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

Abstract

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.

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

“…Preclinical research have demonstrated that environmental enrichment (EE), where animals are socially grouped and exposed to sensorial and motor enriched housing conditions (Crofton et al, 2015 ), prevents and also modulates ongoing EtOH intake and drug addiction as well (Nithianantharajah and Hannan, 2006 ). Consistent with this work, we have recently extended this knowledge by showing the therapeutic and protective role of EE on excessive binge-like consumption of EtOH (Rodríguez-Ortega et al, 2018 ). Interestingly, there is experimental evidence indicating that EE exposure also reduces anxiety (Peña et al, 2006 , 2009 ; Sztainberg et al, 2010 ; Rodríguez-Ortega et al, 2018 ), compulsivity (Muehlmann et al, 2012 ; Bechard et al, 2016 ; Rodríguez-Ortega et al, 2018 ) and modulates EtOH (Deehan et al, 2007 , 2011 ; de Carvalho et al, 2010 ; Rodríguez-Ortega et al, 2018 ) and sucrose intake (Brenes and Fornaguera, 2008 ; Grimm et al, 2010 , 2013 , 2016 ).…”

“…Consistent with this work, we have recently extended this knowledge by showing the therapeutic and protective role of EE on excessive binge-like consumption of EtOH (Rodríguez-Ortega et al, 2018 ). Interestingly, there is experimental evidence indicating that EE exposure also reduces anxiety (Peña et al, 2006 , 2009 ; Sztainberg et al, 2010 ; Rodríguez-Ortega et al, 2018 ), compulsivity (Muehlmann et al, 2012 ; Bechard et al, 2016 ; Rodríguez-Ortega et al, 2018 ) and modulates EtOH (Deehan et al, 2007 , 2011 ; de Carvalho et al, 2010 ; Rodríguez-Ortega et al, 2018 ) and sucrose intake (Brenes and Fornaguera, 2008 ; Grimm et al, 2010 , 2013 , 2016 ). Elevated anxiety (Wand, 2005 ), high sensitivity to stress (Goeders, 2003 ) and/or high compulsivity (Figee et al, 2016 ) might significantly increase vulnerability to develop addiction; on the other hand, we have reported that EE modulate spontaneous binge-intake.…”

“…Also, C57BL/6 mice early socially housed showed reduced EtOH binge-like intake in a DID-2BC schedule when compared with their isolated housed counterparts (Lopez et al, 2011 ). EE access blunted high EtOH binge-like intake elicited by chronic social isolation in C57BL/6J mice (Lopez and Laber, 2015 ) and EE rearing during adolescence protected C57BL/6J mice from excessive EtOH binge-like drinking during adulthood (Rodríguez-Ortega et al, 2018 ). Furthermore, EE access significantly ameliorated steady EtOH binge-like consumption of adult mice housed in standard conditions (Rodríguez-Ortega et al, 2018 ) indicating a therapeutic role of EE on EtOH binge-like intake during that early, pre-dependent stage.…”

“…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.…”

“…Elevated anxiety (Wand, 2005 ), high sensitivity to stress (Goeders, 2003 ) and/or high compulsivity (Figee et al, 2016 ) might significantly increase vulnerability to develop addiction; on the other hand, we have reported that EE modulate spontaneous binge-intake. Taking together the aforementioned data, we have proposed the working hypothesis that EE housing conditions might primarily act on anxiety and impulsivity/compulsivity related brain systems during the intoxication early phase of the addiction cycle, protecting vulnerable non-dependent organisms from excessive binge-like intake and transition to dependence (Rodríguez-Ortega et al, 2018 ).…”