"My project aims at gathering new evidence to treat a major health concern: Eating disorders, including anorexia and bulimia nervosa and food bingeing leading to obesity. Following up on our parallel results showing an addictive component in these disorders and a dual role for serotonin (5-HT) in feeding, we postulate that the transition from the abusive consumption of food (food bingeing) towards excessive food deprivation (anorexia-like behavior), depends on the constitutive activity of the 5-HT-4 receptors (5-HTR4) and on changes from its inactive (R) towards its active state (R*) within the nucleus accumbens (NAc), a structure of the brain’s reward system.
To demonstrate that the constitutive activity of 5-HTR4 in the NAc switches the direction of the addiction to food, I will modify the 5-HTR4 activity state using specific pharmacological treatments (from inverse agonist to overexpression) infused in the NAc of behaving brain-specific 5-HT deficient mice (Tph2-/-). Since my preliminary results show that Tph2-/- display feeding alterations (opposite in Tph2-/- and +/-), my first and second objectives will further characterize in detail their feeding pattern and its correlation with 5-HTR4 density in the NAc, body weight and fat storage. My third and fourth objectives test whether infusion of 5-HTR4 inverse agonist (decreased constitutive activity) and 5-HTR4 overexpression (increased constitutive activity) in the NAc induce respectively food bingeing and food refusal via the molecular cascade: cAMP-CART-FosB-ΔFosB. My experiments will show that controls of the “accumbal addiction pathway” by R and R* 5-HTR4 states are opposed and control the intake of food. Finally, I will realize a preclinical study and pave the way for the first clinical study using 5-HTR4 drugs to treat eating disorders. The realization of this innovative interdisciplinary project is a step further to cure eating disorders and will increase my professional maturity and European excellence."
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