Tunisi, Lea (2020) Orexin-A-mediated control of VTA-NAc mesolimbic pathway contributes to obesity by endocannabinoid 2-AG-mediated disinhibition of dopaminergic neurons. [Tesi di dottorato]

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Abstract

Obesity is a widespread condition due to an imbalance between high food intake and low energy expenditure in combination with genetic, biological, environmental and behavioural factors. The rate of obesity has increased in last decades and it has been considered responsible for a deterioration in the quality of life and a decrease in life expectancy. A pivotal aspect of obesity is the consumption of food beyond homeostatic needs, known as “food addiction”. This condition is driven by abnormal redundant surrounding edible stimuli and vulnerability to hedonic eating that lead to a lack of control over food intake and a progressive worsening reward homeostasis, shifting the effective doses of highly palatable food (HPF) to higher set points. Recent evidence show that the orexin system is implicated in reward and reinforcement processes, widely based on dopamine (DA). An endocannabinoid-mediated disinhibition of OX-A expressing neurons has been described in the lateral hypothalamus (LH) of leptin signalling-defective obese mice (ob/ob mice), with consequent elevation of orexin A trafficking and release to many LH target areas. Here, we found enhancement of OX-A trafficking and release to VTA of obese ob/ob mice. We sought to investigate the effect of this increased OX-A release on dopamine trafficking in obese mice and the molecular mechanism through which the aberrant OX-A signalling could enhance DA synthesis in the ventral tegmental area (VTA) and its release to nucleus accumbens (NAc). Moreover, we want to investigate if the high dopaminergic tone is able to decrease the reward baseline sensitivity in obese mice by promoting the D2R desensitization in the NAc, the main target of VTA in the mesolimbic circuit. With this purpose, by exploiting morphological, pharmacological and biochemical approaches we found a significant increase of OX-A release to the VTA of obese mice concomitantly with elevation of endocannabinoid-mediated DA synthesis and release in the NAc, wherein triggers an overstimulation-induced desensitization of D2R by binding β-arrestin2. These data show that OX-A is a powerful modulator of dopaminergic system and mesolimbic reward processes, which are strictly associated with the hyperphagia that occurs in obese mice. These results are of special relevance since aberrant OX-A signalling during obesity could trigger the vicious circle underlying compulsive reward-associated feeding, because obese individuals overconsume food to counteract the reduced state of reward, thereby contributing to overweight and addiction.

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