Time-Dependent Negative Reinforcement of Ethanol Intake by Alleviation of Acute Withdrawal

Abstract

Background Drinking to alleviate the symptoms of acute withdrawal is included in diagnostic criteria for alcoholism, but the contribution of acute withdrawal relief to high alcohol intake has been difficult to model in animals. Methods Ethanol dependence was induced by passive intragastric ethanol infusions in C57BL/6J (B6) and DBA/2J (D2) mice; non-dependent controls received water infusions. Mice were then allowed to self-administer ethanol or water intragastrically. Results The time course of acute withdrawal was similar to that produced by chronic ethanol vapor exposure in mice, reaching a peak at 7-9 h and returning to baseline within 24 h; withdrawal severity was greater in D2 than in B6 mice (Exp. 1). Post-withdrawal delays in initial ethanol access (1, 3 or 5 days) reduced the enhancement in later ethanol intake normally seen in D2 (but not B6) mice allowed to self-infuse ethanol during acute withdrawal (Exp. 2). The post-withdrawal enhancement of ethanol intake persisted over a 5-d abstinence period in D2 mice (Exp. 3). D2 mice allowed to drink ethanol during acute withdrawal drank more ethanol and self-infused more ethanol than non-dependent mice (Exp. 4). Conclusions Alcohol access during acute withdrawal increased later alcohol intake in a time-dependent manner, an effect that may be related to a genetic difference in sensitivity to acute withdrawal. This promising model of negative reinforcement encourages additional research on the mechanisms underlying acute withdrawal relief and its role in determining risk for alcoholism.

Operant ethanol self-administration in ethanol dependent mice

“…This latter finding provides endorsement of the hypothesis that dependent mice may self-administer more ethanol to prevent and/or alleviate symptoms of withdrawal (Fidler et al, 2012). This was further confirmed with studies in which the delay between the forced infusion phase and self-administration sessions was varied (Cunningham et al, 2013). Specifically, results indicated that increased ethanol self-administration was most robust in mice that had either no delay or a short (1-day) delay between the forced intragastric exposure phase and no-choice self-infusion phase, or between the no-choice and choice self-administration phases of the study.…”

“…More recently, studies in animals with a history of dependence (chronic but ‘forced’ ethanol exposure and withdrawal) have demonstrated that ethanol can serve as a potent negative reinforcer as well. For example, increased ethanol self-administration was shown in studies where dependence was induced by chronic administration of ethanol in a nutritionally fortified liquid diet (that served as the animals’ sole source of calories and fluid) (Brown, Jackson, & Stephens, 1998; Chu, Koob, Cole, Zorilla, & Roberts, 2007; Gilpin et al, 2009; Schulteis, Hyytiä, Heinrichs, & Koob, 1996), via intragastric infusions (Cunningham, Fidler, Murphy, Mulgrew, & Smitasin, 2013; Fidler et al, 2011; Fidler et al, 2012), and via inhalation of alcohol vapors (e.g., Becker & Lopez, 2004; Rimondini, Arlinde, Sommer, & Heilig, 2002; Roberts, Heyser, Cole, Griffin, & Koob, 2000). In such studies, the altered physiological state associated with dependence along with the capacity for ethanol to alleviate withdrawal symptoms is posited to not only sustain ethanol self-administration, but also promote escalation of intake (Becker, 2008; Becker, 2013; Heilig, Egli, Crabbe, & Becker, 2010).…”

Differential effects of ghrelin antagonists on alcohol drinking and reinforcement in mouse and rat models of alcohol dependence

“…When the maximum number of infusions was reached, the S+ tube remained available, but no further infusions were given until the cumulative dose received during the previous 30 minutes fell below the 1.5 g/kg limit. The two no-choice days were included to ensure that all animals encountered the S+ flavor-ethanol contingency during acute ethanol withdrawal (Cunningham et al, 2013). …”

“…Continuous and intermittent ethanol vapor exposure has been shown to reliably produce signs of dependence (e.g., Schulteis et al, 1995; 1996; Macey et al, 1996; Becker et al, 2000), to increase alcohol drinking and operant self-administration of alcohol (e.g., Becker and Lopez, 2004; O'Dell et al, 2004; Finn et al, 2007; Gilpin et al, 2009), and to increase alcohol self-administration to alleviate withdrawal symptoms (Roberts et al, 1996) and during a period of protracted abstinence (Roberts et al, 2000). More recently, the intragastric alcohol consumption (IGAC) model has shown increased alcohol self-administration in dependent mice given ethanol access during acute alcohol withdrawal (Fidler et al, 2012; Cunningham et al, 2013). …”

The Effects of Stress on Measures of Alcohol Drinking in Rodents

“…Following a period of deprivation, rodents consume more alcohol and at higher concentrations in a freechoice drinking paradigm (e.g., Spanagel & Hölter, 1999;Vengeliene et al, 2003), increase alcohol intake in an operant task, and increase breakpoints for alcohol in a progressive ratio test (e.g., Brown, Jackson, & Stephens, 1998;Hölter, Landgraf, Zieglgänsberger, & Spanagel, 1997). Passive administration of ethanol, for example, through exposure to ethanol vapor or intragastric infusions, can also induce dependence and promote consumption during withdrawal, and these effects are most robust when exposure is intermittent, resulting in repeated withdrawal episodes (e.g., Becker & Lopez, 2004;Cunningham, Fidler, Murphy, Mulgrew, & Smitasin, 2012;Griffin, Lopez, Yanke, Middaugh, & Becker, 2009;Lopez & Becker, 2005;O'Dell, 2004).…”