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

Alcaraz-Iborra, Manuel; Navarrete, Francisco; Rodríguez-Ortega, Elisa; Fuente, Leticia de la; Manzanares, Jorge; Cubero, Inmaculada

doi:10.3389/fnbeh.2017.00186

Cited by 14 publications

(24 citation statements)

References 66 publications

(98 reference statements)

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“…Previous studies using systemic Ox1R inhibition have suggested that Ox1Rs promote intake in higher-drinking individuals (Moorman and Aston-Jones, 2009; Alcaraz-Iborra et al, 2017; Moorman et al, 2017). We previously demonstrated that Shell Ox1Rs promote 2bc-DID drinking (Lei et al, 2016b) (see section “Materials and Methods”), and that animals drinking under this model reach binge-level blood alcohol concentrations (Lei et al, 2016a).…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, some studies using systemic Ox1R inhibition have suggested that Ox1Rs are particularly important for promoting alcohol intake in higher-drinking individuals (Moorman and Aston-Jones, 2009; Alcaraz-Iborra et al, 2017; Moorman et al, 2017). However, the brain circuit in which Ox1Rs act to drive consumption in higher drinkers remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Nucleus Accumbens Shell Orexin-1 Receptors Are Critical Mediators of Binge Intake in Excessive-Drinking Individuals

et al. 2019

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Excessive, binge alcohol drinking is a potent and pernicious obstacle to treating alcohol use disorder (AUD), and heavy-drinking humans are responsible for much of the substantial costs and harms of AUD. Thus, identifying key mechanisms that drive intake in higher-drinking individuals may provide important, translationally useful therapeutic interventions. Orexin-1-receptors (Ox1Rs) promote states of high motivation, and studies with systemic Ox1R inhibition suggest a particular role in individuals with higher intake levels. However, little has been known about circuits where Ox1Rs promote pathological intake, especially excessive alcohol consumption. We previously discovered that binge alcohol drinking requires Ox1Rs in medial nucleus accumbens shell (Shell), using two-bottle-choice Drinking-in-the-Dark (2bc-DID) in adult, male C57BL/6 mice. Here, we show that Shell Ox1Rs promoted intake during intermittent-access alcohol drinking as well as 2bc-DID, and that Shell inhibition with muscimol/baclofen also suppressed 2bc-DID intake. Importantly, with this large data set, we were able to demonstrate that Shell Ox1Rs and overall activity were particularly important for driving alcohol consumption in higher-drinking individuals, with little overall impact in moderate drinkers. Shell inhibition results were compared with control data combined from drug treatments that did not reduce intake, including NMDAR or PKC inhibition in Shell, Ox1R inhibition in accumbens core, and systemic inhibition of dopamine-1 receptors; these were used to understand whether more specific Shell Ox1R contributions in higher drinkers might simply result from intrinsic variability in mouse drinking. Ineffectiveness of Shell inhibition in moderate-drinkers was not due to a floor effect, since systemic baclofen reduced alcohol drinking regardless of basal intake levels, without altering concurrent water intake or saccharin consumption. Finally, alcohol intake in the first exposure predicted consumption levels weeks later, suggesting that intake level may be a stable trait in each individual. Together, our studies indicate that Shell Ox1Rs are critical mediators of binge alcohol intake in higher-drinking individuals, with little net contribution to alcohol drinking in more moderate bingers, and that targeting Ox1Rs may substantially reduce AUD-related harms.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nucleus Accumbens Shell Orexin-1 Receptors Are Critical Mediators of Binge Intake in Excessive-Drinking Individuals

et al. 2019

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“…The DID procedure is a mouse model that triggers excessive binge-like EtOH drinking that was originally developed by Rhodes et al ( 2005 ) to generate high levels of voluntary EtOH consumption over a short period of time (2–4 h; Thiele and Navarro, 2014 ). The iDID is a prolonged and intermittent version of the standard DID (Alcaraz-Iborra et al, 2017 ). Thus, in the present study, iDID started at PND67 and continued for a total of eight, 7-day cycles, until PND120.…”

Section: Methodsmentioning

confidence: 99%

“…After every individual trial, the floor and walls of the apparatus were extensively cleaned with soapy water and totally dried with paper towels. Percentage of total number of entries to open arms and percentage of total time spent in open arms were registered for anxiety-like behavior assessment (Hargreaves and McGregor, 2007 ; Walf and Frye, 2007 ; Alcaraz-Iborra et al, 2017 ; Marianno et al, 2017 ). The total number of arm entries were recorded to assess locomotor activity (Hargreaves and McGregor, 2007 ; Alcaraz-Iborra et al, 2017 ; Marianno et al, 2017 ).…”

Section: Methodsmentioning

confidence: 99%

Environmental Enrichment During Adolescence Acts as a Protective and Therapeutic Tool for Ethanol Binge-Drinking, Anxiety-Like, Novelty Seeking and Compulsive-Like Behaviors in C57BL/6J Mice During Adulthood

Rodríguez-Ortega

Fuente

Amo

et al. 2018

Front. Behav. Neurosci.

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Repetitive drug/ethanol (EtOH) binge-like consumption during pre-addictive stages favors a transition to addiction in vulnerable organisms. Experimental evidence points to the therapeutic and preventive effects of environmental enrichment (EE) on drug and EtOH addiction; however, little is known regarding EE modulation of binge-like consumption in non-dependent organisms. Here, we explore the impact of early EE on binge-like EtOH consumption: (1) we test whether early EE exposure prevents binge-like EtOH intake (20% v/v) in adult mice under an intermittent drinking in the dark (iDID) schedule; (2) we evaluate the therapeutic effects of EE housing conditions on binge-like EtOH consumption in adult animals; and (3) we compare novelty-seeking and compulsive-like behaviors, and anxiety-like behavior, as measured by the Hole Board (HB) and Elevated Plus Maze (EPM) tests, respectively, in adult EE/standard environment (SE) animals. Adolescent (postnatal day 28; PND28) mice were randomly allocated to two housing conditions (4 animals/cage): EE or SE. At PND67 all the animals were exposed to a schedule of EtOH binge-like iDID. On PND92 half of the animals in each environmental condition (EE and SE) were randomly allocated to two subgroups in a crossover design, where environmental conditions were kept similar to those previously experienced or switched, finally leading to four experimental conditions: EE-EE, EE-SE, SE-SE, and SE-EE. EtOH binge-like consumption continued until PND140, when EPM and HB tests were finally conducted. The main observations were: (1) EE-reared mice showed lower EtOH binge-like intake than SE-reared mice during adulthood, which supports a protective role for EE. (2) when adult EtOH drinking SE-reared mice were switched to EE conditions, a reduction in EtOH binge-like consumption was observed, suggesting a therapeutic role for EE; however, losing EE during adulthood triggered a progressive increase in EtOH binge-like intake. Moreover, (3) EE-housed adult animals with long-term exposure to EtOH binge-drinking showed lower anxiety-like, compulsive-like, and novelty-seeking behaviors than SE-housed mice, irrespective of the specific housing conditions during adolescence. We discuss the primary impact of EE on anxiety-like neurobehavioral brain systems through which it secondarily modulates EtOH binge-like drinking.

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“…Traditionally, drug and ethanol (EtOH) addiction research is dominated by studies addressing post-dependent stages of the addiction cycle, modeled by drug/EtOH dependence (Yardley and Ray, 2016 ; Spanagel, 2017 ) and drug/EtOH relapse preclinical procedures (Marchant et al, 2013 ; Vengeliene et al, 2014 ). Because continued binge-like consumption represents a risk behavior that favors transition to addiction (Koob and Le Moal, 2006 ; Courtney and Polich, 2009 ; Crabbe et al, 2011 ; Thiele and Navarro, 2014 ), we have alternatively focused our interest during the last years in the early pre-dependent stage of the addiction cycle dominated by repetitive binge-like intake (Alcaraz-Iborra et al, 2014 , 2017 ; Alcaraz-Iborra and Cubero, 2015 ; Carvajal et al, 2015 ; Rodríguez-Ortega et al, 2018 ). It is our, and others authors (Thiele and Navarro, 2014 ) believe, that understanding those neurobehavioral processes involved in repetitive binge consumption in non-dependent animals would help us to develop new approaches preventing transition to dependence.…”

Section: Introductionmentioning

confidence: 99%

Environmental Enrichment Modulates Drug Addiction and Binge-Like Consumption of Highly Rewarding Substances: A Role for Anxiety and Compulsivity Brain Systems?

Rodríguez-Ortega

Cubero

2018

Front. Behav. Neurosci.

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Drug addiction is a chronic disorder comprising components of both impulsivity and compulsivity in the so called “addiction cycle” which develops over time from early non-dependent, repetitive, binge-consumption to later post-dependent compulsive consumption. Thus, frequent binge-like intake is a typical pattern of excessive drug intake characteristic of the pre-dependent phase of the addiction cycle, which represent an important risk factor to develop addiction in vulnerable individuals. In this framework, it is of paramount interest to further understand the earliest stage of the addiction cycle so novel approaches would emerge aimed to control repetitive episodes of binge-consumption in non-dependent subjects, protecting vulnerable individuals from transition to dependence. Environmental enrichment (EE) is a preclinical animal model in which animals are housed under novel, social enriched conditions, which allows exercising and provides sensory and cognitive stimulation. EE promotes important improvements for a variety of cognitive processes and clear therapeutic and protective effects preventing ethanol (EtOH) and drug addiction as well. Interestingly, recent observations suggest that EE might additionally modulate binge-like intake of highly palatable caloric substances, including EtOH, which suggests the ability of EE to regulate consumption during the initial stage of the addiction cycle. We have proposed that EE protective and therapeutic effects on binge-consumption of palatable substances might primarily be mediated by the modulatory control that EE exerts on anxiety and impulsivity/compulsivity traits, which are all risk factors favoring transition to drug addiction.

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

Cited by 14 publications

References 66 publications

Nucleus Accumbens Shell Orexin-1 Receptors Are Critical Mediators of Binge Intake in Excessive-Drinking Individuals

Nucleus Accumbens Shell Orexin-1 Receptors Are Critical Mediators of Binge Intake in Excessive-Drinking Individuals

Environmental Enrichment During Adolescence Acts as a Protective and Therapeutic Tool for Ethanol Binge-Drinking, Anxiety-Like, Novelty Seeking and Compulsive-Like Behaviors in C57BL/6J Mice During Adulthood

Environmental Enrichment Modulates Drug Addiction and Binge-Like Consumption of Highly Rewarding Substances: A Role for Anxiety and Compulsivity Brain Systems?

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