from Revest's lab (Thesis directed by Umberto Spampinato) will defend her thesis a presentation entitled 'Role of central serotonin receptors in the regulation of ascending dopaminergic pathways: implication in the effects of cocaine.'
Link to the Zoom meeting will be sent on the liste.u1215 mailing list.
This thesis investigates the functional role of the central serotonin receptor2B (5-HT2B) in the regulation of ascending dopaminergic (DA) pathways. Recent results from the laboratory have shown that 5-HT2B receptors differentially modulate ascending DA pathways. Indeed, 5-HT2B receptor antagonists reduce DA release in the nucleus accumbens (NAc), increase DA release in the medial prefrontal cortex (mPFC), and do not alter striatal DA release. This differential control of the mesocorticolimbic DA system involves a functional interaction between 5-HT2B receptors in the dorsal raphe (DR) and 5-HT1A receptors expressed in the CPFm, and results from activation of 5-HT neurons in the DR projecting to the CPFm. These results identified the RD as the major site of action of 5-HT2B receptors in controlling the activity of 5-HT and DA neurons. Furthermore, it was shown that blocking 5-HT2B receptors controls the neurochemical and behavioural responses induced by psychostimulants such as amphetamine, 3,4-methylenedioxymethamphine and cocaine, one of the most widely used drugs in the world. Thus, blocking 5-HT2B receptors suppresses the hyperlocomotion caused by cocaine. This effect, which occurs independently of DA release in the NAc and striatum, where DA activity is closely linked to cocaine-induced behavioural effects, may involve a postsynaptic interaction at the level of DA neurotransmission in subcortical regions. However, (1) the involvement of the CPFm DA in this interaction remains to be determined, given that this brain region is known to have anatomical and functional relationships with the NAc and striatum, and to be involved in cocaine behavioural responses. Furthermore, (2) the cellular localisation of 5-HT2B receptors within the DR and the cellular mechanisms underlying their interactions between the DA and 5-HT networks are unknown at the start of this thesis work.
Thus, the objective of this thesis is to address both of the above points. To this end, we studied the effects of two potent and selective 5-HT2B receptor antagonists (RS 127445 and LY 266097) on 5-HT and DA activity, using neurochemical, cellular and behavioural approaches in rats.
A first group of experiments provided anatomical and functional evidence that 5-HT2B receptors on the DR exert a tonic inhibitory control of 5-HT neurons innervating the CPFm, dependent on GABA interneurons. This 5-HT control is the first step in a complex poly-synaptic regulation leading to the differential control of mesocorticolimbic DA pathways. A second group of experiments shows that blocking 5-HT2B receptors in the DR inhibits cocaine-induced hyperlocomotion by acting at the level of DA neurotransmission in the NAc; this effect results from the potentiation of cocaine-induced DA release in the CPFm.
In conclusion, the work accomplished over the past three years provides substantial information regarding the functional role of the 5-HT2B receptor in the regulation of ascending DA pathways. Furthermore, our results not only improve the understanding of the DA and 5-HT interaction, but also highlight the therapeutic potential of 5-HT2B receptor antagonists for the treatment of cocaine addiction.
Key words: Serotonin, serotonin2B receptors, dopamine, cocaine, rat
Sgambato Véronique: Research Fellow (Lyon) - Rapporteur
Maroteaux Luc: Research Director (Paris) - Rapporteur
Cota Daniela : Research Director (Bordeaux) - Examiner
Voisin Daniel: University Professor (Bordeaux) - Examiner
Artigas Francesc: University Professor (Barcelona) - Guest
Spampinato Umberto: University Professor (Bordeaux) - Supervisor
Date de la soutenance: 17/03/2021 - 14h00
Lieu: Visioconférence Zoom
Pour plus de détails: https://www.bordeaux-neurocampus.fr/event/soutenance-de-theseadeline-cathala/