نبذة مختصرة : Atypical antipsychotic drugs such as Olanzapine (Ola) induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these undesired side effects are currently unknown. In this thesis, we showed that both acute and chronic administration of Ola lead to metabolic side effects with regards to glucose metabolism. We found that the long-term exposure to the drug modifies its effect during an acute challenge. Ola has affinity for several receptors and an extensive literature concerning the involvement of those receptors is available. We decided to focus on probable hypothalamic mechanisms because this brain structure plays a key role both in body weight regulation and glucose metabolism. The results in this thesis indicate that the metabolic side effects of Ola are partly mediated by the hypothalamic orexin system. The mechanisms by which Ola affects this system remain unclear but several mechanisms have been proposed in this thesis. Ola might influence the orexin neurons in the lateral hypothalamus directly, via the POMC/CART and NPY/AgRP neurons in the arcuate nucleus or even via the brainstem. In conclusion, lowering orexin receptor-1 (OxR1) activity seems to be efficient in reducing the glucoregulatory effects of Ola in rat models and, by inference seems to be an attractive therapeutic target. However, the orexin system is involved in various functions including sleep regulation, and an OxR1 antagonist concomitantly administered with Ola might lead to unwanted effects in patients including disturbed vigilance, therefore use of OxR1 antagonist merits further research.
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