Repeated episodes of chronic intermittent ethanol promote insensitivity to devaluation of the reinforcing effect of ethanol
Introduction
Alcoholism and alcohol abuse are a major problem worldwide with devastating health and societal consequences. While most individuals who consume alcohol can control their intake, a significant proportion of individuals cannot control their consumption and subsequently develop an addiction to alcohol that is characterized by uncontrollable and compulsive consumption. While studies have demonstrated that both positive and negative reinforcing properties of ethanol contribute to and promote self-administration (Becker, 2013, Heilig et al., 2010, Koob, 2003, Meisch, 1982, Meisch, 1984), accumulating evidence in rodents indicates that prolonged self-administration of ethanol is also associated with the development of a resistance to aversive stimuli associated with ethanol. For example, a study conducted in C57BL/6J mice showed that addition of quinine (an aversive tastant) to the ethanol solution lowered ethanol intake in mice with a short (2-week) history of voluntary ethanol intake. In contrast, when mice were allowed to self-administer ethanol for a longer period of time (8 weeks), they were no longer affected by this quinine-induced adulteration of ethanol, and continued to self-administer it despite the aversive taste (Lesscher, van Kerkhof, & Vanderschuren, 2010). Similar results were obtained in rats that had been drinking ethanol adulterated with quinine after a short (1.5 months) versus a long (3–4 months) history of ethanol self-administration (Hopf, Chang, Sparta, Bowers, & Bonci, 2010).
In addition to the differences in drinking behaviors observed in animals with a short versus long history of drinking, recent evidence has demonstrated that models of ethanol dependence that involve multiple episodes of withdrawal also promote changes in drinking behavior. For example, it was reported that subjecting rats to repeated cycles of chronic ethanol exposure and withdrawal resulted in resistance to the effect of adulteration of ethanol with quinine (Vendruscolo et al., 2012). In addition, studies in mice have shown that repeated cycles of chronic intermittent ethanol (CIE) exposure promote increases in voluntary ethanol consumption when tested using various 2-bottle choice drinking procedures (Becker and Lopez, 2004, Finn et al., 2007, Griffin et al., 2009, Griffin et al., 2009, Lopez and Becker, 2005, Lopez et al., 2012). Importantly, this heightened ethanol intake after CIE exposure is associated with increased blood (Becker & Lopez, 2004) and brain (Griffin, Lopez, Yanke, et al., 2009) ethanol concentrations compared to that measured in non-dependent mice that consume more moderate amounts of ethanol. In a recent study, we further observed that mice trained to lever press for ethanol using a fixed-ratio (FR) schedule exhibited significant increases in ethanol self-administration after CIE exposure (Lopez & Becker, under review). This CIE-induced elevation of operant oral ethanol self-administration engendered responding that was resistant to extinction and more sensitive to cue-induced reinstatement. While CIE-exposure models have clearly demonstrated escalated ethanol self-administration, it is not clear whether this augmented consumption reflects a change in the reinforcing value of ethanol. To begin to address this question, the present study examined whether the CIE-induced escalation of operant self-administration is also associated with changes in response to devaluation of the reinforcing properties of ethanol.
Section snippets
Subjects
Adult male C57BL/6 mice purchased from Jackson Laboratories (Bar Harbor, ME) were individually housed with free access to food (Harland Teklad, Madison, WI) and water throughout all phases of the experiments. Body weights were recorded weekly during ethanol self-administration or daily during chronic intermittent ethanol (CIE) or air exposure (detailed below). Mice were housed in a temperature- and humidity-controlled animal facility under a reversed 12-h light/dark cycle (lights on at 1800 h).
Devaluation before CIE exposure
The first set of studies examined the effects of devaluation on ethanol self-administration and extinction responding in mice that experienced a short history of drinking and no CIE exposure. Since mice were selected based on their baseline self-administration levels, there were no differences between DEV (n = 11) and Non-DEV (n = 10) mice in the number of active lever responses [t(19) = 0.01, p = 0.99] or the amount of ethanol (g/kg) consumed [t(19) = 0.18, p = 0.86] on the last
Discussion
The present study demonstrated that mice with either a short or a long history of operant ethanol self-administration exhibited sensitivity to devaluation of the reinforcing properties of ethanol. In contrast, when mice were exposed to repeated cycles of CIE exposure, ethanol self-administration behavior transitioned to become insensitive to ethanol devaluation. This CIE-induced insensitivity to ethanol devaluation was also associated with an escalation in the amount of ethanol consumed. Taken
Acknowledgments
This work was funded by NIAAA grants P50 AA010761, U01 AA014095, U01 AA020929, R01 AA010983, U01 AA019967, and the Department of Veterans Affairs Medical Research. The authors thank Laura Ralston for her excellent technical assistance in conducting this work and Jacqueline Barker for helpful comments on the manuscript.
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