Intermittent Access to Ethanol Drinking Facilitates the Transition to Excessive Drinking After Chronic Intermittent Ethanol Vapor Exposure

Abstract

Background Alcohol binge drinking in humans is thought to increase the risk for alcohol use disorder. Unclear is whether drinking patterns (e.g., binge-like or stable drinking) differentially affect the transition to compulsive-like drinking in dependent individuals. We examined whether chronic binge-like drinking facilitates the transition to compulsive-like drinking in rats. Methods Male Wistar rats were given 5 months of intermittent access to ethanol (IAE) or continuous access to ethanol (CAE) in a two-bottle choice paradigm. Then rats were given chronic intermittent ethanol (CIE) vapor exposure. Escalation of ethanol intake and compulsive-like responding for ethanol, using a progressive-ratio schedule of reinforcement and quinine-adulterated ethanol, were measured. Results IAE rats escalated ethanol drinking after 2 weeks of two-bottle choice, whereas CAE rats exhibited stable ethanol drinking for 5 months. After 8 weeks of CIE, both IAE+CIE and CAE+CIE rats escalated their ethanol intake. However, IAE rats escalated their ethanol intake weeks sooner than CAE rats and exhibited greater ethanol intake. No differences in compulsive-like responding were found between IAE+CIE and CAE+CIE rats. However, both IAE+CIE and CAE+CIE rats showed strong compulsive-like responding compared with rats without prior IAE or CAE. Conclusions Chronic ethanol drinking at stable or escalated levels for several months is associated with more compulsive-like responding for ethanol in rats that are exposed to CIE compared with rats without a prior history of ethanol drinking. Moreover, IAE facilitated the transition to compulsive-like responding for ethanol after CIE exposure, reflected by the escalation of ethanol intake. These results suggest that IAE may facilitate the transition to alcohol use disorder. The present study indicates that despite a moderate level of ethanol drinking, the IAE animal model is highly relevant to early stages of alcohol abuse and suggests that it may be associated with neuroadaptations that produce a faster transition to alcohol dependence.

Inhibition of Glyoxalase 1 reduces alcohol self-administration in dependent and nondependent rats

“…We used the chronic intermittent ethanol (CIE) model combined with operant self-administration, a model that has been shown to have robust predictive validity for alcoholism and construct validity for the neurobiological mechanisms of alcohol dependence (Heilig and Koob, 2007;Koob, 2009). Rats that are made dependent by CIE exhibit clinically relevant blood alcohol levels (BALs; 150-250 mg/100 ml), an increase in alcohol drinking when tested during early and protracted abstinence, and compulsive-like alcohol drinking (e.g., responding despite adverse consequences; Kimbrough et al, 2017b;Leao et al, 2015;O'Dell et al, 2004;Roberts et al, 1996;Schulteis et al, 1995;Vendruscolo et al, 2012). Alcohol dependence that is induced by alcohol vapor results in withdrawal symptoms during both acute withdrawal and protracted abstinence (de Guglielmo et al, 2017;Kallupi et al, 2014;Macey et al, 1996;Vendruscolo and Roberts, 2014), anxiety-like behavior (Valdez et al, 2002), irritabilitylike behavior (Kimbrough et al, 2017a), and the development of mechanical hyperalgesia (Edwards et al, 2012).…”

CRF1receptor-dependent increases in irritability-like behavior during abstinence from chronic intermittent ethanol vapor exposure

“…One cohort of rats ( n = 24) and an additional cohort of rats ( n = 16) were trained to self-administer ethanol. Both cohorts self-administered 10% (w/v) ethanol during daily sessions in standard operant conditioning chambers (Med Associates) until stable responding was maintained as previously described (de Guglielmo et al, 2016, Leao et al, 2015, Kimbrough et al, 2017). The rats were first subjected to an overnight session in the operant chambers with access to one lever (front lever) that delivered water on a fixed-ratio 1 (FR1) schedule (i.e., each operant response was reinforced with 0.1 ml of the solution).…”

“…A commonly used method to study ethanol dependence and withdrawal is the chronic intermittent ethanol (CIE) vapor exposure model (Kissler et al, 2014, Gilpin et al, 2008c, Gilpin et al, 2008b, Staples et al, 2015, Leao et al, 2015, de Guglielmo et al, 2016, Kimbrough et al, 2017). Rats that are made dependent with CIE exhibit clinically-relevant blood ethanol levels (BELs; 150-250 mg%), an increase in ethanol drinking when tested during early and protracted withdrawal, and compulsive-like ethanol drinking (i.e., responding despite adverse consequences; (Rogers et al, 1979, Roberts et al, 1996, Roberts et al, 2000, O’Dell et al, 2004, Schulteis et al, 1995, Vendruscolo et al, 2012, Seif et al, 2013, Leao et al, 2015, Kimbrough et al, 2017).…”

“…A commonly used method to study ethanol dependence and withdrawal is the chronic intermittent ethanol (CIE) vapor exposure model (Kissler et al, 2014, Gilpin et al, 2008c, Gilpin et al, 2008b, Staples et al, 2015, Leao et al, 2015, de Guglielmo et al, 2016, Kimbrough et al, 2017). Rats that are made dependent with CIE exhibit clinically-relevant blood ethanol levels (BELs; 150-250 mg%), an increase in ethanol drinking when tested during early and protracted withdrawal, and compulsive-like ethanol drinking (i.e., responding despite adverse consequences; (Rogers et al, 1979, Roberts et al, 1996, Roberts et al, 2000, O’Dell et al, 2004, Schulteis et al, 1995, Vendruscolo et al, 2012, Seif et al, 2013, Leao et al, 2015, Kimbrough et al, 2017). Ethanol dependence that is induced by ethanol vapor results in withdrawal symptoms during both acute withdrawal (somatic and motivational) and protracted abstinence (motivational; (Macey et al, 1996, Sommer et al, 2008, Schulteis et al, 1995, Williams et al, 2012, Kallupi et al, 2014, Valdez et al, 2002b, Zhao et al, 2007, Vendruscolo and Roberts, 2014, de Guglielmo et al, 2017), but the effects of abstinence from CIE on irritability-like behavior during withdrawal and after protracted abstinence has not yet been reported.…”

CRF1 Receptor‐Dependent Increases in Irritability‐Like Behavior During Abstinence from Chronic Intermittent Ethanol Vapor Exposure

“…A commonly used method to study ethanol dependence and withdrawal is the chronic intermittent ethanol (CIE) vapor exposure model (Gilpin et al., ,; de Guglielmo et al., ; Kimbrough et al., ; Kissler et al., ; Leao et al., ; Staples et al., ). Rats that are made dependent with CIE exhibit clinically relevant blood ethanol levels (BELs; 150 to 250 mg/100 ml), an increase in ethanol drinking when tested during early and protracted withdrawal, and compulsive‐like ethanol drinking (e.g., responding despite adverse consequences; Kimbrough et al., ; Leao et al., ; O'Dell et al., ; Rogers et al., ; Roberts et al., ; Schulteis et al., ; Seif et al., ; Vendruscolo et al., ).…”