Mécanismes physiopathologiques des comportements impulsifs associés à la maladie de Parkinson : approches expérimentales chez le rat

Abstract : Beyond motor symptoms, Parkinson’s disease (PD) is also characterized by a plethora of neuropsychiatric deficits, ranging from apathy and depression to Impulse control disorders (ICDs). ICDs represent a complex group of behavioral addictions including gambling disorders, hypersexuality and compulsive shopping, displayed by 10 to 14% of PD patients under dopamine replacement therapies, whose quality of life is greatly diminished. Importantly, cognitive impulsivity reflecting in particular, an inability to tolerate delays to reinforcements, appears as a core symptom of ICDs. Indeed, recent evidence suggested that this kind of impulsivity would be exacerbated in PD and under treatment by dopaminergic D2/3 receptor agonists. However, the mechanisms underlying ICDs in PD remain unknown and the respective contribution of dopamine lesion and treatment, combined with factors of vulnerability, remain to be determined. Moreover, waiting impulsivity, another form of behavioral inhibition which may lead to compulsive behaviors, has been poorly investigated in the framework of ICDs.In this thesis project, using a lesional rodent model of non-motor symptoms of PD, we addressed the question of whether denervation of the dopaminergic nigrostriatal system would promote the development of impulsivity when combined with dopamine agonist treatments. Rats were bilaterally injected in the SNc with the neurotoxin 6-OHDA to induce selective and partial denervation of the dorsal striatum. We then treated them with the dopamine D2/3 receptor agonist, pramipexole, a medication known to favor the development of ICDs in PD patients. Two different tasks were used to measure cognitive and motor impulsivity: the delay discounting task (DDT) and the 5-choice serial reaction time task (5-CSRTT) respectively. In the former, rats have to press a lever and choose between a smaller, but immediate reward and a larger, but delayed reward. For the latter, they have to wait for a stimulus light to come on. In the DDT, chronic administration of pramipexole treatment only increased impulsive choices in non-lesioned rats. Indeed, the dopaminergic lesion by itself, or in adjunction with the treatment, did not increase impulsivity. In the 5-CSRTT, pramipexole progressively increased premature responses, reflecting a pro-impulsive effect when the inter-trial interval is constant. However, when the interval was increased, pramipexole reduced the premature responses, exhibiting an anti-impulsive effect. Interestingly, this modulation of motor impulsivity was only observed in rats with a high level of impulsivity, suggesting that an impulsive endophenotype might be an important factor of vulnerability to the iatrogenic effects of pramipexole.The effect of this treatment was then investigated at a cellular level. It promotes overexpression of the dopamine D2 receptor mRNA within the striatum, and seems to alter glutamatergic synaptic connectivity suggested by electron microscopy. Moreover, we showed that the mammalian target of rapamycin complex 1 (mTORC1) pathway is lastingly over-activated in the nucleus accumbens, as already observed in drug addictions. In an attempt to make a causal link between this pathway and the behavioral changes, we treated rats with pramipexole and rapamycine, a specific inhibitor of this pathway. Surprisingly, this combination accentuated impulsivity even more, whereas rapamycine by itself did not promote impulsivity. This effect may be explained by the complexity of the kinetics of activation and inhibition of mTORC1 pathway.Taken together, these results suggest that impulsivity in PD may be triggered by an iatrogenic effect of the dopaminergic pramipexole treatment through an abnormal activation of the mTORC1 pathway within the nucleus accumbens.
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Robin Magnard. Mécanismes physiopathologiques des comportements impulsifs associés à la maladie de Parkinson : approches expérimentales chez le rat. Neurosciences [q-bio.NC]. Université Grenoble Alpes, 2019. Français. ⟨NNT : 2019GREAV006⟩. ⟨tel-02137460⟩

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