Narcoleptic episodes of laboratory rodents : Development of therapeutic strategies and of a rat model

Abstract

Narcolepsy is a neurodegenerative disease with extensive daytime sleepiness, hypnagogic hallucinations and cataplexy. Narcolepsy is connected to the loss of orexin neurons in the lateral hypothalamus. The present dissertation summarizes two projects with different animal models. Narcoleptic episodes of orexin-deficient mice were treated with potential pharmacological agents (project 1). The development and evaluation of a narcoleptic rat model by stereotactic injections of neurotoxins in the lateral hypothalamus (project 2). The orexin-deficient mice with a prepro-orexin gene deletion develop very similar symptoms to human narcoleptic patients. However, even though cataplexy in narcolepsy patients is treated since decades with antidepressant, it is still unclear via which pharmacological mechanisms they mainly exert their effects. Since antidepressants support monoaminergic function, important roles of the brain norepinephrine and serotonin systems were suggested. In project 1, orexin-deficient mice were treated with selective serotonin reuptake inhibitor and selective norepinephrine reuptake Inhibitor to supress narcoleptic episodes. The data showed that narcoleptic episodes can be more efficiently suppressed by adrenergic stimulation than by serotonergic stimulation. In project 2, a targeted neurotoxin, anti-Ox2R-SAP, was administered in the lateral hypothalamus to develop and evaluate a rat model. A reduction of orexin neurons was obtained. However, this reduction was unselective and went along with a loss of MCH neurons. A group of rats with a high number of orexin neurons (group α) and a group with an effective lesion of orexin neurons (group β) were compared irrespectively of the treatment in various behavioral paradigms. For instance, Body weight increase was diminished significantly in group β. Notably, both groups did not express narcoleptic episodes.