Orexin (hypocretin) signaling in ventral tegmental area as a common mediator of sleep disturbances and drug demand in cocaine abstinence

Summary/Abstract: Initial cocaine abstinence is associated with severe sleep disturbances. Poor sleep is one of the strongest predictors of return to use (relapse), suggesting potential overlap in brain arousal and reward networks. Separate literatures link orexin (hypocretin) neurons in lateral hypothalamus (LH) to the regulation of

wake and drug motivation, yet how these neurons might commonly contribute to sleep disturbances and subsequent drug use in CUD is not well understood. In rats, the intermittent access (IntA) schedule of cocaine self-administration increases cocaine demand, a behavioral economics measure of drug motivation. These

motivational changes are persistent and are further enhanced following protracted abstinence. We showed that cocaine IntA is associated with an increase in the number and activity of orexin producing neurons, and that these increases are causally linked to cocaine demand. Our preliminary studies indicate that cocaine IntA rats

also exhibit sleep dysregulation during initial abstinence, characterized by excessive wakefulness and a corresponding reduction in NREM (non-rapid eye movement) sleep. In Aim 1, we test if these sleep disturbances persist throughout protracted (28d) abstinence following cocaine IntA, and how they are related to population

activity of orexin neurons throughout the inactive period. Using a chemogenetic approach, we predict that normalizing orexin neuronal activity during the inactive period will improve sleep outcomes and reduce cocaine demand following protracted abstinence. In Aim 2, we test if orexin projections to ventral tegmental area (VTA)

are involved in mediating excessive wakefulness during cocaine abstinence. This is based on our preliminary data showing that waking is associated with increased orexin binding in VTA, as determined by the novel OxLight1 sensor. We predict OxLight1 signal in VTA will be enhanced in IntA rats during early and protracted

abstinence, and that chemogenetic inhibition of VTA-projecting orexin neurons will normalize both sleep and cocaine demand outcomes at both timepoints. We will also determine how IntA changes levels of orexin 1 (Ox1R) vs orexin 2 (Ox2R) receptors in VTA and their functional role in mediating arousal and cocaine demand during

abstinence. Finally, in Aim 3, we test the potential utility of repurposing the FDA approved dual Ox1R/Ox2R antagonist suvorexant for use in CUD. We predict that daily dosing with suvorexant, administered immediately prior to the inactive period, will normalize sleep and reduce drug motivation in IntA rats. Based on data indicating

that suvorexant can persistently reduce orexin levels, we also predict that chronic suvorexant will normalize orexin cell numbers and their input to VTA, and thus reduce drug demand beyond the treatment period. Together, these studies combine several cutting-edge approaches to determine how orexin neurons, and their inputs to

VTA, might serve as a neurobiological link between sleep disturbances and drug motivation during abstinence. This project is therefore an important step forward in the development of an orexin-based treatment for CUD.