The Role of Orexins/Hypocretins in Alcohol Use and Abuse

Lawrence, Andrew J

doi:10.1007/7854_2016_55

Cited by 40 publications

(34 citation statements)

References 111 publications

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“…Orexin system seems to play a unified role in coordinating motivational activation under numerous behavioral conditions (James et al, 2016) as showed, for example, by its involving in alcohol use and drug-addiction (Martin-Fardon et al, 2016; Walker and Lawrence, 2016). Recent studies focused their attention on reward system modulation by orexin system.…”

Section: Reward Systemmentioning

confidence: 99%

Orexin System: The Key for a Healthy Life

et al. 2017

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The orexin-A/hypocretin-1 and orexin-B/hypocretin-2 are neuropeptides synthesized by a cluster of neurons in the lateral hypothalamus and perifornical area. Orexin neurons receive a variety of signals related to environmental, physiological and emotional stimuli, and project broadly to the entire CNS. Orexin neurons are “multi-tasking” neurons regulating a set of vital body functions, including sleep/wake states, feeding behavior, energy homeostasis, reward systems, cognition and mood. Furthermore, a dysfunction of orexinergic system may underlie different pathological conditions. A selective loss orexin neurons was found in narcolepsia, supporting the crucial role of orexins in maintaining wakefulness. In animal models, orexin deficiency lead to obesity even if the consume of calories is lower than wildtype counterpart. Reduced physical activity appears the main cause of weight gain in these models resulting in energy imbalance. Orexin signaling promotes obesity resistance via enhanced spontaneous physical activity and energy expenditure regulation and the deficiency/dysfunction in orexins system lead to obesity in animal models despite of lower calories intake than wildtype associated with reduced physical activity. Interestingly, orexinergic neurons show connections to regions involved in cognition and mood regulation, including hippocampus. Orexins enhance hippocampal neurogenesis and improve spatial learning and memory abilities, and mood. Conversely, orexin deficiency results in learning and memory deficits, and depression.

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Section: Reward Systemmentioning

confidence: 99%

Orexin System: The Key for a Healthy Life

et al. 2017

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“…To this end, a biomarker that predicts how an individual might respond to a specific pharmacological treatment would be very useful. A large number of studies now point to the hypothalamic orexin (hypocretin) system as a promising target for pharmacotherapies designed to reduce craving and drug‐seeking behavior (James et al ., , ; Yeoh et al ., ; Walker & Lawrence, ; Campbell et al ., ; Perrey & Zhang, ). Orexin peptides act at two receptors, orexin receptor 1 and 2 (OxR1, OxR2); studies generally support a dichotomy of function with respect to OxR1 vs. OxR2 signaling, with OxR1 mediating motivational processes and OxR2 being more important in governing sleep/wake function (Sakurai, ; James et al ., ; Brodnik et al ., ).…”

Section: Introductionmentioning

confidence: 99%

Demand elasticity predicts addiction endophenotypes and the therapeutic efficacy of an orexin/hypocretin‐1 receptor antagonist in rats

James

Bowrey

Stopper

et al. 2018

Eur J of Neuroscience

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Behavioral economics is a powerful, translational approach for measuring drug demand in both humans and animals. Here, we asked if demand for cocaine in rats with limited drug experience could be used to identify individuals most at risk of expressing an addiction phenotype following either long‐ or intermittent access self‐administration schedules, both of which model the transition to uncontrolled drug‐seeking. Because the orexin‐1 receptor antagonist SB‐334867 (SB) is particularly effective at reducing drug‐seeking in highly motivated individuals, we also asked whether demand measured after prolonged drug experience could predict SB efficacy. Demand elasticity (α) measured immediately following acquisition of cocaine self‐administration (‘baseline α’) was positively correlated with α assessed after 2w of long‐ or intermittent access. Baseline α also predicted the magnitude of compulsive responding for cocaine, drug‐seeking in initial abstinence and cued reinstatement following long‐, intermittent‐ or standard short access. When demand was measured after these differential access conditions, α predicted the same addiction endophenotypes predicted by baseline α, as well as primed reinstatement and the emergence of negative emotional mood behavior following abstinence. α also predicted the efficacy of SB, such that high demand rats showed greater reductions in motivation for cocaine following SB compared to low demand rats. Together, these findings indicate that α might serve as a behavioral biomarker to predict individuals most likely to progress from controlled to uncontrolled drug use, and to identify individuals most likely to benefit from orexin‐based therapies for the treatment of addiction.

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“…Finally, we seek to identify key gaps in our knowledge regarding orexin function in addiction that will be important to address in the coming decade of research in this field. Throughout this article, we focus primarily on psychostimulant drugs, as the role of orexin in alcohol use and abuse is covered elsewhere in this volume [22]. …”

Section: Introductionmentioning

confidence: 99%

A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?

James

Mahler

Moorman

et al. 2016

Current Topics in Behavioral Neurosciences

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One decade ago, our laboratory provided the first direct evidence linking orexin/hypocretin signaling with drug seeking by showing that activation of these neurons promotes conditioned morphine-seeking behavior. In the years since, contributions from many investigators have revealed roles for orexins in addiction for all drugs of abuse tested, but only under select circumstances. We recently proposed that orexins play a fundamentally unified role in coordinating “motivational activation” under numerous behavioral conditions, and here we unpack this hypothesis as it applies to drug addiction. We describe evidence collected over the past 10 years that elaborates the role of orexin in drug seeking under circumstances where high levels of effort are required to obtain the drug, or when motivation for drug reward is augmented by the presence of external stimuli like drug-associated cues/contexts or stressors. Evidence from studies using traditional self-administration and reinstatement models, as well as behavioral economic analyses of drug demand elasticity, clearly delineates a role for orexin in modulating motivational, rather than the primary reinforcing aspects of drug reward. We also discuss the anatomical interconnectedness of the orexin system with wider motivation and reward circuits, with a particular focus on how orexin modulates prefrontal and other glutamatergic inputs onto ventral tegmental area dopamine neurons. Last, we look ahead to the next decade of the research in this area, highlighting the recent FDA approval of the dual orexin receptor antagonist suvorexant (Belsomra®) for the treatment of insomnia as a promising sign of the potential clinical utility of orexin-based therapies for the treatment of addiction.

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The Role of Orexins/Hypocretins in Alcohol Use and Abuse

Cited by 40 publications

References 111 publications

Orexin System: The Key for a Healthy Life

Orexin System: The Key for a Healthy Life

Demand elasticity predicts addiction endophenotypes and the therapeutic efficacy of an orexin/hypocretin‐1 receptor antagonist in rats

A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?

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