Do Orexins contribute to impulsivity-driven binge consumption of rewarding stimulus and transition to drug/food dependence?

Alcaraz-Iborra, Manuel; Cubero, Inmaculada

doi:10.1016/j.pbb.2015.04.012

Cited by 12 publications

(17 citation statements)

References 54 publications

(66 reference statements)

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“…Such initially transient neuroplastic changes might become consolidated through repeated episodes of binge-like drinking, contributing to the transition to addictive states (Cox et al, 2013 ; Thiele and Navarro, 2014 ). Consistent with this idea, we have recently proposed that repetitive episodes of binge-like consumption of a rewarding stimulus in non-dependent organisms may enhance OX transmission in vulnerable organisms in a positive loop that favors the transition to addiction, from non-dependent/impulse-driven binge consumption to compulsion-driven consumption (Alcaraz-Iborra and Cubero, 2015 ). Under this hypothesis, excessive OX activity might work as a neurobiological mechanism predisposing the transition from EtOH binge drinking to EtOH addiction.…”

Section: Introductionmentioning

confidence: 73%

Different Molecular/Behavioral Endophenotypes in C57BL/6J Mice Predict the Impact of OX1 Receptor Blockade on Binge-Like Ethanol Intake

Alcaraz-Iborra

Navarrete

Rodríguez-Ortega

et al. 2017

Front. Behav. Neurosci.

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Ethanol (EtOH) research has focused on stages of dependence. It is of paramount importance to more deeply understand the neurobehavioral factors promoting increased risk for EtOH binge drinking during the early stages of the addiction cycle. The first objective of this study was to evaluate whether C57BL/6J mice showing high drinking in the dark (DID) exhibit neurobehavioral traits known to contribute to EtOH binge-drinking disorders. Comparing high vs. low drinkers (HD/LD), we evaluated different types of basal anxiety-like responses, EtOH preference and sensitivity to the reinforcing properties of EtOH, and basal mRNA expression of the OX1/OX2 receptors (OX1r/OX2r) within the prefrontal cortex (PFC) and the nucleus accumbens (NAcc). Additionally, we tested binge drinking by LD/HD in response to a selective OX1r antagonist following intermittent episodes of DID (iDID). We report that DID consistently segregates two neurobehavioral endophenotypes, HD vs. LD, showing differences in neophobia and/or impulsivity/compulsivity traits. Additionally, HD mice show decreased basal OX1r and OX2r mRNA expression within the NAcc and elevated OX1r within the PFC. Exposure to several intermittent episodes of EtOH DID triggered a rapid increase in EtOH intake over time in LD mice matching that observed in HD mice. Despite HD/LD endophenotypes did not show differences in EtOH intake, they still predicted the response to a pharmacological challenge with a selective OX1r antagonist. The present data underscore the relevance of HD/LD endophenotypes stemming from DID procedures for exploring neurobehavioral processes underlying the early stages of the addiction cycle and EtOH binge-drinking disorders.

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Section: Introductionmentioning

confidence: 73%

Different Molecular/Behavioral Endophenotypes in C57BL/6J Mice Predict the Impact of OX1 Receptor Blockade on Binge-Like Ethanol Intake

Alcaraz-Iborra

Navarrete

Rodríguez-Ortega

et al. 2017

Front. Behav. Neurosci.

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“…Moreover, in humans and rodents, dual orexin receptor antagonists act primarily to prevent awakening (ie reduced wake after sleep onset) rather than to induce sleep (ie modest effect on sleep latency; Brisbare-Roch et al, 2007). Together, these results suggest that basal orexin tone at OX 1 Rs facilitates prepotent locomotor responses and may mediate impulsivity which itself is characteristic of substance use disorders (reviewed in Alcaraz-Iborra and Cubero, 2015). The decrease in motor impulsivity in the high-dose suvorexant group (30 mg/kg, i.p.)…”

Section: Discussionmentioning

confidence: 99%

Effects of Suvorexant, a Dual Orexin/Hypocretin Receptor Antagonist, on Impulsive Behavior Associated with Cocaine

Gentile

Simmons

Watson

et al. 2017

Neuropsychopharmacol.

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Hypothalamic hypocretin (orexin) peptides mediate arousal, attention, and reward processing. Fibers containing orexins project to brain structures that govern motivated behavior, including the ventral tegmental area (VTA). A number of psychiatric conditions, including attention deficit hyperactivity disorder (ADHD) and substance use disorders, are characterized by deficits in impulse control, however the relationship between orexin and impulsive behavior is incompletely characterized. The effects of systemic or centrally administered orexin receptor (OXR) antagonists on measures of impulsive-like behavior in rats were evaluated using the five-choice serial reaction time task (5-CSRTT) and delay discounting procedures. These paradigms were also used to test the capacity of OXR antagonists to attenuate acute cocaine-evoked impulsivity. Finally, immunohistochemistry and calcium imaging were used to assess potential cellular mechanisms by which OXR blockade may influence motor impulsivity. Suvorexant, a dual (OXR) orexin receptor antagonist, reduced cocaine-evoked premature responses in 5-CSRTT when administered systemically or directly into VTA. Neither suvorexant nor OXR- or OXR-selective compounds (SB334867 or TCS-OX2-29, respectively) altered delay discounting. Finally, suvorexant did not alter Fos-immunoreactivity within tyrosine hydroxylase-immunolabeled neurons of VTA, but did attenuate cocaine- and orexin-induced increases in calcium transient amplitude within neurons of VTA. Results from the present studies suggest potential therapeutic utility of OXR antagonists in reducing psychostimulant-induced motor impulsivity. These findings also support the view that orexin transmission is closely involved in executive function in normal and pathological conditions.

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“…The current results, combined with previous work from our lab (Lopez et al, 2016; Moorman and Aston-Jones, 2009), strongly indicate that these individual differences in ethanol motivation result, at least in part, from differential activation of the ORX system. We and others have emphasized that one of the major functions of the ORX system is in regulating strong drive states, including behaviors such as compulsive seeking of alcohol, other drugs, or other highly-motivating rewards such as high-fat foods (Alcaraz-Iborra and Cubero, 2015; Mahler et al, 2014; Sakurai, 2014; Thompson and Borgland, 2011). Understanding the contribution of the ORX system to highly-motivated alcohol seeking is of particular importance when considering alcohol abuse and addiction.…”

Section: Discussionmentioning

confidence: 99%

Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats

et al. 2017

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The orexin/hypocretin (ORX) system regulates motivation for natural rewards and drugs of abuse such as alcohol. ORX receptor antagonists, most commonly OX1R antagonists including SB-334867 (SB), decrease alcohol drinking, self-administration and reinstatement in both genetically-bred alcohol-preferring and outbred strains of rats. Importantly, levels of alcohol seeking and drinking in outbred rats are variable, as they are in humans. We have shown that OX1R antagonism selectively decreases homecage alcohol drinking in high-, but not low-alcohol-preferring rats. It is unknown, however, whether this effect is selective to homecage drinking or whether it also applies to alcohol seeking paradigms such as self-administration and reinstatement following extinction, in which motivation is high in the absence of alcohol. Here we trained Sprague Dawley rats to self-administer 20% ethanol paired with a light-tone cue on an FR3 regimen. Rats were then extinguished and subjected to cue-induced reinstatement. Rats were segregated into high- and low-ethanol-responding groups (HR and LR) based on self-administration levels. During self-administration and cue-induced reinstatement, rats were given SB or vehicle prior to ethanol seeking. In both conditions, OX1R antagonism decreased responding selectively in HR, but not LR rats. There were no non-specific effects of SB treatment on arousal or general behavior. These data indicate that ORX signaling at the OX1R receptor specifically regulates high levels of motivation for alcohol, even in the absence of direct alcohol reinforcement. This implicates the ORX system in the pathological motivation underlying alcohol abuse and alcoholism and demonstrates that the ORX1R may be an important target for treating alcohol abuse.

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Do Orexins contribute to impulsivity-driven binge consumption of rewarding stimulus and transition to drug/food dependence?

Cited by 12 publications

References 54 publications

Different Molecular/Behavioral Endophenotypes in C57BL/6J Mice Predict the Impact of OX1 Receptor Blockade on Binge-Like Ethanol Intake

Different Molecular/Behavioral Endophenotypes in C57BL/6J Mice Predict the Impact of OX1 Receptor Blockade on Binge-Like Ethanol Intake

Effects of Suvorexant, a Dual Orexin/Hypocretin Receptor Antagonist, on Impulsive Behavior Associated with Cocaine

Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats

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