Title: Role of central serotonin2B receptors in the regulation of ascending dopaminergic pathways: implication in the effects of cocaine.
Thesis supervisor: Umberto Spampinato
Defense in french
This thesis work focuses on the study of the functional role of the central serotonin2B receptor (5-HT2BR) in the regulation of ascending dopaminergic (DA) pathways. Recent results obtained in the laboratory have shown that 5-HT2BRs differentially modulate ascending dopaminergic (DA) pathways. Indeed, 5-HT2BR antagonist reduces DA release in the nucleus accumbens (NAc), increases DA release in the medial prefrontal cortex (mPFC), and had no effect on striatal DA release. This differential control on the DA system involves an interaction between 5-HT2BR in the dorsal raphe nucleus (DRN) and 5-HT1AR expressed in the mPFC, and results from an activation of DRN 5-HT neurons projecting to the mPFC. These results point out the DRN as the major site of action of 5-HT2BRs to the control of 5-HT and DA activity. In addition, it has been shown that 5-HT2BRs blockade control the neurochemical and behavioral responses induced by psychostimulants as amphetamine, 3,4-methylenedioxymethamphetamine and cocaine, one of the most worldwide abused drugs. Indeed, 5-HT2BR blockade suppresses cocaine-induced hyperlocomotion. This effect, which occurs independently of DA release in the NAc and striatum, where DA activity is tightly related to cocaine-induced behavioral reponses, likely involves post-synaptic interaction in subcortical DA brain regions. Nevertheless, (1) the involvement of mPFC DA release in this interaction remained to be determined, as this brain region is known for its anatomical and functional relationships with the NAc and striatum, and its involvement in cocaine-induced behavioral responses. (2) In addition, the cellular localization of 5-HT2BR within the DRN and the cellular mechanisms underlying their interactions between DA and 5-HT networks are unknown at the beginning of this study. Thus, the objective of this thesis is to answer the two points mentioned above. To this purpose, we assessed the effects of two potent and selective 5-HT2BR antagonists (RS 127445 and LY 266097) on 5-HT and DA activity, by using neurochemical, cellular and behavioral approaches in rats.
In a first group of experiments, we provided anatomo-functional evidences showing that 5-HT2BR exert a GABA-mediated tonic inhibitory control on DRN 5-HT neurons innervating mPFC. This 5-HT control is a first step of a complex poly-synaptic regulation leading to differential control of DA mesocorticolimbic pathways. A second group of experiments shown that 5-HT2BR blockade inhibits cocaine-induced hyperlocomotion by acting at the level of DA neurotransmission in NAc, this effect resulting from the potentiation of cocaine-induced mPFC DA release.
To conclude, the work accomplished over the past three years provides substantial information with regards to the functional role of 5-HT2BRs in the regulation of the activity of ascending DA pathways. Moreover, while improving the understanding of the interaction between DA and 5-HT systems, the present findings altogether highlight the therapeutic potential of 5-HT2BR antagonists for the treatment of cocaine addiction.
Keywords: Serotonin, serotonin2B receptors, dopamine, cocaine, rat
Sgambato Véronique : Chargé de recherche (Lyon) – Rapporteur
Maroteaux Luc: Directeur de recherche (Paris) – Rapporteur
Cota Daniela : Directrice de recherche (Bordeaux) – Examinateur
Voisin Daniel: Professeur d’université (Bordeaux) – Examinateur
Artigas Francesc: Professeur d’université (Barcelone) – Invité
Spampinato Umberto : Professeur d’université (Bordeaux) – Directeur de thèse
Cathala A., Devroye C., Vallée M., Revest J.M., Spampinato U. 2020. Serotonin2B receptor blockade in the rat dorsal raphe nucleus suppresses cocaine-induced hyperlocomotion through an opposite control of mesocortical and mesoaccumbens dopamine pathways. DOI: 10.1016/j.neuropharm.2020.108309.
Spampinato U. Cathala A., Devroye C. 2020. The serotonin2B receptor and neurochemical regulation in the brain. Handbook of the behavioural Neurobiology of serotonin, Second edition; 147-156.
Cathala A., Spampinato U. 2020. Serotonin2B receptor interactions with dopamine network: implications for therapeutics in schizophrenia. Chapitre, sous presse
Cathala A., Devroye C., Drutel G., Revest J.M., Artigas F., Spampinato U. 2019. Serotonin2B receptors in the rat dorsal raphe nucleus exert a GABA-mediated tonic inhibitory control on serotonin neurons. Exp Neurol. 311, 57-66.