Objective
Serotonin (5-hydroxytryptamine, S-HT) is a major neurotransmitter in the central nervous system.
Currently, 7 types (5-HT1 7) and no less than 15 subtypes of 5-HT receptors have been described. All of them are G-protein linked, with the exception of the 5-HT3 receptor which is a ligand-gated ion channel.
5-HT receptors appear to be involved in basic and integrated physiological processes of the brain (e.g.
presynaptic control of neurotransmitter release, sleep, memory, mood) as well as in socially relevant pathologies (depression, generalised anxiety, obsessive compulsion, dementia, and parkinsonism) and the psychic effects of drugs of abuse (LSD, cocaine, ecstasy).
All the above mentioned diseases share depressive symptomatology, and treatment with antidepressants proves to be of beneficial effect. One of the major targets of antidepressants is the 5-HT transporter, responsible for 5-HT reuptake by serotoninergic neurones. However, treatment with selective 5-HT transporter blockers produces profound modifications in 5-HT receptor responsiveness, which may be also involved in the therapeutic effects of antidepressants.
The understanding of the mechanisms of cellular transduction of 5-HT receptor-mediated signals, as well as of plasticity and degeneration of the 5-HT system, is crucial for developing new drugs and pharmacological strategies for managing these pathologies.
The proposed research aims to elucidatethe roles of 5-HT receptors and 5-HT transporter in physiology and pathology.
The measurable objectives of the present proposal will be:
1) Development of a new preparation of purified serotoninergic synaptosomes suitable for studying, with patch clamp recording, the effects and the mechanisms of action of selective 5-HT agonists (or antagonists) on presynaptic terminals, i.e. at the very site of 5-HT release. This preparation will be adapted also to the dynamic study of intrasynaptosomal calcium. 2) An advancement of knowledge on the cellular mechanisms triggered by stimulation of selected subtypes of 5-HT receptors, namely 5-HTIA, 5-HTlDß, 5-HT7.
3) Functional studies in-vivo will elucidate the relative contributions of 5-HT1A and 5-HTlDß receptors in the modulation of 5-HT release in different brain areas, and investigate the modifications of this balance induced by treatments with antidepressants.
Achievement of these goals will possibly allow identification of receptor subtypes and molecular targets for designing innovative pharmaceutical compounds.
4) Assessment of the changes in expression and responsiveness of several subtypes of 5-HT receptors brought about by pathological states or by administration of drugs of abuse or for management of such pathologies. In particular, the alterations in 5-HT neuro-transmission caused by drugs of abuse, such as "ecstasy", or by treatment with antidepressants will be analysed in animal models including a model of Parkinson disease in primates. 5) Assessment of the changes in density, affinity and distribution of several subtypes of 5-HT receptors associated with Alzheimer disease or induced by treatment with antidepressants in various human brain areas. This new information will possibly allow identification of receptor subtypes as targets for directing new strategies of pharmacological treatment of pathological states.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences neurobiology
- medical and health sciences basic medicine neurology dementia alzheimer
- medical and health sciences basic medicine pathology
- medical and health sciences basic medicine physiology
- medical and health sciences basic medicine neurology parkinson
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Coordinator
75013 Paris
France
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