Batiment BBS
Soutenance en anglais
Directeur de thèse :Philippe De Deurwaerdère
Title
Action des récepteurs 5-HT2A sur les systèmes de neurotransmetteurs dans le cerveau de souris : application aux psychédéliques
Action of 5-HT2A receptors on neurotransmitter systems in the mouse brain: application to Psychedelics
Résumé
Le sous-type de récepteur de la sérotonine 2A (5-HT2AR) suscite un grand intérêt suite aux recherches clinique et préclinique sur les psychédéliques sérotoninergiques. Ces composés ont une action agoniste convergente sur le 5-HT2AR et ont des propriétés antidépressives et anxiolytiques. Cet intérêt s’ajoute à des données antérieures montrant que l’antagonisme du récepteur 5-HT2AR, qui fait partie du profil pharmacologique des antipsychotiques atypiques, pourrait avoir des effets bénéfiques dans plusieurs pathologies dont la schizophrénie. Néanmoins, l’impact des 5-HT2AR sur le fonctionnement cérébral, en particulier sur la neurotransmission, est peu connu. Les réseaux cérébraux fonctionnels ont été conceptualisés en corrélant des signaux électriques ou métaboliques entre les régions du cerveau grâce à l’imagerie par résonance magnétique fonctionnelle ou l’encéphalographie. Ces études de neuroimagerie ont montré que les psychédéliques modifient la connectivité de réseaux cérébraux mais elles ne peuvent pas évaluer la neurochimie des systèmes de neurotransmetteurs et leur interaction. Cette thèse aborde l’hypothèse selon laquelle les agonistes 5-HT2AR psychédéliques perturbent l’organisation fonctionnelle des systèmes de neurotransmetteurs à l’échelle du cerveau. Le contenu tissulaire des neurotransmetteurs classiques (glutamate et GABA) et monoaminergiques (sérotonine, dopamine et noradrénaline) et de leurs métabolites a été mesuré dans 28 régions du cerveau de souris après l’administration d’un agoniste et d’un antagoniste 5-HT2AR de haute affinité, le TCB-2 et le MDL100,907, respectivement. Pour promouvoir une organisation cohérente des systèmes de neurotransmetteurs, les souris ont été placées dans un paradigme d’exploration forcée et leur comportement a été filmé avant la quantification neurochimique post-mortem. Un défi important de cette thèse fut la manipulation d’un large nombre de données neurochimiques qui, au-delà de l’aspect quantitatif, permet une approche corrélative incorporant la théorie des graphes pour construire des réseaux de connectivité neurochimique. Cette nouvelle analyse a entraîné le développement d’un code accompagnant le lancement d’une base de données neurochimiques pour rendre accessible ces données.
Mots clés: Neurochimie, neurotransmetteurs, réseaux neurochimiques, comportement, pharmacologie, récepteur de la sérotonine 2A
Abstract
The serotonin 2A receptor subtype (5-HT2AR) has gained interest following a resurgence of clinical and pre-clinical research on serotonergic psychedelics, compounds with converging agonist action on the 5-HT2AR. Psychedelics have antidepressant and anxiolytic properties, particularly when paired with therapy. Antagonism at the 5-HT2AR, as part of the pharmacological profile of atypical antipsychotics, may have benefits for schizophrenia and bipolar disorder. Despite their clinical relevance, the known impact of 5-HT2ARs on brain function, particularly neurotransmission, is limited. Functional brain networks have been conceptualised by correlating electrical or metabolic neuroimaging signals between brain regions using functional magnetic resonance imaging or encephalography. These studies have shown that psychedelic 5-HT2AR agonists alter the connectivity of these brain-wide networks. However, neuroimaging is currently unable to assess the neurochemistry of neurotransmitter systems and their interplay. This thesis addresses the hypothesis that psychedelic 5-HT2AR agonists disrupt the functional organization of brain-wide neurotransmitter systems. Tissue content of both classical (glutamate and GABA) and monoaminergic (serotonin, dopamine and noradrenaline) neurotransmitters and their metabolites were measured in 28 regions of the mouse brain following high-affinity 5-HT2AR agonist and antagonist, TCB-2 and MDL100,907 respectively. To promote a coherent organisation of neurotransmitter systems mice were placed in a forced exploration paradigm and their behaviour was filmed before post-mortem neurochemical quantification. A significant challenge of this thesis lies in manipulating such a large neurochemical dataset that, beyond quantitative modulation, allows for a correlative approach incorporating graph theory to build networks of neurochemical connectivity. This novel analysis prompted the development of code to accompany the launch of a neurochemical database, including this dataset, making analysis using this new approach accessible.
The obtained results demonstrate that a variety of compounds across the 28 brain regions form distinct neurobiological networks that can be monitored with high-pressure liquid chromatography coupled to electrochemical detection. A striking density of neurochemical correlations between brain regions in vehicle-treated animals was observed, with a distinct regional organisation for dopamine and noradrenaline. The 5-HT2AR agonist TCB-2 (0.3, 3, and 10 mg/kg) as well as the 5-HT2AR antagonist MDL-100,907 (0.2 mg/kg) reduced the number of correlations and disrupted the organisation of correlations for all neurotransmitters across the brain. Some effects of TCB-2, notably on serotonergic parameters were independent of 5-HT2ARs in several brain regions. Other effects including behavioural parameters such as head twitches or components of the exploratory behaviour, as well as the levels of serotonin, dopamine, and noradrenaline in the anterior cingulate cortex were reduced by MDL-100,907 pretreatment. MDL-100,907 alone had very few effects on the quantity of neurochemicals across brain regions. Overall, this thesis highlights that 5-HT2ARs likely play an important role in organising the coherence of neurotransmitter systems in response to a forced exploratory behaviour whether or not it is associated with quantitative changes. The thesis offers a new paradigm to address the function of neurotransmitter systems. It enlarges the understanding of the mechanism of psychedelic action in the brain including vast brain territories (sensory, motor, cognitive) with some lateralized effects, and altered connectivity of neurotransmission systems.
Keywords: Neurochemistry, neurotransmitters, neurochemical networks, behaviour, pharmacology, serotonin 2A receptor
Publications
Butler, J. J. *, Parrot, S. *, Aman, C., & De Deurwaerdère, P. (2024). Neurochemical Databases: Purpose and Expectations. ACS Chemical Neuroscience, acschemneuro.4c00812. https://doi.org/10.1021/acschemneuro.4c00812
Butler, J. J., Ricci, D., Aman, C., Beyeler, A., & De Deurwaerdère, P. (2024). Classical psychedelics’ action on brain monoaminergic systems. The International Journal of Biochemistry & Cell Biology, 176, 106669. https://doi.org/10.1016/j.biocel.2024.106669
Marty, V.*, Butler, J. J.*, Coutens, B., Chargui, O., Chagraoui, A., Guiard, B. P., De Deurwaerdère, P., & Cavaillé, J. (2023). Deleting Snord115 genes in mice remodels monoaminergic systems activity in the brain toward cortico-subcortical imbalances. Human Molecular Genetics, 32(2), 244–261. https://doi.org/10.1093/hmg/ddac139
Martin, H., Bullich, S., Martinat, M., Chataigner, M., Di Miceli, M., Simon, V., Clark, S., Butler, J., Schell, M., Chopra, S., Chaouloff, F., Kleinridders, A., Cota, D., De Deurwaerdere, P., Pénicaud, L., Layé, S., Guiard, B. P., & Fioramonti, X. (2022). Insulin modulates emotional behavior through a serotonin-dependent mechanism. Molecular Psychiatry. https://doi.org/10.1038/s41380-022-01812-3
Martin, H., Coursan, A., Lallement, J., Di Miceli, M., Kandiah, J., Raho, I., Buttler, J., Guilloux, J., De Deurwaerdere, P., Layé, S., Routh, V. H., Guiard, B. P., Magnan, C., Cruciani‐Guglielmacci, C., & Fioramonti, X. (2023). Serotonergic neurons are involved in the counter‐regulatory response to hypoglycemia. Journal of Neuroendocrinology, 35(12), e13344. https://doi.org/10.1111/jne.13344
Submitted
Butler JJ, Virgili M, Di Giovanni G, Chagraoui A, Beyeler A, De Deurwaerdère P. 5-HT2A Receptors Structure Monoaminergic Connectivity in the male Mouse Brain. Submitted December 7th to Progress in Neuropsychopharmacology and Biological Psychiatry.
Butler JJ*, Aman C*, Rivalan M, Parrot S, Dellu-Hagedorn F, De Deurwaerdère P. Neurochemical assessment of tissue levels of neurotransmitters: from quantification to correlative networks. Submitted January 24th to ACS Chemical Neuroscience.
In preparation
Butler JJ, Virgili M, Di Giovanni G, Chagraoui A, Beyeler A, De Deurwaerdère P. 5-HT2A Receptor Activation and Blockade Disrupt Amino Acid Connectivity in the Male Mouse Brain: Possible Role of Monoaminergic Neurotransmitters. To be submitted Included in the thesis.
Butler JJ, Aman C, Bharatiya R, Chagraoui A, Cathala A, De Deurwaerdère P. Neurochemistry and post-mortem neurotransmitters: toward the study of neurochemical connectivity. To be submitted Included in the thesis.
Composition du jury
- Mme DARNAUDERY Muriel Université de Bordeaux, Pr Président du jury
- NAASSILA Mickael Université Jules Vernes, Amiens, Pr Rapporteur
- Mme BECAMEL Carine Université de Montpellier, MCU Rapporteur