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

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          Abstract

          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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          Most cited references54

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          The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness.

          Sleep and wakefulness are regulated to occur at appropriate times that are in accordance with our internal and external environments. Avoiding danger and finding food, which are life-essential activities that are regulated by emotion, reward and energy balance, require vigilance and therefore, by definition, wakefulness. The orexin (hypocretin) system regulates sleep and wakefulness through interactions with systems that regulate emotion, reward and energy homeostasis.
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            Transition from moderate to excessive drug intake: change in hedonic set point.

            Differential access to cocaine self-administration produced two patterns of drug intake in rats. With 1 hour of access per session, drug intake remained low and stable. In contrast, with 6 hours of access, drug intake gradually escalated over days. After escalation, drug consumption was characterized by an increased early drug loading and an upward shift in the cocaine dose-response function, suggesting an increase in hedonic set point. After 1 month of abstinence, escalation of cocaine intake was reinstated to a higher level than before. These findings may provide an animal model for studying the development of excessive drug intake and the basis of addiction.
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              Review. Neurobiological mechanisms for opponent motivational processes in addiction.

              The conceptualization of drug addiction as a compulsive disorder with excessive drug intake and loss of control over intake requires motivational mechanisms. Opponent process as a motivational theory for the negative reinforcement of drug dependence has long required a neurobiological explanation. Key neurochemical elements involved in reward and stress within basal forebrain structures involving the ventral striatum and extended amygdala are hypothesized to be dysregulated in addiction to convey the opponent motivational processes that drive dependence. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission such as dopamine and opioid peptides in the ventral striatum, but also recruitment of brain stress systems such as corticotropin-releasing factor (CRF), noradrenaline and dynorphin in the extended amygdala. Acute withdrawal from all major drugs of abuse produces increases in reward thresholds, anxiety-like responses and extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence and to contribute to stress-induced relapse. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for the long hypothesized opponent motivational processes responsible for the negative reinforcement driving addiction.
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                Author and article information

                Journal
                European Journal of Neuroscience
                Eur J Neurosci
                Wiley
                0953816X
                October 14 2018
                Affiliations
                [1 ]Brain Health Institute; Rutgers University and Rutgers Biomedical and Health Sciences; 683 Hoes Lane West Piscataway NJ 08854 USA
                [2 ]The Florey Institute of Neuroscience and Mental Health; Parkville Vic Australia
                [3 ]Save Sight Institute; The University of Sydney; Sydney NSW Australia
                Article
                10.1111/ejn.14166
                7083201
                30240516
                bbf065a3-b435-426b-a776-382f5337bfd5
                © 2018

                http://doi.wiley.com/10.1002/tdm_license_1.1

                http://onlinelibrary.wiley.com/termsAndConditions#vor


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