CPhospholipase CExcitatory
5-HT33A, 3B, 3CLigand-gated ion channelExcitatory
5-HT454Adenylate cyclaseExcitatory
5-HT55A, 5BAdenylate cyclaseInhibitory
5-HT656Adenylate cyclaseExcitatory
5-HT7Adenylate cyclaseExcitatory

Table 1.

Classification and mechanism of the 5-HT receptor.

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2. Distribution and ontogeny of the 5-HT1A-R

The 5-HT can interact with different types of receptors, whose effect depends on the activation of different subtypes and location of these [1, 3] (Table 1). In this sense, the use of such techniques as ligand binding, immunohistochemistry, and hybridization in situ in the brains of the rat, mouse, cat, and human has reported significant levels of 5-HT1A-R in almost all regions of the brain [59]. A study performed in cats used positron emission tomography (PET) and 2′-methoxyphenyl-(N-2′-pyridinyl)-p-fluoro-benzamidoethyipiperazin marked with fluorine (MPPF [18F]) in combination with in vitro autoradiography with [3H] MPPF, 8-hydroxy-2-(di-n-propylamino)tetralin ([3H] 8-OH-DPAT) and [3H] paroxetine, to visualize the distribution of the 5-HT1A-R. These showed high levels of expression in the hippocampus, cingulate, septum, infralimbic cortex, and raphe nuclei, with low levels being detected in the cerebellum [9]. However, studies with PET using [11C] WAY-100635 reported some regional heterogeneity of the 5-HT1A-R in the human cerebellum [10]. The absence of 5-HT1A-R expression was observed in the cerebellar white matter, while the other regions displayed detectable levels of this receptor. On the other hand, studies of the cellular distribution of this receptor and its messenger ribonucleic acid (mRNA) have reported that approximately 60% of all glutamatergic cells express the transcript 5-HT1A-R, and about 25% of cells that express the enzyme glutamate decarboxylase (GAD) contain mRNA for 5-HT1A-R [5]. In addition, studies using immunohistochemistry, in vitro autoradiography with [3H] 8-OH-DPAT, and in situ hybridization have reported mRNA and protein expression for the 5-HT1A-R in the pyramidal neurons of layer 2 of the prefrontal, insular, and occipital cortex [9], but labeling with [3 H] 8-OH-DPAT is only detected the layers 1 and 2 of the prefrontal and occipital cortex and in the pyramidal neurons of the cloister and the anterior olfactory nucleus. Neurons of the hippocampal CA1 region expressed the mRNA of the 5-HT1A-R, and [3H] 8-OH-DPAT labeling was observed in the stratum oriens and stratum radiatum. Low receptor expression was observed in CA3 pyramidal neurons, but the granule neurons in the dentate gyrus contained moderate concentrations of this receptor.

Turning now to the ontogeny of the 5-HT1A-R, immunohistochemistry has shown that almost all neurons of the hippocampus begin to express the 5-HT1A-R at the end of mitosis [11]. It is well known that at day 5 of postnatal age (P5), this receptor is expressed mainly in the cell bodies, while at day P10 it appears in the cell bodies and proximal apical dendrites. At the end of neuronal maturation (P21), a relatively scarce distribution is seen in the dendrites of the stratum radiatum and oriens of the hippocampus. During the early postnatal development of the hippocampus, glial cells that are positive to S100 (protein saturated ammonium sulfate soluble) and glial fibrillary acidic protein (GFAP) temporarily express the 5-HT1A-R and more than 90% of astrocytes that are positive to S100 in CA1, CA3, and the dentate gyrus also show moderate immunoreactivity to the 5-HT1A-R in P7, though this decreases sharply in P16. Although the specific distribution of the 5-HT1A-R has been studied in different brain regions, this does not ensure that receptor signaling activity will always be proportional to the levels of receptor expression. 5-HT1A-R signaling in neurons is important for functionality, and this intracellular effect is regulated by the coupling of second messengers.

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3. Presynaptic and postsynaptic 5-HT1A-R and their signaling effects

The main electrophysiological response to the activation of the 5-HT1A-R in neurons is mediated by the hyperpolarization of K+ channels [12, 13], which attenuates the propagation of action potentials, causing a consequent decrease in the release of the neurotransmitter. The hyperpolarizing effect is observed in both pre- and postsynaptic terminals; however, the desensitization profiles of those receptors and molecules activated in the pre- and postsynaptic terminals seem to differ. One of the mechanisms that cause desensitization of G-protein-coupled receptors is internalization, and studies have demonstrated the internalization (i.e., transfer of the plasmatic membrane in the cytoplasm) of the 5-HT1A auto-receptors in the dorsal raphe nucleus (DRN) of rats after acute treatment with the specific 8-OH-DPAT agonist to the 5-HT1A-R, or with recapture inhibitors of the 5-HT (selective inhibitors of serotonin reuptake, SSRIs). Although this phenomenon has not been observed in the hippocampus, we know that in this structure the 5-HT1A-Rs are located in the soma and dendrites of neurons (heteroreceptors) [14]. The SSRIs in the presynaptic terminals, in turn, increase the release of 5-HT, which binds to the 5-HT1A-R auto-receptors present in the soma of the raphe neurons, thus inhibiting neuronal firing. Subsequently, these auto-receptors are internalized, causing the end of 5-HT1A-R signaling in the presynaptic neurons, and again at onset of the 5-HT release of the rape neurons in the synapse with the dendritic terminals of the postsynaptic neurons. In the absence of the 5-HT1A auto-receptors, the 5HT released binds only to the postsynaptic 5-HT1A-R, thereby eliciting the anxiolytic effect of the SSRIs [15]. On the other hand, agonists to 5-HT1A-R, such as buspirone or flesinoxan, show an antidepressant effect, probably due to the desensitization of the 5-HT1A auto-receptors [16, 17]. Thus, the acute agonist treatment has its effect due to interaction with the auto-receptors present in the soma of the raphe neurons. The hyperpolarizing effect of the activation of this auto-receptor inhibits the release of 5-HT in the presynaptic terminal. It has been reported that under this treatment, the free or excess agonist can activate the postsynaptic (dendritic) 5-HT1A-R, resulting in the inhibition of postsynaptic neurons. Thus, an overstimulation of the receptor by an agonist causes desensitization and internalization of the 5-HT1A-R in raphe neurons, but not in postsynaptic neurons. The absence of 5-HT1A auto-receptors in the presynaptic raphe terminal facilitates neural firing by blocking inhibition by 5-HT, which is attached to the 5-HT1A-R in the postsynaptic neurons and causes the anxiolytic effect.

The activation of both pre- and postsynaptic 5-HT1A-R and their subsequent signaling seems to differ in at least one biochemical pathway. It has been shown that HN2-5 cells derived from neurons in the hippocampus, as well as in organotypic cultures of slices of the hippocampus, which are agonists to the 5-HT1A-R, stimulate the protein kinase pathway activated by mitogen (MAPK) [18]. However, in the raphe-derived cell line RN46A, activation of this receptor by agonists inhibits the basal activity of the MAPK pathway [19]. Nonetheless, it has been reported that activation of the 5-HT1A-R located both pre- and postsynaptically with the agonist inhibits intracellular cyclic adenosine monophosphate (cAMP) [20]. There are also reports that activation of 5-HT1A-R in a postsynaptic neuron-derived cell line and in non-neuronal cells promotes synthesis of phospholipase C (PLC), but this response has not been reported in presynaptic (serotonergic) or raphe-derived neurons [20, 21].

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4. Aberrant 5-HT1A-R expression, anxiety and depression disorders

In recent decades, such psychiatric disorders as anxiety (mainly generalized anxiety) and depression (mainly severe) have increased in prevalence and are now responsible for 3.12 and 6.86%, respectively, of years lived with disability (YLDs), according to estimates by the Global Burden of Diseases in 2015. Anxiety is a normal human emotion that allows us to respond to everyday stress situations, where the stressor—work, for example—can be identified. However, anxiety becomes a disorder when it no longer allows the individual to remain functional in her/his daily activities and when no trigger can be identified [22]. Both anxiety and depression have been attributed to a varied etiology that includes the person’s social, economic, family, employment and academic condition, combined with the persistence of an inherent biological factor. In this sense, the findings of clinical and preclinical studies have identified a dysfunctionality of the serotonergic system associated with low availability of L-tryptophan (a precursor of 5-HT), low concentrations of 5-hydroxyindoleacetic acid (5-HIIA)—the main metabolite of 5-HT in the cerebrospinal fluid—a reduction in the synthesis, release, recapture, and metabolism of 5-HT, a decrease in the density of 5-HT1A-R pre- and postsynaptic, low neural activity in brain areas involved in regulating the emotions (such as the septum and prefrontal cortex), factors that increase the propensity (serotoninergic vulnerability) to suffer mood disorders like anxiety and depression. This is reinforced by the fact that serotonergic antidepressant treatments are prescribed to reverse these types of alterations [2325]. In addition, functional brain imaging and postmortem studies of the limbic structures of depressed patients—which are responsible for integrating the emotions, and include the striatum, amygdala, and frontal cortex—have reported a low capacity for recapture 5-HT coupled with a decrease in the expression of 5-HT (5-HTT) transporters, which are responsible for recapturing the unused 5-HT in the 5-HT synapse and so regulate the magnitude and duration of serotoninergic neurotransmission [26]. Alterations of this kind in the 5-HTT have also been detected in patients with major depression using PET, which reveals a low capacity for 5-HT recapture in the thalamus, an area involved in controlling cortical excitability that contributes to establishing anxiety in patients so affected [27].

In addition, the involvement of deregulation of pre- and postsynaptic 5-HT1A-R in anxiety and depression is widely known, since it has been observed in patients with panic disorder by PET studies. There, reports indicate a reduction in the availability of both pre- and postsynaptic 5-HT1A-R in brain areas that regulate cognitive and emotional responses, such as the raphe, the orbitofrontal cortex, the temporal cortex, and the amygdala [28]. In support of this, preclinical studies have reported that knockout mice for 5-HT1A-R present an anxious phenotype that includes observations of such behaviors as a decrease of thigmotaxis (i.e., exploratory activity in central areas of an open field), increased fear in aversive environments, increased reactivity to stress, autonomic activation, and neuroendocrine alterations in models of experimental anxiety using the open-field, elevated-zero maze, and novel-object tests. However, an antidepressant-like effect has been observed in the tail suspension model of experimental depression, more markedly in females than in males. This is not associated with morphological abnormalities in brain tissues or changes in cell bodies or 5-HTergic fibers, nor is there evidence of changes in brain levels of 5-HT and 5-HIIA in the striatum, dorsal raphe, or frontal cortex [29, 30], though there is an increase in the turnover of 5-HT [31] and the firing of 5-HTergic neurons [32] in knockout mice to 5-HT1A-R. However, the possibility of such long-term changes cannot be discarded [33]. This situation can be interpreted as a disinhibition of 5-HTergic neuronal activity that increases the release of 5-HT in limbic areas, causing the establishment of anxiety through its interaction with other receptor subtypes, but without modifying levels of 5-HT or its metabolite, since the amount of stored 5-HT greatly exceeds the extracellular 5-HT content.

In support of this, differences in the function of the pre- and postsynaptic 5-HT1A-R in different brain areas seem to be decisive in establishing anxiety and depression, given that stimulation of the postsynaptic 5-HT1A-R in the dorsal hippocampus and amygdala produces anxiogenic effects, while anxiolytic effects are seen in areas such as the middle and dorsal raphe (where the 5-HT1A auto-receptors are located) [3335]. In contrast, stimulation of the presynaptic receptors produces anxiolytic effects by suppressing 5-HTergic neuronal activity with the resulting decrease of 5-HT in axonal terminals of limbic areas [36]. These findings suggest that there are differences in the role played by pre- and postsynaptic 5-HT1A-R receptors in regulating emotions. This may be reflected in the fact that acute administration of antidepressants causes a reduction in neural activity due to the immediate stimulation of the 5-HT1A auto-receptors, while chronic antidepressant treatments cause desensitization and, consequently, the downregulation of the 5-HT1A auto-receptors, though with no changes in postsynaptic 5-HT1A-R. This leads to the recovery of 5-HTergic neuronal activity, which matches the long latency to the onset of the therapeutic effects of SSRIs antidepressants.

It is important to note that mice require proper 5-HTergic signaling through 5-HT1A-R stimulation of the prosencephalon during the early postnatal period as this produces lasting chemical and structural changes in the brain that are essential for effective response behaviors in the face of normal anxiety during adulthood [37]. Thus, clinically effective antidepressant or anti-anxiety treatments must stimulate the 5-HT1A auto-receptors with direct agonists (such as buspirone) or indirect agonists like fluoxetine to obtain therapeutic efficacy. This suggests that in both the developmental and adult stage efficient activation of the 5-HT1A auto-receptors can produce changes that decrease expressions of pathological anxiety.

Donaldson et al. [38] reported that a decrease in the 5-HT1A auto-receptors in the 21st postnatal leads to increased long-term anxiety levels but does not modify depressive behaviors. In this regard, lifelong abolition of the 5-HT1A auto-receptors suffices to increase anxiety behaviors in adult mice [39], though without necessarily affecting depressive-like behaviors in the forced swimming test [40]. Based on these results, it has been suggested that 5-HT1A auto-receptors are involved in establishing anxious and depressive phenotypes, while the heteroreceptor is implicated in the depressive phenotype observed in experimental tests of depression [40]. Moreover, Albert and François [41] suggest that a reduction in the activity of postsynaptic receptors is involved in anxiety and that an increase in the transcription of 5-HT1A auto-receptors is associated with both depression and resistance to chronic treatment with SSIR drugs [41]. Hence, the reduced expression of the auto-receptors with no modification of postsynaptic 5-HT1A-R expression is enough to produce depression-like behaviors in mice [42].

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5. Therapeutic agents that function by regulating 5-HT1A-R signaling

5-HT1A-R is involved in the pathology and treatment of mental disorders, such as anxiety and depression [23, 43, 44]. Several studies have suggested that the 5-HT1A-Rs are potential targets for these psychiatric disorders [4549]. In this regard, agonists (total and partial) to the 5-HT1A-R have shown antidepressant and anxiolytic properties and have been employed as adjunct treatments to improve the therapeutic action of several antidepressant and anxiolytic drugs in several preclinical and clinical studies [5053]. They offer a different pharmacological mechanism from that of the monoamine oxidase inhibitors (IMAO), tricyclic drugs, SSIRs, and other antidepressants.

Buspirone is perhaps the most widely studied partial 5-HT1A-R agonist. It belongs to the chemical class of the azapirones [54, 55] and has been used primarily due to its anxiolytic effects and absence of side effects such as sedation and dependence that are often associated with benzodiazepines [56]. It is also utilized to treat patients who are resistant to the SSRIS, due to its capacity to stimulate the release of catecholamines [57]. In this regard, a clinical trial carried out with ambulatory patients diagnosed with generalized anxiety disorder (GAD) found that after weeks 3 and 4, buspirone showed efficacy in relieving patients’ symptoms with a therapeutic effect comparable to that of lorazepam. Also, after discontinuing this therapy, the individuals treated with buspirone showed no withdrawal symptoms, while those medicated with lorazepam saw their symptoms worsen in week 9 after ceasing treatment [58]. Similarly, buspirone (15 mg/day) prescribed for 4 weeks to ambulatory patients with GAD produced a significant reduction of anxiety symptoms compared to alprazolam. Moreover, the patients treated with buspirone experienced fewer adverse effects and symptoms of abstinence than those who received alprazolam [59]. The anxiolytic properties of buspirone have been confirmed in animal models. For example, in a study conducted with Swiss Albino mice that received buspirone at 2.5 and 5 mg/kg, i.p., the drug significantly increased the number of step-through by 46 and 61%, respectively [60]. This demonstrates that buspirone is effective in treating anxiety disorders without causing adverse effects or signs of benzodiazepine dependence.

Gepirone is another component of the class of the azapirones that has shown antidepressant properties [61] due to its partial 5-HT1A-R antagonism, which improves 5-HTergic activity [62]. The structure of this azapirone is similar to that of buspirone, and it has similar anxiolytic properties that have been identified in clinical studies [63, 64]. But it also has antidepressant action. In a study of patients with major depressive disorder (DDM), prolonged-release gepirone (60–80 mg/day) administered for 3 weeks produced a significant reduction in total HAM-D17 scores (Hamilton Depression Scale) compared to a placebo group, thus improving the symptomatology of patients [65]. Similarly, gepirone (40–80 mg/day) prescribed for 8 weeks improved the sexual function of male patients diagnosed with DDM, in addition to its antidepressant action [66].

Tandospirone is a partial 5-HT1A-R agonist that has been shown to have antidepressant effects. In a study with male Sprague-Dawley rats, chronic treatment (28 days) with tandospirone at 10 mg/kg inhibited changes induced by psychosocial stress in the neurogenesis of the dorsal and ventral hippocampus, thus producing a type of antidepressant effect. It has been suggested that chronic administration of tandospirone desensitizes the 5-HT1A-R in the raphe. This decreases self-inhibition mediated by the somatodendritic receptor and, consequently, increases the firing rate and release of 5-HT [67].

Brexpiprazole is a second-generation antipsychotic that exerts partial antagonism to the 5-HT1A-R and D2. A study in adults diagnosed with DDM, but inadequate responses to antidepressants, showed that brexpiprazole as an adjunct therapy improved patients’ symptoms. In that research, a series of drugs—escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, and venlafaxine—all significantly improved scores on the Clinical Global Impressions Scale (CGI-I scale), Zung Self-Rating Depression Scale (SDS), and HAM-D17 scale when administered jointly with brexpiprazole (2 mg) for 6 weeks. Improvement was remarkable from the first week of treatment [68]. Finally, flesinoxan is a phenylpiperazine derivative initially developed as an antihypertensive [69]. This drug has total antagonism to 5-HT1A-R with high affinity [70]. Various studies have demonstrated its antidepressant properties, particularly in treatment-resistant DDM patients [71]. For example, in a double-blind, placebo-controlled and fixed-dose study of treatment-resistant DDM patients, flesinoxan (1.2 mg/day) administered for 6 weeks improved scores on the HAM-D17, Montgomery-Asberg Depression Rating Scale (MADRS) and CGI scales with improvement in subjects’ mood. Nausea and dizziness were the most common side effects reported [72]. The therapeutic effects of flesinoxan have also been reported in animal models. In research with male Sprague-Dawley rats after olfactory bulbectomy, subjects were given flesinoxan (1 and 3 mg/kg, s.c.) for 17 days. They presented reduced total immobility time on the forced swimming test [73]. This therapeutic action may be associated with the desensitization effect of the 5-HT1A-R in the nucleus of the dorsal raphe as an action mechanism [71].

The antidepressant activity of agonists to the 5-HT1A-R in presynaptic and postsynaptic neurons has been widely reported. Studies using the model of experimental learned helplessness in relation to depression have reported that stimulation of the 5-HT1A-R with 8-OH-DPAT at dosages of 0.03, 0.06, 0.125, 0.25, and 1 mg/kg i.p. for 5 days shows an antidepressant effect. To explore the role of the pre- and postsynaptic 5-HT1A-R, in that study, 8-OH-DPAT (0.1 and 1 µg/0.5 µl) was microinjected into the raphe and septum. While this showed an antidepressant effect when microinjected into the septum, no such effect was seen in the raphe of male rats [74]. This indicates that stimulation of the postsynaptic 5-HT1A receptors is responsible for establishing the antidepressant effect caused by 5-HT1A-R agonists when managed through a systemic pathway, since stimulation of the 5-HT1A somatodendritic auto-receptors in the raphe inhibits the release of 5-HT and the electrical activity of the raphe [75].

In recent years, administration of vilazodone has shown antidepressant [75, 76] and anxiolytic effects by eliminating physical and somatic symptoms in women with generalized anxiety disorder, after 8 weeks of treatment at daily doses of 20–40 mg [77, 78]. This effect is due to the action mechanism of this SSRI, which is a partial agonist of postsynaptic 5-HT1A receptors. In addition, it desensitizes 5-HT1A auto-receptors in the raphe more quickly than fluoxetine or paroxetine [79], is 30 times more powerful than serotonin transporter (SERT), and causes a larger increase of extracellular 5-HT in the ventral hippocampus and frontal cortex [80]. These facts justify the short latency to the appearance of therapeutic effects. Similar data have been reported in models of experimental anxiety using ultrasonic vocalizations. Observations suggest that vidazolam produces an anxiolytic effect that can be reversed by coadministration with an antagonist of the presynaptic 5-HT1A receptors such as WAY-100635.

This substance also produced an anxiolytic effect in the model of predator-induced stress at doses of 20–40 mg/kg and in the defensive burial model at doses of 10–40 mg/kg. However, no anxiolytic effect was seen in the elevated arms maze model [81]. Antidepressant effects at doses of 1 mg/kg were found in models of experimental depression based on the forced swimming and tail suspension tests [82].

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6. Recent advances in the use of serotonin-norepinephrine reuptake inhibitors (SNRIs) for treating affective disorders

Affective disorders are characterized by vigorousness in neurotransmission pathways at the cerebral level with reductions in serotonergic, noradrenergic, and dopaminergic concentrations, among other neurochemical and neuroanatomical changes. Consequently, therapeutic strategies designed to treat affective disorders include combinations of drugs and, in other cases, chemical compounds that act on one or more neurotransmission systems [83]. In this way, serotonin-norepinephrine reuptake inhibitors (SNRIs) have the capacity to block serotonin and noradrenalin reuptake in the brain, and so have been used successfully to treat such affective disorders as depression, emotional disorders like anxiety, and other illnesses related to the control of overweightness, fibromyalgia, peripheral diabetic neuropathic pain, and attention deficit-hyperactivity disorders, among others (Table 2).

Active compoundTherapeutic useReference
VenlafaxineMDD, AD, syndrome of chronic pain, BDD[85, 86]
DesvenlafaxineMDD in adult patients[89]
DuloxetineMDD, DPNP, fibromyalgia[96, 104, 107]
AtomoxetineADHD in adults and pediatric patients under 6 years old[103, 108]
SibutramineTreatment of obesity[106]
MilnacipranMDD, fibromyalgia[85, 105]
LevomilnacipranMDD, AD in adult patients[90]

Table 2.

Principal serotonin-norepinephrine reuptake inhibitors and their therapeutic uses.

Abbreviations: MDD, major depression disorder; BDD, bipolar depression disorder; AD, anxiety disorder; DPNP, diabetic peripheral neuropathy pain; ADHD, attention deficit hyperactivity disorder.

The SNRIs were introduced into therapeutic use in the USA in 1993 under the name venlafaxine, a chemical compound included in a group of molecules named phenylethylamines, whose action mechanism principally involves the reuptake inhibition of serotonin and noradrenaline, though a lower degree of dopamine reuptake inhibition has also been reported. Through their dual action, these substances quickly increase concentrations of both neurotransmitters, apparently producing better therapeutic actions in major depression disorders than conventional antidepressant drugs that act upon only a single neurotransmission system. But SNRIs can produce side effects that include loss of appetite, reduced body weight and sleep, fatigue, headaches, nausea/vomiting, sexual dysfunction, and urinary retention, among others. To a lesser degree, they can also produce anxiety and high blood pressure. It is important to point out that some patients treated with SNRIs have increased suicidal thoughts, though this is still subject to controversy [84]. Despite their side effects, SNRIs are used frequently to control several depressive disorders due to their therapeutic efficacy. Indeed, in some cases they work better than classic antidepressant drugs (e.g., SSRIs and tricyclic drugs) in certain groups of patients. For example, a clinical study of patients diagnosed with major depression disorder (aged 18–65) found remission of symptoms after 24 weeks of treatment with venlafaxine (initial dose of 75 mg/day, maximum dose of 225 mg/day) and milnacipran (50 mg twice a day), with a greater effect than that produced by 20 mg/day of the SSRI paroxetine [85]. However, in patients diagnosed with Alzheimer’s and major depression disorders, the SSRIs sertraline and venlafaxine had a greater effect than the tricyclic antidepressant desipramine, all at doses of 150 mg/day during 12 weeks of treatment [86]. In a randomized, double-blind, parallel group study that evaluated the effect of long-term treatment (12 weeks) with venlafaxine in adult patients, there was a significant reduction of depressive symptoms compared to patients under the same conditions but treated with a lithium monotherapy [87]. Another SNRI used to treat major depression disorder is desvenlafaxine [88]. An integrated analysis of the efficacy of this drug found that treatment with 50 and 100 g/day reduced depression symptoms in patients diagnosed with major depression disorder compared to a placebo group [89].

Similarly, treatment with levomilnacipran (40–120 mg) in patients aged 18–80 diagnosed with some depression disorder, significantly reduced symptoms after 8–10 weeks of treatment [90]. These data show that the effect of SNRIs in treating major depression disorders depends on the characteristics of patients and the dosage schedule. One double-blind, controlled, randomized study compared two treatment schedules with venlafaxine: one fixed (75 mg/day) the other flexible (75–225 mg/day). It found that the fixed program gave a better response to this antidepressant treatment than the flexible approach [91]. Similarly, the use of SNRIs in young depressed patients (7–18) did not produce better therapeutic effects than a placebo treatment, though duloxetine has shown therapeutic potential in such patients [92]. A meta-analysis of the efficacy of venlafaxine, duloxetine, fluoxetine, and imipramine in children and adolescents found that SNRIs and tricyclic antidepressants do not seem to offer a significant advantage in treating major depression disorder in this population, as only fluoxetine produced an adequate therapeutic effect in those patients [93].

SNRIs are also often used to treat depressive symptoms associated with menopause. It is well known that in this biological phase, women are more susceptible and vulnerable to socio-environmental factors that predispose them to develop emotional and affective disorders [94]. Menopausal women diagnosed with major depression disorders and vasomotor symptoms treated with duloxetine for 8 weeks experienced a reduction in their depressive and vasomotor symptoms, positive anxiolytic effects, and improved sleep quality, so it is believed that SNRIs may be an effective therapeutic option for treating mood and emotional disorders, as well as the more general symptoms associated with menopause [95]. In addition to its role as an effective treatment for major depression disorders associated with menopause, duloxetine is used to control other symptoms, such as hot flashes and anxiety [96]. Meanwhile, menopausal women treated with venlafaxine (75–300 mg/day) or fluoxetine (20–60 mg/day) felt a reduction in their depressive symptoms after 6 weeks of treatment, with no significant differences between these two antidepressants [97]. Administration of desvenlafaxine (50, 100, or 200 mg/day) to peri- and postmenopausal women also reduced depressive symptom compared to a placebo [98].

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7. Mechanism of action of selective serotonin reuptake inhibitors (SSRIs) and affective disorders

The action mechanism of SSRIs consists in inhibiting the 5-HT transporters (SERT) in the soma of raphe dorsal neurons (Figure 1). It has been shown that SSRIs, such as fluoxetine, that have an antidepressant effect possess a mechanism that inhibits SERT, thus increasing the availability of 5-HT in the synaptic cleft. This is accompanied by an increase in 5-HTergic neurotransmission associated with the establishment of the antidepressant effect [99]. This pharmacological effect is not immediate, suggesting that the 5-HT1A transporter blockade, per se, does not produce therapeutic effects during acute treatment, since in the first week of antidepressant therapy with SSRIs increases 5-HTergic neurotransmission due to the availability of 5-HT, which causes an overstimulation of the 5-HT1A auto-receptors, located in the cell body and dendrites of neurons in the raphe. Therefore, its neuronal activity, which is in charge of releasing 5-HT, is reduced in limbic areas, though we know that treatment with SSRI antidepressants requires 2–3 weeks to establish its therapeutic effect, because regulation of 5-HTergic neurotransmission in depressed patients requires the desensitization and subsequent internalization of the 5-HT1A auto-receptors of presynaptic neurons that eliminate the negative feedback on the raphe, thus increasing its neuronal activity and normalizing the release of 5-HT to the synaptic cleft that, finally, translates into an antidepressant effect.

Figure 1.

Mechanism of SSRIs: the 5-HT transporters (SERT) in the soma of raphe dorsal neurons; modified according to Garcia-Garcia et al. [40].

The postsynaptic mechanism and cellular signaling of the 5-HT1A-R in relation to mood control are very complex. In this regard, it has been reported that some accompany the establishment of the therapeutic effect of SSRI antidepressants. One of the most important effects is the desensitization of the 5-HT1A auto-receptors. Normally in 5-HTergic neurotransmission, once the 5-HT is released into the synaptic cleft, it mainly has a three-point coupling. The first is to the postsynaptic serotonergic receptors, mainly 5-HT1A. These receptors are coupled to the inhibition of protein G (Gi/o) and the consequent decrease in AMPc synthesis due to the inhibition of adenylate cyclase which, in conjunction with other second messengers, are responsible for activating the opening of ion channels, including Na+ and K+, for its input and output, respectively (Figure 2). This contributes to the hyperpolarization of the postsynaptic neurons so that they can go with the flow of neural inhibition. The second coupling is with the SERT, which are responsible for the reuptake of unused synapse 5-HT, which is returned to the presynaptic neuron through recycling, where it is stored for later release or to be metabolized to reset the synthesis of 5-HT. The energetic cost of its production is very high. The third coupling is with the 5-HT1A auto-receptors and, to a lesser extent, 5-HT1B and 5-HT1D. This causes inhibition of the opening of Ca2+ channels from the presynaptic neuron, which then inhibits the release of 5-HT into the synaptic cleft, thus regulating the intensity and duration of the nerve impulse from the presynaptic neuron (i.e., negative feedback or self-inhibition), mainly in neurons of the raphe, exerting the end the signaling of the presynaptic neurons and the resumption of the release of 5-HT neurons from the raphe to the postsynaptic neurons through the limbic areas [100]. In this context, chronic administration of SSRIs induces internalization of the 5-HT1A auto-receptors and the neurons of the raphe [101], since the increase in the availability of 5-HT in the cleft overstimulates those auto-receptors while also desensitizing and internalizing them. This process is associated with the phosphorylation of the carboxylic chain and the third intracellular loop of the receptor. The absence of 5-HT1A auto-receptors induces the binding of 5-HT only to postsynaptic 5-HT 1A receptors, which in turn triggers the antidepressant effect of SSRIs, though only after 2–3 weeks of treatment. However, this desensitization effect on the auto-receptors depends on the type of SSRIs administered, as it has not been observed when sertraline is administered chronically in humans [102].

Figure 2.

Model of the transduction pathways that may be activated by the 5-HT1A-R; modified according to Polter and Li [100].

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8. Conclusion

Multiple antidepressant drugs are known to function through the 5-HT1A-R. New findings related to dysfunctions in the serotoninergic system, specifically in both pre- and postsynaptic 5-HT1A-R in the signaling pathways that modulate the 5-HT1A-R, demonstrate that 5HTergic alterations—whether in the expression or functionality associated with such disorders as anxiety and depression, and their subsequent association with alterations in signaling pathways that indirectly modulate and involve survival and neuronal development—can interfere with responses to antidepressant treatment. However, we require additional studies that accurately identify signaling mechanisms in different brain areas and differentiate their functions between the pre- and postsynaptic 5-HT1A-R present in intact animals and animals subjected to clinically effective antidepressant and anti-anxiety treatments. Since we know that differences in the distribution of receptors in the brain determine the physiological and behavioral functions, a better understanding of the underlying mechanisms associated with abnormal activity of the 5-HT1A-R will contribute to the search for novel therapeutic strategies that explore new ways of enhancing treatment of the most common psychiatric disorders around the world, including those of anxiety and depression, which severely impair the quality of life of individuals.

In general, the participation of the 5-HT1A-R in psychiatric disorders such as anxiety and depression has been widely explored in numerous clinical studies and animal models. All findings seem to indicate that including agonist components to the 5-HT1A-R in drug treatment of individuals with anxiety and depression is a promising option for improving the efficiency and implementation of the therapeutic effect of conventional drugs. It is important to emphasize that stimulation of the 5-HT1A-R activates indirect signaling mechanisms that have not yet been studied, so further research is necessary to explore possible alternative signaling mechanisms that accompany the establishment of the antidepressant effects mediated by 5-HT1A-R. Finally, in order to better understand the etiology of many disorders of brain development and advance in the elaboration of drugs that target 5-HT1A-R, it is important to study the profile of this receptor’s activity in brain signaling during development.

In summary, there is ample clinical evidence to support the idea that SNRIs may be used to treat major depression disorder and other psychiatric disorders in certain groups of patients. However, the scarcity of controlled clinical studies and the wide age range of patients included in existing work, in addition to the scarce comparisons of the effects of SNRIs and classic antidepressant drugs (e.g., SSRIs and tricyclic antidepressants), raise the challenge of determining whether SNRIs produce greater, similar, or lower therapeutic effects than traditional therapeutic schedules. Nonetheless, the data currently available open doors for future research designed to explore new therapeutic options that will benefit patients with major depression disorders or other affective or emotional alterations.

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Acknowledgments

The writing of this chapter was made possible, in part, by funding from the Programa de Apoyo a la Mejora de las Condiciones de Producción de los Miembros del SNI y SNCA (PRO-SNI) 2017. The sixth author received financial support from Consejo Nacional de Ciencia y Tecnología (CONACyT) for postdoctoral studies at the University Center of Los Lagos, Universidad de Guadalajara (Laboratory of Biomedical Sciences/Histology). The fourth author received fellowship from CONACyT for postgraduate studies in Neuroethology Reg. 297560.

References

  1. 1. Nichols DE, Nichols CD. Serotonin receptors. Chemical Review. 2008;108:1614-1641. DOI: 10.1021/cr078224o
  2. 2. Hjorth S, Bengtsson HJ, Kullberg A, Carlzon D, Peilot H, Auerbach SB. Serotonin autoreceptor function and antidepressant drug action. Journal of Psychopharmacology. 2000;14:177-185. DOI: 10.1177/026988110001400208
  3. 3. Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacology Biochemistry and Behavior. 2002;71:533-554. DOI: 10.1016/S0091-3057(01)00746-8
  4. 4. Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD, Sequeira A, Kushwaha N, Morris SJ, Basak A, Ou XM, Albert PR. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. The Journal of Neuroscience. 2003;23:8788-8799
  5. 5. Santana N, Bortolozzi A, Serrats J, Mengod G, Artigas F. Expression of serotonin 1A and serotonin 2A receptors in pyramidal and GABAergic neurons of the reat pre-frontal cortex. Cerebral Cortex. 2004;14:1100-1109. DOI: 10.1093/cercor/bhh070
  6. 6. Day HE, Greenwood BN, Hammack SE, Watkins LR, Fleshner M, Maier SF, Campeau S. Differential expression of 5HT-1A, alpha 1b adrenergic, CRFR1, and CRF-R2 receptor mRNA in serotonergic, gamma-aminobutyric acidergic, and catecholaminergic cells of the rat dorsal raphe nucleus. Journal of Comparative Neurology. 2004;474:364-378. DOI: 10.1002/cne.20138
  7. 7. Palchaudhuri M, Flugge G. 5-HT1A receptor expression in pyramidal neurons of cortical and limbic brain regions. Cell and Tissue Research. 2005;321:159-172. DOI: 10.1007/s00441-005-1112-x
  8. 8. Luna-Munguia H, Manuel-Apolinar L, Rocha L, Meneses A. 5-HT1A receptor expression during memory formation. Psychopharmacology (Berl). 2005;181:309-318. DOI: 10.1007/s00213-005-2240-4
  9. 9. Aznavour N, Rbah L, Leger L, Buda C, Sastre JP, Imhof A, Charnay Y, Zimmer L. A comparison of in vivo and in vitro neuroimaging of 5-HT1A receptor binding sites in the cat brain. Journal of Chemical Neuroanatomy. 2006;31:226-232. DOI: 10.1016/j.jchemneu.2006.01.006
  10. 10. Parsey RV, Arango V, Olvet DM, Oquendo MA, Van Heertum RL, Mann JJ. Regional heterogeneity of 5-HT1A receptors in human cerebellum as assessed by positron emission tomography. Journal of Cerebral Blood Flow & Metabolism. 2005;25:785-793. DOI: 10.1038/sj.jcbfm.9600072
  11. 11. Patel TD, Zhou FC. Ontogeny of 5-HT1A receptor expression in the developing hippocampus. Brain Research. Developmental Brain Research. 2005;157:42-57. DOI: 10.1016/j.devbrainres.2005.03.006
  12. 12. Chen Y, Penington NJ. Differential effects of protein kinase C activation on 5-HT1A receptor coupling to Ca2+ and K+ currents in rat serotonergic neurones. Journal of Physiology. 1996;496:129-137. DOI: 10.1113/jphysiol.1996.sp021670
  13. 13. Jeong HJ, Han SH, Min BI, Cho YW. 5-HT1A receptor-mediated activation of G-protein-gated inwardly rectifying K+ current in rat periaqueductal gray neurons. Neuropharmacology. 2001;41:175-185. DOI: 10.1016/S0028-3908(01)00062-4
  14. 14. Zimmer L, Riad M, Rbah L, Belkacem-Kahlouli A, Le Bars D, Renaud B, Descarries L. Toward brain imaging of serotonin 5-HT1A autoreceptor internalization. Neuroimage. 2004;22:1421-1426. DOI: 10.1016/j.neuroimage.2004.03.020
  15. 15. Albert PR, Lemonde S. 5-HT1A receptors, gene repression, and depression: Guilt by association. Neuroscientist. 2004;10:575-593. DOI: 10.1177/1073858404267382
  16. 16. Haddjeri N, Ortemann C, de Montigny C, Blier P. Effect of sustained administration of the 5-HT receptor agonist 1A flesinoxan on rat 5-HT neurotransmission. European Neuropsychopharmacology. 1999;9:427-440
  17. 17. Blier P, Ward NM. Is there a role for 5-HT1A agonists in the treatment of depression? Biological Psychiatry. 2003;53:193-203. DOI: 10.1016/S0006-3223(02)01643-8
  18. 18. Adayev T, El-Sherif Y, Barua M, Banerjee P. Agonist stimulation of the serotonin1A receptor causes suppression of anoxia-induced apoptosis via mitogen-activated protein kinase in neuronal HN2-5 cells. Journal of Neurochemistry. 1999;72:1489-1496
  19. 19. Kushwaha N, Albert N. Coupling of 5-HT1A auto-receptors to inhibition of mitogen-activated protein kinase activation via G beta gamma subunit signaling. European Journal of Neuroscience. 2005;21:721-732. DOI: 10.1111/j.1460-9568.2005.03904.x
  20. 20. Adayev T, Ranasinghe B, Banerjee P. Transmembrane signaling in the brain by serotonin, a key regulator of physiology and emotion. Bioscience Reports. 2005;25:363-385. DOI: 10.1007/s10540-005-2896-3
  21. 21. Adayev T, Ray I, Sondhi R, Sobocki T, Banerjee P. The G protein-coupled 5-HT1A receptor causes suppression of caspase-3 through MAPK and protein kinase C. Biochimica et Biophysica Acta. 2003;1640:85-96. DOI: 10.1016/S0167-4889(03)00023-5
  22. 22. Bromet E, Andrade LH, Hwang I, Sampson NA, Alonso J, Girolamo Gd, Graaf Rd, Demyttenaere K, Hu C, Iwata N, Karam AN, Kaur J, Kostyuchenko S, Lépine JP, Levinson D, Matschinger H, Medina Mora ME, Oakley Browne M, Posada-Villa J, Viana MC, Williams WR, Kessler RC. Cross-national epidemiology of DSM-IV major depressive episode. BMC Medicine. 2011;9:90. DOI: 10.1186/1741-7015-9-90
  23. 23. Dell'Osso L, Carmassi C, Mucci F, Marazziti D. Depression, serotonin and tryptophan. Current Pharmaceutical Design. 2016;22:949-954. DOI: 10.2174/1381612822666151214104826
  24. 24. Aberg-Wistedt A, Hasselmark L, Stain-Malmgren R, Apéria B, Kjellman BF, Mathé AA. Serotonergic 'vulnerability' in affective disorder: A study of the tryptophan depletion test and relationships between peripheral and central serotonin indexes in citalopram-responders. Acta Psychiatrica Scandinavica. 1998;97:374-380. DOI: 10.1111/j.1600-0447.1998.tb10017.x
  25. 25. Jans LAW, Riedel WJ, Markus CR, Blokland A. Serotonergic vulnerability and depression: Assumptions, experimental evidence and implications Molecular Psychiatry. 2007;12:522-543. DOI: 10.1038/sj.mp.4001920
  26. 26. Kambeitz JP, Howes OD. The serotonin transporter in depression: Meta-analysis of in vivo and post mortem findings and implications for understanding and treating depression. Journal of Affective Disorders. 2015;186:358-366. DOI: 10.1016/j.jad.2015.07.034
  27. 27. Reimold M, Batra A, Knobel A, Smolka MN, Zimmer A, Mann K, Solbach C, Reischl G, Schwärzler F, Gründer G, Machulla HJ, Bares R, Heinz A. Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: A [11C]DASB PET study. Molecular Psychiatry. 2008;13:606-613. DOI: 10.1038/sj.mp.4002149
  28. 28. Nash JR, Sargent PA, Rabiner EA, Hood SD, Argyropoulos SV, Potokar JP, Grasby PM, Nutt DJ. Serotonin 5-HT1A receptor binding in people with panic disorder: Positron emission tomography study. British Journal of Psychiatry. 2008;193:229-234
  29. 29. He M, Sibille E, Benjamin D, Toth M, Shippenberg T. Differential effects of 5-HT1A receptor deletion upon basal and fluoxetine-evoked 5-HT concentrations as revealed by in vivo microdialysis. Brain Research. 2001;902:11-17. DOI: 10.1016/S0006-8993(01)02271-5
  30. 30. Guilloux JP, David DJ, Guiard BP, Chenu F, Reperant C, Toth M, Bourin M, Gardier AM. Blockade of 5-HT1A receptors by (+/-)-pindolol potentiates cortical 5-HT outflow, but not antidepressant-like activity of paroxetine: Microdialysis and behavioral approaches in 5-HT1A receptor knockout mice. Neuropsychopharmacology. 2006;31:2162-2172
  31. 31. Ase AR, Reader TA, Hen R, Riad M, Descarries L. Altered serotonin and dopamine metabolism in the CNS of serotonin 5-HT (1A) or 5-HT (1B) receptor knockout mice. Journal of Neurochemistry. 2000;75:2415-2426
  32. 32. Heisler LK, Chu HM, Brennan TJ, Danao JA, Bajwa P, Parsons LH, Tecott LH. Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proceedings of the National Academy of Sciences of the United States of America. 1998;95:15049-15054
  33. 33. Andrews N, Hogg S, Gonzalez LE, File SE. 5-HT1A receptors in the median raphe nucleus and dorsal hippocampus may mediate anxiolytic and anxiogenic behaviors respectively. European Journal of Pharmacology. 1994;264:259-264
  34. 34. Gonzalez LD, Andrews N. File SE. 5-HT1A and benzodiazepine receptors in the basolateral amygdala modulate anxiety in the social interaction test, but not in the elevated plusmaze. Brain Research. 1996;732:145-153
  35. 35. Cervo L, Mocaer E, Bertaglia A, Samanin R. Roles of 5-HT (1A) receptors in the dorsal raphe and dorsal hippocampus in anxiety assessed by the behavioral effects of 8-OH-DPAT and S 15535 in a modified Geller–Seifter conflict model. Neuropharmacology. 2000;39:1037-1043
  36. 36. De Vry J. 5-HT1A receptor agonists: Recent developments and controversial issues. Psychopharmacology (Berl). 1995;121:1-26
  37. 37. Gross C, Zhuang X, Stark K, Ramboz S, Oosting R, Kirby L, Santarelli L, Beck S, Hen R. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature. 2002;416:396-400
  38. 38. Donaldson ZR, Piel DA, Santos TL, Richardson-Jones J, Leonardo ED, Beck SG, Champagne FA, Hen R. Developmental effects of serotonin 1A auto-receptors on anxiety and social behavior. Neuropsychopharmacology. 2014;39:291-302
  39. 39. Richardson-Jones JW, Craige CP, Nguyen TH, Kung HF, Gardier AM, Dranovsky A, David DJ, Guiard BP, Beck SG, Hen R, et al. Serotonin-1A auto-receptors are necessary and sufficient for the normal formation of circuits underlying innate anxiety. The Journal of Neuroscience. 2011;31:6008-6018
  40. 40. Garcia-Garcia AL, Newman-Tancredi A, Leonardo ED. 5-HT (1A) receptors in mood and anxiety: Recent insights into autoreceptor versus heteroreceptor function. Psycho-pharmacology. 2014;231:623-636
  41. 41. Albert PR, Francois BL. Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy. Frontiers in Neuroscience. 2010;4:35. DOI: 10.3389/fnins.2010.00035
  42. 42. Bortolozzi A, Castane A, Semakova J, Santana N, Alvarado G, Cortes R, Ferres-Coy A, Fernandez G, Carmona MC, Toth M, et al. Selective siRNA-mediated suppression of 5-HT1A auto-receptors evokes strong anti-depressant-like effects. Molecular Psychiatry. 2012;17:612-623
  43. 43. Wang L, Zhou C, Zhu D, Wang X, Fang L, Zhong J, Mao Q, Sun L, Gong X, Xia J, Lian B, Xie P. Serotonin-1A receptor alterations in depression: A meta-analysis of molecular imaging studies. BMC Psychiatry. 2016;16:319. DOI: 10.1186/s12888-016-1025-0
  44. 44. Kaufman J, DeLorenzo C, Choudhury S, Parsey RV. The 5-HT 1A receptor in major depressive disorder. European Neuropsychopharmacology. 2016;26:397-410
  45. 45. Okita K, Shiina A, Nakazato M, Iyo M. Tandospirone, a 5-HT1A partial agonist is effective in treating anorexia nervosa: A case series. Annals of General Psychiatry. 2013;12:7. DOI: 10.1186/1744-859X-12-7
  46. 46. Robinson DS, Rickels K, Feighner J, Fabre LF, Gammans RE, Shrotriya RC, Alms DR, Andary JJ, Messina ME. Clinical effects of the 5-HT1A partial agonists in depression: A composite analysis of buspirone in the treatment of depression. Journal of Clinical Psychopharmacology. 1990;10:67S-76S
  47. 47. Sato S, Mizukami K, Asada T. A preliminary open-label study of 5-HT 1A partial agonist tandospirone for behavioural and psychological symptoms associated with dementia. The International Journal of Neuropsychopharmacology. 2007;10:281-283
  48. 48. Stahl SM. Action mechanism of serotonin selective reuptake inhibitors: Serotonin receptors and pathways mediate therapeutic effects and side effects. Journal of Affective Disorders. 1998;51:215-235
  49. 49. Sumiyoshi T, Higuchi Y, Uehara T. Neural basis for the ability of atypical antipsychotic drugs to improve cognition in schizophrenia. Frontiers in Behavioral Neuroscience. 2015;2013. DOI: 10.3389/fnbeh.2013.00140
  50. 50. Carr GV, Lucki I. The role of serotonin receptor sub-types in treating depression: A review of animal studies. Psychopharmacology. 2011;213:265-287
  51. 51. Artigas F. Serotonin receptors involved in antidepressant effects. Pharmacology & Therapeutics. 2013;137:119-131
  52. 52. Czopek A, Kołaczkowski M, Bucki A, Byrtus H, Pawłowski M, Siwek A, Bojarski AJ, Bednarski M, Wróbel D, Wesołowska A. Novel mannich bases, 5‐arylimidazolidine‐2,4‐dione derivatives with dual 5‐HT1A receptor and serotonin transporter affinity. Archiv der Pharmazie. 2013;346:98-109
  53. 53. Waszkielewicz AM, Pytka K, Rapacz A, Wełna E, Jarzyna M, Satała G, Bojarski A, Sapa J, Żmudzki P, Filipek B, Marona H. Synthesis and evaluation of antidepressant‐like activity of some 4‐substituted 1‐(2‐methoxyphenyl) piperazine derivatives. Chemical Biology & Drug Design. 2015;85:326-335. DOI: 10.1111/cbdd.12394
  54. 54. Pavlaković G, Tigges J, Crozier TA. Effect of buspirone on thermal sensory and pain thresholds in human volunteers. BMC Pharmacology and Toxicology. 2009;9:12
  55. 55. Fulton B, Brogden B. Buspirone: an updated review of its clinical pharmacology, therapeutic pharmacology, and therapeutic applications. Adis Drug Evaluation. CNS Drugs. 1997;7:68-88. DOI: 10.2165/00023210-199707010-00007
  56. 56. Chen JJ. Pharmacologic safety concerns in Parkinson's disease: Facts and insights. International Journal of Neuroscience. 2011;121(Suppl 2):45-52. DOI: 10.3109/00207454.2011.620193
  57. 57. Díaz-Mataix L, Scorza MC, Bortolozzi A, Toth M, Celada P, Artigas F. Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: Role in atypical antipsychotic action. The Journal of Neuroscience. 2005;25:10831-10843. DOI: 10.1523/JNEUROSCI.2999-05.2005
  58. 58. Petracca A, Nisita C, McNair D, Melis G, Guerani G, Cassano GB. Treatment of generalized anxiety disorder: Preliminary clinical experience with buspirone. The Journal of Clinical Psychiatry. 1990;51:31-39
  59. 59. Dimitriou EC, Parashos AJ, Giouzepas JS. Buspirone vs alprazolam: A double-blind comparative study of their efficacy, adverse effects and withdrawal symptoms. Drug Investigation. 1992;4:316-321. DOI: 10.1007/BF03259411
  60. 60. Pytka K, Zmudzka E, Lustyk K, Rapacz A, Olczyk A, Galuszka A, Waszkielewicz A, Marona H, Sapa J, Barbara F. The antidepressant-and anxiolytic-like activities of new xanthone derivative with piperazine moiety in behavioral tests in mice. Indian Journal of Pharmacology. 2016;48:286
  61. 61. Jenkins SW, Robinson DS, Fabre JR, Andary JJ, Messina ME, Reich IA. Gepirone in the treatment of major depression. Journal of Clinical Psychopharmacology. 1990;10:77S-85S
  62. 62. Blier P, de Montigny C. Electrophysiological investigation of the adaptive response of the 5-HT system to the administration of 5-HT1A receptor agonists. Journal of Cardiovascular Pharmacology. 1990;15:S42-S48
  63. 63. DeVeaugh‐Geiss J. Gepirone treatment of generalized anxiety disorder (GAD). 50th NCDEU Annual Meeting; June 14-17, 2010; Boca Raton, FL
  64. 64. Rickels K, Schweizer E, DeMartinis N, Mandos L, Mercer C. Gepirone and diazepam in generalized anxiety disorder: A placebo-controlled trial. Journal of Clinical Psychopharmacology. 1997;17:272-277
  65. 65. Bielski RJ, Cunningham L, Horrigan JP, Londborg PD, Smith WT, Weiss K. Gepirone extended-release in the treatment of adult outpatients with major depressive disorder: A double-blind, randomized, placebo-controlled, parallel-group study. The Journal of Clinical Psychiatry. 2008;69:571-577
  66. 66. Fabre LF, Clayton AH, Smith LC, Goldstein I, Derogatis LR. The effect of Gepirone‐ER in the treatment of sexual dysfunction in depressed men. The Journal of Sexual Medicine. 2012;9:821-829. DOI: 10.1111/j.1743-6109.2011.02624.x
  67. 67. Murata Y, Yanagihara Y, Mori M, Mine K, Enjoji M. Chronic treatment with tandospirone, a serotonin 1A receptor partial agonist, inhibits psychosocial stress-induced changes in hippocampal neurogenesis and behavior. Journal of Affective Disorders. 2015;180:1-9. DOI: http://dx.doi.org/10.1016/j.jad.2015.03.054
  68. 68. Beyer JL, Weisler RH. Adjunctive brexpiprazole for the treatment of major depressive disorder. Expert Opinion on Pharmacotherapy. 2016;17:2331-2339. DOI: 10.1007/s40263-016-0320-0
  69. 69. Schoeffter P, Hoyer D. Centrally acting hypotensive agents with affinity for 5‐HT1A binding sites inhibit forskolin‐stimulated adenylate cyclase activity in calf hippocampus. British Journal of Pharmacology. 1988;95:975-985
  70. 70. Pitchot W, Wauthy J, Hansenne M, Pinto E, Fuchs S, Reggers J, Legros JJ, Ansseau M. Hormonal and temperature responses to the 5-HT1A receptor agonist flesinoxan in normal volunteers. Psychopharmacology. 2002;164:27-32. DOI: 10.1007/s00213-002-1177-0
  71. 71. Grof P, Joffe R, Kennedy S, Persad E, Syrotiuk J, Bradford D. An open study of oral flesinoxan, a 5-HT1A receptor agonist, in treatment-resistant depression. International Clinical Psychopharmacology. 1993;8:167-172
  72. 72. Prinsze C, Stevens G. Flesinoxan in the treatment of major depressive disorder: A fixed dose, placebo-controlled trial. European Neuropsychopharmacology. 1996;6:S4-S73
  73. 73. Cryan JF, Redmond AM, Kelly JP, Leonard, BE. The effects of the 5-HT 1A agonist flesinoxan, in three paradigms for assessing antidepressant potential in the rat. European Neuropsychopharmacology. 1997;7:109-114. DOI: 10.1016/S0924-977X(96)00391-4
  74. 74. Hjorth S, Magnusson T. The 5-HT 1A receptor agonist, 8-OH-DPAT, preferentially activates cell body 5-HT auto-receptors in rat brain in vivo. Naunyn-Schmiedeberg's Archives of Pharmacology. 1988;338:463-471. DOI: 10.1007/BF00179315
  75. 75. Thase ME, Chen D, Edwards J, Ruth A. Efficacy of vilazodone on anxiety symptoms in patients with major depressive disorder. International Clinical Psychopharmacology. 2014;29:351-356. DOI: 10.1097/YIC.0000000000000045
  76. 76. Mathews M, Gommoll C, Chen D, et al. Efficacy and safety of vilazodone 20 and 40 mg in major depressive disorder: A randomized, double-blind, placebo-controlled trial. International Clinical Psychopharmacology. 2015;30:67-74. DOI: 10.1097/YIC.0000000000000057
  77. 77. Durgam S, Gommoll C, Forero G, Nunez R, Tang X, Mathews M, Sheehan DV. Efficacy and safety of vilazodone in patients with generalized anxiety disorder: A randomized, double-blind, placebo-controlled, flexible-dose trial. The Journal of Clinical Psychiatry. 2016;77:1687-1694. DOI: 10.4088/JCP.15m09885
  78. 78. Khan A, Durgam S, Tang X, Ruth A, Mathews M, Gommoll CP. Post hoc analyses of anxiety measures in adult patients with generalized anxiety disorder treated with vilazodone. The Primary Care Companion for CNS Disorders. 2016;18(2). DOI: 10.4088/PCC.15m01904
  79. 79. Ashby Jr CR, Kehne JH, Bartoszyk GD, Renda MJ, Athanasiou M, Pierz KA, Seyfried CA. Electrophysiological evidence for rapid 5-HT₁A autoreceptor inhibition by vilazodone, a 5-HT₁A receptor partial agonist and 5-HT reuptake inhibitor. European Journal of Pharmacology. 2013;714:359-365. DOI: 10.1016/j.ejphar.2013.07.014
  80. 80. Page ME, Cryan JF, Sullivan A, Dalvi A, Saucy B, Manning DR, Lucki I. Behavioral and neurochemical effects of 5-{4-[4-(5-Cyano-3-indolyl)-butyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide (EMD 68843): A combined selective inhibitor of serotonin reuptake and 5-hydroxytryptamine1A receptor partial agonist. Journal of Pharmacology and Experimental Therapeutics. 2002;302(3):1220-1227. DOI: 10.1124/jpet.102.034280
  81. 81. Adamec R, Bartoszyk GD, Burton P. Effects of systemic injections of vilazodone, a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist, on anxiety induced by predator stress in rats. European Journal of Pharmacology. 2004;504:65-77. DOI: 10.1016/j.ejphar.2004.09.009
  82. 82. de Paulis T. Drug evaluation: Vilazodone—A combined SSRI and 5-HT1A partial agonist for the treatment of depression. IDrugs. 2007;10:193-201
  83. 83. Rodríguez-Landa JF, Bernal-Morales B, Gutiérrez-García AG. Estrés, miedo, ansiedad y depresión. En: Coria-Ávila GA, editor. Neurofisiología de la conducta. Xalapa: Universidad Veracruzana; 2012. pp. 136-165. ISBN: 978-607-502-191-1
  84. 84. Valuck RJ, Libby Am, Anderson HD, Allen RR, Strombon I, Marangell LB, Perahia D. Comparison of antidepressant classes and the risk and the course of suicide attempts in adults: Propensity matched, retrospective cohort study. British Journal of Psychiatry. 2016;208:271-279. DOI: 10.1192/bjp.bp.114.150839
  85. 85. Chuang HY, Chang YH, Cheng LY, Wang YS, Chen SL, Chen SH, Chu CH, Lee IH, Chen PS, Yeh TL, Yang YK, Lu RB. Venlafaxine, paroxetine and milnacipran for major depression disorders: A pragmatic 24-week study. Chinese Journal of Physiology. 2014;57:265-270. DOI: 10.1111/j.1365-2710.2007.00828.x
  86. 86. Mokhber N, Abdollahian E, Soltanfar A, Samadi R, Saghebi A, Haghighi MB, Azarpazhooh A. Comparison of sertraline, venlafaxine and desipramine effects on depression, cognition and the daily living activities in Alzheimer patients. Pharmacopsychiatry. 2014;47:131-140. DOI: 10.1055/s-0034-1377041
  87. 87. Amsterdam JD, Lorenzo-Luaces L, Soeller I, Li SQ, Mao JJ, DeRubeis RJ. Short-term venlafaxine v. lithium monotherapy for bipolar type II major depressive episodes: Effectiveness and mood conversion rate. British Journal of Psychiatry. 2016;208:359-365. DOI: 10.1192/bjp.bp.115.169375
  88. 88. Clayton AH, Tourian KA, Focht K, Hwang E, Cheng RJ, Thase ME. Desvenlafaxine 500 and 100 mg/d versus placebo for treatment of major depressive disorder: A phase 4, randomized controlled trial. The Journal of Clinical Psychiatry. 2015;76:562-569. DOI: 10.4088/JCP.13m08978
  89. 89. Carrasco JL, Kornstein SG, McIntyre RS, Fayyard R, Prieto R, Salas M, Mackell J, Boucher M. An integrated analysis of the efficacy and safety of desvenlafaxine in the treatment of major depressive disorder. International Clinical Psychopharmacology. 2016;31:134-146. DOI: 10.1097/YIC.0000000000000121
  90. 90. Huang Q, Zhong X, Yun Y, Yu B, Huang Y. Efficacy and safety of multiple doses of levomilnacepran extended-release for the treatment of major depressive disorder. Neuropsychiatric Disease and Treatment. 2016;12:2707-2714. DOI: 10.2147/NDT.S114955
  91. 91. Higuchi T, Kamijima K, Nakagome K, Itamura R, Asami Y, Kuribayashi K, Imaeda T. A randomized, double-blinded, placebo-controlled study to evaluate the efficacy and safety of venlafaxine extended release and long-term extension study for patients with major depressive disorder in Japan. International Clinical Psychopharmacology. 2016;31:8-19. DOI: 10.1097/YIC.0000000000000105
  92. 92. Xu Y, Bai SJ, Lan XH, Qin B, Huang T, Xie P. Randomized controlled trials of serotonin-norepinephrine reuptake inhibitors in treating major depressive disorder in children and adolescents: A meta-analysis of efficacy and acceptability. Brazilian Journal of Medical and Biological Research. 2016;49:e4806. DOI: 10.1590/1414-431X20164806
  93. 93. Cipriani A, Zhou X, Giovane C, Hetrick SE, Qin B, Whittington C, Coghill D, Zhang Y, Hazell P, Leucht S, Cuijpers P, Pu J, Cohen D, Ravindran AV, Liu Y, Michael KD, Yang L, Liu L, Xie P. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: A network meta-analysis. The Lancet. 2016;388:881-890. http://dx.doi.org/10.1016/S0140-6736(16)30385-3
  94. 94. Rodríguez-Landa JF, Puga-Olguín A, Germán-Ponciano LJ, García-Ríos RI, Soria-Fregozo C. Anxiety in natural and surgical menopause—Physiologic and therapeutic bases. In: Durbano F, editor. A Fresh Look Anxiety Disorders. Rijeka: InTech; 2015. pp. 173-198. http://dx.doi.org/10.5772/6062
  95. 95. Joffe H, Soares CN, Petrillo LF, Viguera AC, Somley BL, Koch JK, Cohen LS. Treatment of depression and menopause-related symptoms with the serotonin-norepinephrine reuptake inhibitor duloxetine. Journal of Clinical Psychiatry. 2007;68:943-950
  96. 96. Freeman MP, Hirschberg AH, Wang B, Petrillo LF, Connors S, Regan S, Joffe H, Cohen L. Duloxetine for major depressive disorder and daytime and nighttime hot flashes associated with the menopause transition. Maturitas. 2013;75:170-174. DOI: 10.1016/j.maturitas.2013.03.007
  97. 97. Kornstein SG, Pedersen RD, Holland PJ, Nemeroff CB, Rotschild AJ, Thase ME, Trivedi MH, Ninan PT, Keller MB. Influence of sex and menopause status on response, remission, and recurrence in patients with recurrent major depressive disorder treated with venlafaxine extended release or fluoxetine: Analysis of data from the PREVENT study. The Journal of Clinical Psychiatry. 2014;75:62-68. DOI: 10.4088/JCP.12m07841
  98. 98. Kornstein SG, Clayton AH, Bao Weihang, Guico-Pabia CJ. A pooled analysis of the efficacy of desvenlafaxine for the treatment of major depressive disorder in perimenopausal and postmenopausal women. Journal of Women's Health. 2015;24:281-290. DOI: 10.1089/jwh.2014.4900
  99. 99. Kendler KS, Gatz M, Gardner CO, Pedersen NL. A Swedish national twin study of lifetime major depression. Journal of Clinical Psychiatry. 2006;163:109-114. DOI: http://dx.doi.org/10.1176/appi.ajp.163.1.109
  100. 100. Polter AM, Li X. 5-HT1A receptor-regulated signal transduction pathways in brain. Cell Signal. 2010;22:1406-1412. DOI: 10.1016/j.cellsig.2010.03
  101. 101. Riad M, Zimmer L, Rbah L, Watkins KC, Hamon M, Descarries L. Acute treatment with the antidepressant fluoxetine internalizes 5-HT1A auto-receptors and reduces the In vivo binding of the PET radioligand [18F] MPPF in the nucleus raphe dorsalis of rat. Journal of Neuroscience. 2004;4:5420-5426. DOI: 10.1523/JNEUROSCI.0950-04.2004
  102. 102. Rossi DV, Burke TF, McCasland M, Hensler JG. Serotonin-1A receptor function in the dorsal raphe nucleus following chronic administration of the selective serotonin reuptake inhibitor sertraline. Journal of Neurochemistry. 2008;105:1091-1099. DOI: 10.1111/j.1471-4159.2007.05201.x
  103. 103. Murakami M, Osaka K, Ichibayashi H, Mizuno H, Ochiai T, Ishida M, Alev L, Nishioka K. An open-label, long-term, phase III extension trial of duloxetine in Japanese patients with fibromyalgia. Modern Rheumatology 2016; 31:1-8. http://dx.doi.org/10.1080/14397595.2016.1245237
  104. 104. Häuser W, Ablin J, Perrot S, Fitzcharles MA. Management of fibromyalgia: practical guides from recent evidence-based guidelines. Polish Archives of Medicine 2017; 127(1):47-56. DOI: 10.20452/pamw.3877.
  105. 105. Ravishankar V, Chowdappa SV, Benegal V, Muralidharan K. The efficacy of atomixetine in treating adult attention deficit hyperactivity disorder (ADHD): a meta-analysis of controlled trial. Asian Journal of Psychiatry 2016; 24:53-58. DOI: 10.1016/j.ajp.2016.08.017
  106. 106. Gayleard JL, Mychailyszyn MP. Atomoxetine treatment for children and adolescents with attention-deficit/hyperactivity disorder (ADHD): a comprehensive meta-analysis of outcomes on parent-related core symptomatology. Attention Deficit and Hyperactivity Disorders 2017; In press. DOI: 10.1007/s12402-01716-y.
  107. 107. McElroy SL, Frye MA, Altshuler LL, Suppes T, Hellemann G, Black D, Mintz J, Kupka R, Nolen W, Leverich GS, Denicoff KD, Post RM, Keck E. A 24-week, randomized, controlled trial of adjunctive sibutramine versus topiramate in the treatment of weigth gain in overweight or obese patients with bipolar disorder. Bipolar Disorders 2007; 9:426-434. DOI: 10.1111/j.1399-5618.2007.00488.x
  108. 108. Lee YH, Song GG. Comparative efficacy and tolerability of duloxetine, pregabalin, and milnacipran for treatment of fibromyalgia: a Bayesian network meta-analysis of randomized control trial. Rheumatology International 2016;36(5):663-672. DOI: 10.1007/s00296-016-3468-5.

Written By

Cesar Soria-Fregozo, Maria Isabel Perez-Vega, Juan Francisco Rodríguez-Landa, León Jesús Germán-Ponciano, Rosa Isela García- Ríos and Armando Mora-Perez

Submitted: 14 October 2016 Reviewed: 04 April 2017 Published: 26 July 2017