A decreased level of brain 5-hydroxytryptamine (5-HT) has been theorized to be a core pathogenic factor in depression for half a century. The theory arose from. Jun 24, Levels of 5-HT1BRs are also a key determinant of stress reactivity, and therefore 5-HT1BRs may be a potential pharmacological target for. Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. It has a popular .. In humans, levels of 5-HT1A receptor activation in the brain show negative correlation with aggression, and a mutation in the gene that codes for the.
A recent study found that two distinct agonists that are selective for 5-HT 6 Rs both produce antidepressant and anxiolytic-like effects in rodents [ 95 ].
Somewhat paradoxically, 5-HT 6 R antagonists also can induce antidepressant- and anxiolytic-like effects in rodent models [ 96 — 99 ]. It is currently unclear whether these similar behavioral outcomes are due to diverse neurochemical effects associated with 5-HT 6 R agonists and antagonists or whether distinct actions are being mediated in different brain regions [ 74 , 98 ].
Future studies are necessary to further explore the role of 5-HT 6 R receptor subtypes in antidepressant-like responses. Hippocampal 5-HT 7 Rs appear to be involved in the interaction between the serotonergic system and the hypothalamus-pituitary-adrenal HPA axis since 5-HT 7 R agonists increase glucocorticoid receptor expression in hippocampal cell cultures [ ]. Antidepressant administration downregulates 5-HT 7 in the hypothalamus [ ]. Mice lacking 5-HT 7 Rs exhibit antidepressant-like behaviors in stressful environments and pharmacological blockade of 5-HT 7 Rs results in a faster antidepressant responses in rats [ 97 , — ].
Furthermore, the atypical antipsychotic, amisulpride, also acts as an antidepressant that is a high affinity 5-HT 7 R antagonist. Interestingly, the antidepressant-like behavioral effects of amisulpride are abolished in mice lacking 5-HT 7 Rs [ ].
Therefore, 5-HT 7 Rs antagonists may also represent a new class of antidepressants that could have faster therapeutic action in treating depression.
Since the original development of the monoamine hypothesis of depression, more recent data has expanded this theory to the non-mutually exclusive neurotrophic and neurogenesis hypotheses. These hypotheses speculate that decreases in neurotrophic factors such as brain-derived neurotrophic factor BDNF or decreases in adult hippocampal neurogenesis are respectively involved in the pathophysiology of depression, and that their restoration is critical for the therapeutic efficacy of antidepressant treatment [ — ].
BDNF in limbic areas and this decrease correlates with neuronal atrophy [ , , ]. Specifically, following exposure to stressful experiences researchers have observed decreases in BDNF in rodent hippocampus and prefrontal cortex [ , , , ].
Similarly, in humans, postmortem studies find reduced levels of BDNF in these regions of depressed patients [ , , ]. SSRI administration increases the maturation of young abGCs, as measured by dendritic arborization complexity [ ]. Interestingly, direct infusions of BDNF into the DG of rodents results in antidepressant-like behavioral effects [ ]. Unlike the established association between BDNF levels and adult hippocampal neurogenesis, these neurotrophic factors are implicated to varying degrees in mediating effects on neurogenesis and synaptogenesis [ , — ].
Similar to BDNF, direct cerebral infusions of any one of these growth factors can result in antidepressant-like behavioral responses [ , , , , , ]. Furthermore, antidepressants were ineffective in treating this increased anxiety [ ].
Several studies attempt to directly link the role of BDNF and other neurotrophic factors with 5-HT receptors and signaling [ 54 , — ]. Since expression of BDNF and other neurotrophic factors are positively regulated by activity, activation of 5-HT receptors positively coupled to cAMP levels such as 5-HT 4 and 5-HT 7 should yield enhancement of neurotrophic factor levels.
However, since findings from Samuels and colleagues are based on chronic, not acute, SSRI administration, it is possible that the effects are mediated through an indirect downstream mechanism that has yet to be resolved [ 54 ]. Additionally, transactivation of these receptor complexes results in synergistic increases in neurite density and protrusions, suggesting a combined role of FGFR1 and 5-HT 1A Rs in synaptogenesis [ ].
Overall, 5-HT receptors and neurotrophic factors appear to be synergistically involved in both the pathophysiology of depression and the antidepressant response. Over the last two decades, it has become accepted that new neurons are produced in mammals in two discrete locations, the subventricular zone SVZ of the lateral ventricle and the subgranular zone SGZ of the DG in the hippocampus [ ].
The neurons born in the SVZ migrate through the rostral migratory stream into the olfactory bulb and become interneurons, while those born in the SGZ migrate into the granular layer of the DG and eventually develop into mature granule neurons. The process of adult neurogenesis involves several steps, which include proliferation and fate specification of neural progenitors, neuronal migration and maturation, as well as synaptic integration of young neurons into the existing neuronal circuitry.
Various well-established molecular markers are used to identify cells at distinct points, with electrophysiological cell membrane properties well understood throughout the neurogenesis process [ , ]. Chronic, but not acute, antidepressant treatment increases proliferation of dividing NPCs in the SGZ, differentiation of precursor cells into young abGCs, and the rate by which young abGCs mature and integrate into the DG circuitry [ 57 , ].
Furthermore, the effects of chronic antidepressants seem to be specific to the SGZ as they do not increase neurogenesis in the SVZ [ 57 , ]. Critically, ablation of the adult hippocampal neurogenic niche, by focal radiological approaches, results in a loss of the behavioral antidepressant response, suggesting a necessary role for adult neurogenesis in mediating the behavioral effects of chronic antidepressant treatment [ 56 , , ].
These studies directly resulted in the neurogenesis hypothesis [ , ]. However, it is important to note that ablation of adult hippocampal neurogenesis in rodents does not result in increases in anxiety- and depression-related behaviors [ 56 , ]. Similarly, while decreases in the number of DG GCs have been found in postmortem samples of untreated depressed patients, there does not appear to be a decrease in the number of progenitor cells [ ].
Furthermore, specifically enhancing neurogenesis via a genetic approach does not result in an antidepressant-like phenotype under baseline conditions [ ].
Therefore, while increasing adult hippocampal neurogenesis is necessary for the antidepressant response, it is not sufficient to mediate an antidepressant response and there is limited data to suggest that decreases in adult hippocampal neurogenesis may underlie the pathophysiology of depression. The mechanisms by which SSRIs increase adult hippocampal neurogenesis is likely mediated by several different 5-HT receptors. By contrast, 5-HT 4 R antagonists reduce differentiation of NPCs with minimal effect on cell proliferation, maturation, or morphology [ 93 , ].
Furthermore, the beneficial effects of 5-HT 4 R agonists are not only rapid acting on behavior but also on adult hippocampal neurogenesis. Three days of treatment with the 5-HT 4 R agonist RS significantly increases adult hippocampal neurogenesis [ 92 , ]. However, recent data suggests that the rapid behavioral effects of 5-HT 4 R agonists are mediated by a neurogenesis-independent mechanism [ 93 ].
One interesting alternative to the traditional neurogenesis hypothesis is that SSRI treatment may also cause mature GCs in the DG to undergo a dematuration process that yields cells with properties more similar to young abGCs. Chronic SSRI treatment causes a decrease in expression of the mature granule cell marker calbindin in the DG [ , ]. Therefore, it is possible that what is commonly measured to be maturation of young adult born granule cells assessed by dendritic complexity of Dcx-positive cells could also be dematuration of previously mature granule cells.
Furthermore, this dematuration phenomenon is attenuated in mice germline deficient for the 5-HT 4 R [ ]. Further studies have found that chronic SSRI treatment can also induce dematuration of parvalbumin-positive interneurons in the basolateral amygdala and the frontal cortex in adult mice [ , ].
Thus, the antidepressant response may rely on both increases in neurogenesis and dematuration. It would be particularly interesting to determine whether signaling via distinct serotonin receptors can result in either increases in neurogenesis or dematuration. In addition, while not nearly as well established as SGZ and SVZ adult neurogenesis, several studies have suggested that adult neurogenesis can occur in other brain regions such as the cortex and hypothalamus [ — ].
A recent study by Ohira and colleagues found that SSRI treatment increased cortical inhibitory neuron proliferation [ ]. Some have speculated that GABAergic interneurons are involved in the etiology of depression [ ], so it will be interesting to determine whether cortical neurogenesis plays a role in mediating the beneficial effects of antidepressants on behavior.
In this model inhibition of mature GCs via direct activation of 5-HT 1A Rs or via the local microcircuitry is therefore critical for the antidepressant response.
A proposed model of the hippocampal microcircuit underlying the effects of increased serotonin on the dentate gyrus. NPCs then proliferate and differentiate into young adult born granule cells abGCs , which will begin to migrate, mature, and finally integrate into the granule cell layer. However, the young abGCs have distinct plasticity properties from the mature dentate gyrus granule cells and activate local GABAergic interneurons to evoke strong inhibitory input to the mature granule cells.
Interestingly, 5-HT 1A Rs show a unique expression pattern in the rodent DG as expression levels dramatically increase along the dorsoventral axis to the point that the vast majority of DG 5-HT 1A Rs are expressed in the ventral pole [ 55 ].
Several studies imply that the dorsal hippocampus dHPC and vHPC may serve different functions, where the dHPC is more involved in cognitive functions, while the vHPC is important in regulating emotional affective states [ ]. For instance, dHPC lesions reduce spatial memory in Morris water maze and radial arm maze whereas by vHPC lesions do not impair spatial memory [ , ].
By contrast, inhibition of vHPC projections to medial prefrontal cortex mPFC decreases anxiety-related behavior [ ]. Directly activating granule neurons in the dorsal DG with acute stimulation of ChR2 reduces freezing behavior and recall in the contextual fear conditioning paradigm, however, this effect is not seen when stimulating the vHPC [ ].
By contrast, acute optogenetic inhibition of ventral DG but not dorsal DG results in anxiolytic-like behavioral effects. The different roles dorsal and ventral DG have in mediating diverse behaviors is likely due to a distinct connectivity.
Dorsal DG receives inputs from dorsolateral and caudomedial entorhinal cortex, and medial septal nucleus, which relay inputs from V1, S1, and thalamic nuclei. Efferent outputs from dorsal DG are sent to the mammillary complex, dorsal lateral septum, lateral entorhinal cortex, and anterior cingulate cortex [ , ] Fig. Many of these regions are critical for memory, locomotion, and exploration, thereby demonstrating the importance of the dHPC in cognitive rather than mood related tasks.
Conversely, the ventral DG receives inputs from rostromedial entorhinal cortex and medial septal nucleus that convey information from auditory and piriform cortices. Unlike dorsal DG, ventral DG projects to areas important for regulating emotional affect, with outputs extending to the prefrontal cortex, NAc, hypothalamus, amygdala, medial entorhinal cortex, BNST, as well as rostral and ventral lateral septal nuclei Fig.
The expression of 5-HT 1A receptors along the dorsoventral axis of the hippocampus in a rodent brain. The dorsal and ventral hippocampus participate in distinct circuitry, with the ventral hippocampus projecting to limbic structures. Therefore, 5-HT 1A Rs on dentate gyrus granule cells are well positioned to exert an influence on mood related behaviors. Aside from circuit connectivity, there are electrophysiological, molecular, and anatomic differences between the dHPC and vHPC [ ].
Given that dentate gyrus 5-HT 1A Rs are necessary and sufficient for mediating the behavioral effects of SSRIs, their location in the ventral pole positions these receptors to directly influence limbic circuitry in order to regulate mood-related behavior. Future work is necessary to determine whether specific pharmacological or electrical manipulations of ventral DG may be a novel therapeutic avenue for the treatment of depression and anxiety.
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Benjamin Adam Samuels, Email: National Center for Biotechnology Information , U. Journal List Mol Brain v. Published online Jun Yohn , Mark M. Gergues , and Benjamin Adam Samuels. Author information Article notes Copyright and License information Disclaimer.
Received Dec 1; Accepted Jun This article has been cited by other articles in PMC. Abstract Depression is a polygenic and highly complex psychiatric disorder that remains a major burden on society. Introduction Major depressive disorder MDD is a ubiquitous illness that plagues more than million people worldwide across all races and socioeconomic groups [ 1 , 2 ].
SERT polymorphism Within humans, variants that affect serotonergic function can affect disease susceptibility and response to antidepressant treatment. Serotonin and Neurotrophic factors Since the original development of the monoamine hypothesis of depression, more recent data has expanded this theory to the non-mutually exclusive neurotrophic and neurogenesis hypotheses.
Serotonin and Neurogenesis Over the last two decades, it has become accepted that new neurons are produced in mammals in two discrete locations, the subventricular zone SVZ of the lateral ventricle and the subgranular zone SGZ of the DG in the hippocampus [ ].
Open in a separate window. Availability of data and materials Not applicable. Competing interests The authors declare that they have no competing interests. Consent for publication Not applicable. Ethics approval and consent to participate Not applicable. Contributor Information Christine N. Evidence-based health policy--lessons from the global burden of disease study. Comorbid depression and anxiety spectrum disorders. A clinical and pharmacodynamic evaluation of iproniazid as a psychic energizer.
Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Glowinski J, Axelrod J. Inhibition of uptake of Tritiated-Noradrenaline in the intact rat brain by Imipramine and structurally related compounds. Inhibition of the uptake of tritiated 5-hydroxytryptamine in brain tissue.
Selective serotonin reuptake inhibitors, 2nd edition: Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. Antidepressants most prescribed drugs in U. CNN; [ http: Accessed 1 May Beyond the monoaminergic hypothesis: The myth of reserpine-induced depression: Relapse of depression after rapid depletion of tryptophan. The 5-HT deficiency theory of depression: In , a novel 5-HT receptor was isolated from the small white butterfly, Pieris rapae , and named pr5-HT 8.
It does not occur in mammals and shares relatively low similarity to the known 5-HT receptor classes. Functions in rodents, pseudogene in humans. Note that there is no 5-HT 1C receptor since, after the receptor was cloned and further characterized, it was found to have more in common with the 5-HT 2 family of receptors and was redesignated as the 5-HT 2C receptor.
The genes coding for serotonin receptors are expressed across the mammalian brain. Genes coding for different receptors types follow different developmental curves.
Specifically, there is a developmental increase of HTR5A expression in several subregions of the human cortex, paralleled by a decreased expression of HTR1A from the embryonic period to the post-natal one. A number of receptors were classed as "5-HT 1 -like" - by it was being argued that, since these receptors were "a heterogeneous population of 5-HT1B, 5-HT1D and 5-HT7" receptors the classification was redundant.
From Wikipedia, the free encyclopedia. MolecularCellular, and Medical Aspects. Sydor A, Brown RY, eds. A Foundation for Clinical Neuroscience 2nd ed. American College of Neurophyscopharmacology. Archived from the original on 21 April International Union of Basic and Clinical Pharmacology. Polish Journal of Pharmacology. Methods Find Exp Clin Pharmacol.
American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. Full Prescribing Information, Section J Pharmacol Exp Ther. At just about the same time, the opposite observation was made for another medication: A more extensive analysis of this molecule revealed that it inhibited the normal degradation of monoamines by the enzyme monoamine oxidase MAO.
The researchers inferred that this beneficial effect on the patients' depression was attributable to higher levels of monoamines' being active in the synapses of their brains.
This insight quickly led to the development of monoamine oxidase inhibitors MAOIs , the first generation of antidepressants.
Many different molecules are now regarded as antidepressants. Each of these molecules increases the amount of certain specific neurotransmitters in certain specific regions of the brain. Over the years, as scientists have demonstrated the involvement of additional neurotransmitters in depression , they have established a classification of antidepressants according to their molecular structure and mode of action.
Antidepressants are now classified into three main families: There are also a number of new medications that act through unique mechanisms and are therefore known as atypical antidepressants. Though they have no action mechanisms in common, all of these atypical antidepressants increase the level of certain neurotransmitters in the synapses.
Lastly, a mood-stabilizing medication such as lithium plays a distinctive role in the treatments available for bipolar disorder, both because of its effectiveness and because it consists of a single chemical element.
The role of 5-HT receptors in depression
5-hydroxytryptamine receptors or 5-HT receptors, or serotonin receptors, are a group of G Increasing cellular levels of IP3 and DAG. Excitatory. 5-HT3. 5-HT receptors are clearly main players in various physiologic and Finally, receptor distribution studies need to reach the subcellular level if we are to. The aim of the present study was to investigate whether changes in brain 5-HT concentrations affect the expression of BDNF mRNA in rat brain. Brain 5-HT.