Molecular Connections between Arousal and Metabolic Disease: Orexin and Modafinil

Obesity and metabolic diseases are known to be tightly linked to arousal-sleep cycles. Further, both metabolic disease and arousal are known to have significant impacts on cognitive function in humans and animals. Importantly, the armed forces represent a population at significant risk for increased stress and disrupted arousal-sleep cycles. Because the incidence of metabolic disease and obesity is increasing, even in these physically fit individuals, understanding the interactions between these systems is highly significant. Further, some anti-fatigue pharmacologies e.g.,modafinil are already used in military settings, though their long-term effects on metabolism or central nervous system function are not well-understood. We have completed Year 1 of the proposed funding period to assess the physiological and behavioral effects of this pharmacology on rat subjects. Our first year data demonstrate that chronic administration of intraperitoneal modafinil decreases food intake and body weight in rats. Additionally, we observed that acute central modafinil has deleterious effects on some hippocamapaldependent forms of learning. These findings support out overall hypothesis that pharmacological activation of the central orexin system may modulate energy balance. Ongoing studies are assessing the effects of treatment on insulin sensitivity and also the effects of drug withdrawal on body weight regulation and cognitive function.