Several lines of evidence implicate serotonin (5-hydroxytryptamine, 5-HT)in regulating personality traits and mood control. Serotonergic neurons are classically thought to be tonic regular-firing, ..."clock-like" neurons. Neurotransmission by serotonin is tightly regulated by the serotonin transporter (SERT) and by autoreceptors (serotonin receptors expressed by serotonin neurons) through negative feedback inhibition at the cell bodies and dendrites (5-HT
receptors) of the dorsal raphe nuclei or at the axon terminals (5-HT
receptors). In dorsal raphe neurons, the release of serotonin from vesicles in the soma, dendrites, and/or axonal varicosities is independent of classical synapses and can be induced by neuron depolarization, by the stimulation of L-type calcium channels, by activation of glutamatergic receptors, and/or by activation of 5-HT
receptors. The resulting serotonin release displays a slow kinetic and a large diffusion. This process called volume transmission may ultimately affect the rate of discharge of serotonergic neurons, and their tonic activity. The therapeutic effects induced by serotonin-selective reuptake inhibitor (SSRI) antidepressants are initially triggered by blocking SERT but rely on consequences of chronic exposure, i.e., a selective desensitization of somatodendritic 5-HT
autoreceptors. Agonist stimulation of 5-HT
receptors mimicked behavioral and neurogenic SSRI actions, and increased extracellular serotonin in dorsal raphe. By contrast, a lack of effects of SSRIs was observed in the absence of 5-HT
receptors (knockout-KO), even restricted to serotonergic neurons (
mice). The absence of 5-HT
receptors in serotonergic neurons is associated with a higher 5-HT
-autoreceptor reactivity and thus a lower firing activity of these neurons. In agreement, mice with overexpression of 5-HT
autoreceptor show decreased neuronal activity and increased depression-like behavior that is resistant to SSRI treatment. We propose thus that the serotonergic tone results from the opposite control exerted by somatodendritic (Gi-coupled) 5-HT
and (Gq-coupled) 5-HT
receptors on dorsal raphe neurons. Therefore, 5-HT
receptors may contribute to SSRI therapeutic effects by their positive regulation of adult raphe serotonergic neurons. Deciphering the molecular mechanism controlling extrasynaptic release of serotonin, and how autoreceptors interact in regulating the tonic activity of serotonergic neurons, is critical to fully understand the therapeutic effect of SSRIs.
Serotonergic dysfunction is mainly associated with neuropsychiatric and cardiovascular disorders but has also been linked with many other pathological conditions. Serotonin (5-hydroxytryptamine, ...5-HT) mediates numerous physiological functions in the brain and the periphery by activating a variety of receptors. 5-HT receptors are divided into four classes, three of which belong to the G protein-coupled receptor family. This review provides an overview of the recent pharmacological developments involving the Gq-coupled 5-HT2 receptor subfamily as well as the pathological implications of this receptor subfamily with regard to fibrosis, the central nervous system, cardiovascular disorders, and cancer. The final section highlights new therapeutic opportunities and emerging research revealing unexplored medical opportunities for this class of 5-HT receptors. The development of biased 5-HT2 receptor ligands appears to be an interesting topic in various areas. In light of recent discoveries, the need for the development of new and safer drugs should take into account the risk of cardiovascular side effects such as pulmonary hypertension and heart valve disease.
Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT
receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A ...lack of 5-HT
receptors in mice eliminates the effects of molecules that directly target serotonergic neurons including amphetamine derivative serotonin releasers, and selective serotonin reuptake inhibitor antidepressants. In this work, we tested the hypothesis that 5-HT
receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT
receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT
receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT
-receptor stimulation by BW723C86 counteracted 5-HT
autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT
receptor expression specifically and exclusively from Pet1-positive serotonin neurons (Htr2b
mice), we demonstrated that behavioral and sensitizing effects of MDMA (3,4-methylenedioxy-methamphetamine), as well as acute behavioral and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT
receptor expression in serotonergic neurons. In Htr2b
mice, dorsal raphe serotonin neurons displayed a lower firing frequency compared to control Htr2b
mice as assessed by in vivo extracellular recordings and a stronger hypothermic effect of 5-HT
-autoreceptor stimulation was observed. The increase in head-twitch response to DOI (2,5-dimethoxy-4-iodoamphetamine) further confirmed the lower serotonergic tone resulting from the absence of 5-HT
receptors in serotonin neurons. Together, these observations indicate that the 5-HT
receptor acts as a direct positive modulator of serotonin Pet1-positive neurons in an opposite way as the known 5-HT
-negative autoreceptor.
Addiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, leading to lifelong changes. Common among these changes are alterations of ...neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT
receptor has been involved in various behaviors, including impulsivity, response to antidepressants, and response to psychostimulants, pointing toward putative interactions with the dopamine system. Despite these findings, it remains unknown whether 5-HT
receptors directly modulate dopaminergic activity and the possible mechanisms involved. To answer these questions, we investigated the contribution of 5-HT
receptors to cocaine-dependent behavioral responses. Male mice permanently lacking 5-HT
receptors, even restricted to dopamine neurons, developed heightened cocaine-induced locomotor responses. Retrograde tracing combined with single-cell mRNA amplification indicated that 5-HT
receptors are expressed by mesolimbic dopamine neurons.
and
electrophysiological recordings showed that 5-HT
-receptor inactivation in dopamine neurons affects their neuronal activity and increases AMPA-mediated over NMDA-mediated excitatory synaptic currents. These changes are associated with lower ventral striatum dopamine activity and blunted cocaine self-administration. These data identify the 5-HT
receptor as a pharmacological intermediate and provide mechanistic insight into attenuated dopamine tone following exposure to drugs of abuse.
Here we report that mice lacking 5-HT
receptors totally or exclusively in dopamine neurons exhibit heightened cocaine-induced locomotor responses. Despite the sensitized state of these mice, we found that associated changes include lower ventral striatum dopamine activity and lower cocaine operant self-administration. We described the selective expression of 5-HT
receptors in a subpopulation of dopamine neurons sending axons to the ventral striatum. Increased bursting
properties of these dopamine neurons and a concomitant increase in AMPA synaptic transmission to
dopamine neurons were found in mice lacking 5-HT
receptors. These data support the idea that the chronic 5-HT
-receptor inhibition makes mice behave like animals already exposed to cocaine with higher cocaine-induced locomotion associated with changes in dopamine neuron reactivity.
The serotonin receptor subtypes 2 comprise 5-HT2A, 5-HT2B, and 5-HT2C, which are Gαq-coupled receptors and display distinct pharmacological properties. Although co-expressed in some brain regions and ...involved in various neurological disorders, their functional interactions have not yet been studied. We report that 5-HT2 receptors can form homo- and heterodimers when expressed alone or co-expressed in transfected cells. Co-immunoprecipitation and bioluminescence resonance energy transfer studies confirmed that 5-HT2C receptors interact with either 5-HT2A or 5-HT2B receptors. Although heterodimerization with 5-HT2C receptors does not alter 5-HT2C Gαq-dependent inositol phosphate signaling, 5-HT2A or 5-HT2B receptor-mediated signaling was totally blunted. This feature can be explained by a dominance of 5-HT2C on 5-HT2A and 5-HT2B receptor binding; in 5-HT2C-containing heterodimers, ligands bind and activate the 5-HT2C protomer exclusively. This dominant effect on the associated protomer was also observed in neurons, supporting the physiological relevance of 5-HT2 receptor heterodimerization in vivo. Accordingly, exogenous expression of an inactive form of the 5-HT2C receptor in the locus ceruleus is associated with decreased 5-HT2A-dependent noradrenergic transmission. These data demonstrate that 5-HT2 receptors can form functionally asymmetric heterodimers in vitro and in vivo that must be considered when analyzing the physiological or pathophysiological roles of serotonin in tissues where 5-HT2 receptors are co-expressed.
The serotonin receptor subtypes 2 comprise 5-HT
, 5-HT
, and 5-HT
, which are Gα
-coupled receptors and display distinct pharmacological properties. Although co-expressed in some brain regions and ...involved in various neurological disorders, their functional interactions have not yet been studied. We report that 5-HT
receptors can form homo- and heterodimers when expressed alone or co-expressed in transfected cells. Co-immunoprecipitation and bioluminescence resonance energy transfer studies confirmed that 5-HT
receptors interact with either 5-HT
or 5-HT
receptors. Although heterodimerization with 5-HT
receptors does not alter 5-HT
Gα
-dependent inositol phosphate signaling, 5-HT
or 5-HT
receptor-mediated signaling was totally blunted. This feature can be explained by a dominance of 5-HT
on 5-HT
and 5-HT
receptor binding; in 5-HT
-containing heterodimers, ligands bind and activate the 5-HT
protomer exclusively. This dominant effect on the associated protomer was also observed in neurons, supporting the physiological relevance of 5-HT
receptor heterodimerization
Accordingly, exogenous expression of an inactive form of the 5-HT
receptor in the locus ceruleus is associated with decreased 5-HT
-dependent noradrenergic transmission. These data demonstrate that 5-HT
receptors can form functionally asymmetric heterodimers
and
that must be considered when analyzing the physiological or pathophysiological roles of serotonin in tissues where 5-HT
receptors are co-expressed.
The serotonin 2B (5-HT2B) receptor coupled to Gq-protein contributes to the control of neuronal excitability and is implicated in various psychiatric disorders. The mechanisms underlying its brain ...function are not fully described. Using peptide affinity chromatography combined with mass spectrometry, we found that the PDZ binding motif of the 5-HT2B receptor located at its C-terminal end interacts with the scaffolding protein channel interacting PDZ protein (CIPP). We then showed, in COS-7 cells, that the association of the 5-HT2B receptor to CIPP enhanced receptor-operated inositol phosphate (IP) production without affecting its cell surface and intracellular levels. Co-immunoprecipitation experiments revealed that CIPP, the 5-HT2B receptor, and the NR1 subunit of the NMDA receptor form a macromolecular complex. CIPP increased 5-HT2B receptor clustering at the surface of primary cultured hippocampal neurons and prevented receptor dispersion following agonist stimulation, thus potentiating IP production and intracellular calcium mobilization in dendrites. CIPP or 5-HT2B receptor stimulation in turn dispersed NR1 clusters colocalized with 5-HT2B receptors and increased the density and maturation of dendritic spines. Collectively, our results suggest that the 5-HT2B receptor, the NMDA receptor, and CIPP may form a signaling platform by which serotonin can influence structural plasticity of excitatory glutamatergic synapses.
Background and Purpose
Valvular heart disease (VHD) is highly prevalent in industrialized countries. Chronic use of anorexigens, amphetamine or ergot derivatives targeting the 5‐HT system is ...associated with VHD. Here, we investigated the contribution of 5‐HT receptors in a model of valve degeneration induced by nordexfenfluramine, the main metabolite of the anorexigens, dexfenfluramine and benfluorex.
Experimental Approach
Nordexfenfluramine was infused chronically (28 days) in mice ((WT and transgenic Htr2B ‐/‐, Htr2A ‐/‐, and Htr2B/2A ‐/‐) to induce mitral valve lesions. Bone marrow transplantation was also carried out. Haemodynamics were measured with echocardiography; tissues and cells were analysed by histology, immunocytochemistry, flow cytometry and RT –qPCR. Samples of human prolapsed mitral valves were also analysed.
Key Results
Chronic treatment of mice with nordexfenfluramine activated 5‐HT2B receptors and increased valve thickness and cell density in a thick extracellular matrix, mimicking early steps of mitral valve remodelling. Lesions were prevented by 5‐HT2A or 5‐HT2B receptor antagonists and in transgenic Htr2B −/− or Htr2A/2B −/− mice. Surprisingly, valve lesions were mainly formed by numerous non‐proliferative CD34+ endothelial progenitors. These progenitors originated from bone marrow (BM) as revealed by BM transplantation. The initial steps of mitral valve remodelling involved mobilization of BM‐derived CD34+CD31+ cells by 5‐HT2B receptor stimulation. Analysis of human prolapsed mitral valves showing spontaneous degenerative lesions, demonstrated the presence of non‐proliferating CD34+/CD309+/NOS3+ endothelial progenitors expressing 5‐HT2B receptors.
Conclusions and Implications
BM‐derived endothelial progenitor cells make a crucial contribution to the remodelling of mitral valve tissue. Our data describe a new and important mechanism underlying human VHD.
Les neurones sérotoninergiques forment des réseaux complexes avec les autres systèmes de neurotransmission dans le système nerveux central. Le rôle du récepteur 5-HT2B dans ces réseaux est peu connu. ...L’ablation génétique ou la surexpression virale du récepteur 5-HT2B dans les neurones sérotoninergiques, nous ont permis de mettre en évidence sa participation à l’excitabilité de ces neurones. De fait, le récepteur 5-HT2B est nécessaire à l’action des antidépresseurs et de l'ecstasy qui provoquent une accumulation extracellulaire de sérotonine. Aussi, le récepteur 5-HT2B est capable d’agir tel un modulateur positif, à l’opposé des autorécepteurs 5-HT1A, sur l’activité des neurones sérotoninergiques. Ensuite, l’étude de la distribution du récepteur 5-HT2B et de son interaction avec la protéine de pontage CIPP nous a permis de décrire la distribution subcellulaire du récepteur 5-HT2B dans des cultures primaires de neurones d’hippocampe. La co-expression du récepteur 5-HT2B avec CIPP augmente significativement son adressage somatodendritique dans les synapses excitatrices. Au niveau fonctionnel, CIPP augmente la libération dendritique de calcium dépendante de la stimulation du récepteur 5-HT2B. En synergie avec CIPP, cette stimulation augmente le regroupement des récepteurs glutamatergiques NMDA suggérant un rôle dans la plasticité synaptique pouvant expliquer certains résultats précédents.
Serotonergic neurons are organized in complex networks interacting with other neurotransmitter systems in the brain. The 5-HT2B receptor contribution in these networks remains unclear. Using 5-HT2B receptor genetic ablation or a viral overexpression in the serotoninergic neurons, we have demonstrated its participation to the excitability of these neurons. In fact, 5-HT2B receptors are necessary for serotonin accumulation induced by ecstasy and antidepressants effects. Moreover, 5-HT2B receptors activation counteracts the 5-HT1A dependant inhibition on serotonergic neurons activity. Here we propose 5-HT2B receptor as positive modulator of serotonergic neurons. Then, studying 5-HT2B receptors and CIPP scaffold protein interaction allow us to identify the subcellular distribution of the receptor and a functional role of CIPP. Indeed, overexpression of both proteins in primary hippocampal cultures of neurons increases 5-HT2B receptors somatodendritic targeting at excitatory synapses. Thus CIPP increases dendritic calcium release dependent on 5-HT2B receptor stimulation. In synergy with CIPP, this stimulation increases NMDA receptors clustering suggesting a role in synaptic plasticity that could explain some of the previous findings.
Valvular heart disease (VHD) is highly prevalent in industrialized countries. Chronic use of anorexigens, amphetamine or ergot derivatives targeting the 5-HT system is associated with VHD. Here, we ...investigated the contribution of 5-HT receptors in a model of valve degeneration induced by nordexfenfluramine, the main metabolite of the anorexigens, dexfenfluramine and benfluorex.
Nordexfenfluramine was infused chronically (28 days) in mice ((WT and transgenic Htr
, Htr
, and Htr
) to induce mitral valve lesions. Bone marrow transplantation was also carried out. Haemodynamics were measured with echocardiography; tissues and cells were analysed by histology, immunocytochemistry, flow cytometry and RT -qPCR. Samples of human prolapsed mitral valves were also analysed.
Chronic treatment of mice with nordexfenfluramine activated 5-HT
receptors and increased valve thickness and cell density in a thick extracellular matrix, mimicking early steps of mitral valve remodelling. Lesions were prevented by 5-HT
or 5-HT
receptor antagonists and in transgenic Htr
or Htr
mice. Surprisingly, valve lesions were mainly formed by numerous non-proliferative CD34
endothelial progenitors. These progenitors originated from bone marrow (BM) as revealed by BM transplantation. The initial steps of mitral valve remodelling involved mobilization of BM-derived CD34
CD31
cells by 5-HT
receptor stimulation. Analysis of human prolapsed mitral valves showing spontaneous degenerative lesions, demonstrated the presence of non-proliferating CD34
/CD309
/NOS3
endothelial progenitors expressing 5-HT
receptors.
BM-derived endothelial progenitor cells make a crucial contribution to the remodelling of mitral valve tissue. Our data describe a new and important mechanism underlying human VHD.
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