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Mécanismes dopaminergiques des symptômes schizophréniques et nouvelles perspectives de modulation thérapeutique

Abstract : Until now, the sole effective treatments in schizophrenia act by blocking the dopaminergic receptors. The hypothesis according to which the so-called “positive” symptoms of schizophrenia (i.e. hallucinations and delusions) are the expression of a hyperdopaminergic transmission within the Ventral Striatum, has be for forty years the main neurobiological explication that has been proposed for these symptoms. However, this hypothesis is questioned as other pharmacological models have been considered about the occurrence of the positive symptoms, notably of the visual hallucinations. In addition, the key role of the Ventral Striatum has been called into question by recent neuroimaging data. Today, schizophrenia is seen as a dynamic process, which consists of both neurodevelopmental and neurodegenerative anomalies, in which oxidative stress might be involved. Therefore, the deregulation of the dopaminergic transmission and the subsequent symptoms may be considered as the final expression of a pathological mechanisms cascade whose beginning is much prior to the symptoms onset. An early pharmacological intervention that may reduce the impact of such mechanisms could have some direct or delayed consequences on the dopaminergic transmission and the related symptoms. We hypothesize that the early activation of Peroxisome-Proliferator Activated Receptors (PPARs), molecules that reduce the oxidative stress processes and may have a direct action on the dopamine transmission, have a potential pharmacological interest in schizophrenia. We want to show that the use of the PPARα agonist fenofibrate during the onset of schizophrenia, can reduce the dopaminergic dysfunction state and the positive symptoms intensity, and thus have a disease-modifier effect. Objectives : Our first goal is to study the effect of fenofibrate on behavioral dopamine-related anomalies that are triggered by a neonatal oxidative lesion. Meanwhile, anticipating a clinical study, we want to prove that the ventral Striatum and the dopamine are involved in the different types of positive symptoms.Methods: The effect of fenofibrate is studied on an experimental model of oxidative neurodevelopmental lesion which induces only at adult age a dopaminergic dysfunction with an alteration of the Prepulse Inhibition (PPI), a behavioral dopamine-related reflex. In addition, we have performed a functional Magnetic Resonance Imaging (fMRI) study that compares the functional connectivity of the Nucleus Accumbens, which belongs to the Ventral Striatum, in case of sole auditory hallucinations or of both visual and auditory hallucinations. Results: we observe that the early introduction of fenofibrate after a neonatal oxidative lesion allows to partially but significantly restore the PPI’s integrity at adult age. Moreover, we show in our fMRI study on patients with schizophrenia that the dopaminergic transmission appears to be involved in the different hallucinatory modalities. Discussion: A disease modifier effect of fenofibrate is reported on neurodevelopmentally-induced dopaminergic dysfunctions. We will complete our results using other models which allow getting additional behavioural, histological and electrophysiological data. Meanwhile, we report that the Ventral Striatum is involved in different types of positive symptoms. Our work makes considering a future evaluation of the fenofibrate’s effect on the positive symptoms and the Ventral Striatum functioning in patient at the onset of schizophrenia.
Keywords : Disease-modifier
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Benjamin Rolland. Mécanismes dopaminergiques des symptômes schizophréniques et nouvelles perspectives de modulation thérapeutique. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2012. Français. ⟨NNT : 2012LIL2S044⟩. ⟨tel-00951780⟩

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