SCVDD2B · Serotonin, Cardiovascular disease and depression: Contribution of Serotonin 2B Receptors
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2006-05-01 → 2007-10-31
- EU contribution
- €114,237
- Participants
- 1
- Scheme
- IIF
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Results in brief
Final Activity Report Summary - SCVDD2B (Serotonin, Cardiovascular Disease and Depression: Contribution of Serotonin 2B Receptors)
The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is known to modulate a wide range of physiological functions both during embryonic development and in adults, inside and outside the central nervous system. Serotonin has been implicated in the regulation of several cardiovascular and psychiatric disorders including depression. Serotonin receptor diversity and complexity has already been appreciated. However, its physiological integration into the whole organism remains to be elucidated. Our study was an attempt to integrate initial information on the coupling of one of these receptors, the 5-HT2B receptor, into whole organism physiology. By a combination of genetic (5-HT2B receptor mutant mice) and pharmacological ablation (selective 5-HT2B receptor antagonists), the laboratory of Luc Maroteaux previously established a role of serotonin via 5-HT2B receptors: 1. in cardiac development and left ventricular hypertrophy in adult mice; 2. in pathogenesis of pulmonary hypertension in the hypoxic mice model. From the evidence that cardiac fibroblasts from 5-HT2B receptor mutant mice altered responses to hypertrophic stimuli in respect to cytokines production by specifically expressing 5-HT2B receptor specifically in cardiomyocytes, we genetically confirmed that 5-HT2B receptors were required in the cardiac fibroblasts to trigger responses following cardiac neurohumoral stimulation in left ventricular dysfunctions. This work could lead to the development of new cardiac anti-hypertrophic compounds. Given the inhibitory effect of 5-HT2B receptors on 5-HT1B receptor signalling, physical interaction between the two receptors seemed plausible. Our results indicated that the stimulation of 5-HT1B receptors affected the internalisation dynamics of 5-HT2B receptors and vice versa. Our findings revealed that co-expression of 5-HT1B and 5-HT2B receptors affected both the kinetics of receptor internalisation and the internalisation pathway which was employed compared to either receptor expressed alone. Given the wide clinical use of 5-HT1B receptor agonists in the treatment of migraines and the suspected prophylactic effect of 5-HT2B receptor antagonists, these newly identified functional interactions might be involved in therapeutic effects of these compounds. The phenomenon could also be relevant to the design of novel antimigraine therapies. We then evaluated the role of 5-HT2B receptors in mediating the actions of the drug of abuse MDMA, ecstasy. We used a pharmacological approach and a genetic approach to demonstrate that functional 5-HT2B receptors were required for MDMA-induced behavioural effects and 5-HT release in vivo and in vitro. Our findings revealed a novel regulatory component in the actions of MDMA and represented the first demonstration that 5-HT2B receptor played an important role in the brain, i.e. in the modulation of 5-HT release in serotonergic neurons. There are currently no pharmacological treatments for the wide range of symptoms associated with MDMA abuse. Antagonists of the 5-HT2B receptor have no intrinsic effect on basal 5-HT extracellular concentration, suggesting that 5-HT2B receptor antagonists could serve as a promising therapeutic drug for the prevention of the acute and long-term effects associated with MDMA abuse.
Data: CORDIS, © European Union
Project objective
Serotonin (5-hydroxytrypatmine, 5-HT) regulates diverse processes in both the central nervous system (e.g., cognition, perception, mood, feeding behaviour) and the periphery (e.g., smooth muscle contractility, platelet aggregation). As such, dysregulation in the 5-HT system has been shown to contribute to several pathophysiological states, including depression, migraine headaches, and, more recently, some cardiovascular diseases.During my thesis research with Bryan Roth, we demonstrated that 5-HT, the level s of which are elevated in carcinoid syndrome, causes heart valve fibrosis (i.e., cardiac valvulopathy) via activation of 5-HT2B receptors. An additional cardiovascular complication stemming from 5-HT levels is pulmonary hypertension (PH). Prof. Maroteaux has shown, using genetic and pharmacological approaches, that functional 5-HT2B receptors are required for the development of PH in the hypoxic mouse model of the disease. Also, Prof. Maroteaux's in vivo studies have shown that decreased 5-HT2B receptor function prevents hypoxia-induced increases in plasma 5-HT. Thus, 5-HT2B receptors appear to play an unappreciated role in 5-HT synthesis, release, and/or uptake in the cardiovascular system and likely elsewhere (e.g., the CNS).Indeed, preliminary findings from Prof. Maroteaux's group reveal a role for 5-HT2B receptors in the plasma membrane targeting of the 5-HT transporter (SERT), suggesting that 5-HT2B receptors affect 5-HT levels by modulating SERT function. Thus, Prof. Maroteaux and I propose to characterize, through in vitro and tissue-specific in vivo studies, the mechanism of 5-HT2B receptors regulate SERT function and 5-HT levels in the cardiovascular system. These studies are likely to uncover previously unidentified mechanisms regulating 5-HT in the cardiovascular system; mechanisms that may be pertinent in the CNS. As such, our efforts could lead to novel strategies to treat cardiovascular diseases and, possibly, psychiatric disorders.
Original text from CORDIS.
Participants
- INSERM ADR6 ST ANTOINE · PARISCoordinatorCity levelFrance
Links
Data: CORDIS, © European Union