Specific and Nonspecific Effects of Naltrexone on Goal-Directed and Habitual Models of Alcohol Seeking and Drinking

Abstract

Introduction The opioid receptor antagonist naltrexone (NTX) reduces goal-directed alcohol drinking in rats presumably by blunting alcohol reward. However, different operant conditioning behavior can be produced by different reinforcement schedules, with goal-directed operant behavior being more sensitive to changes in reward value than less flexible, habit-associated models. Objectives We tested the hypothesis that NTX more effectively reduces alcohol drinking and seeking in a goal-directed than in a habit-associated operant model, and more effectively reduces alcohol versus sucrose self-administration, consistent with diminished alcohol reward. Materials and Methods Rats were trained to self-administer 10% alcohol or 1.5% sucrose in a lever-press task and then underwent a within-subject assessment of NTX (0.1–1mg/kg) effects on operant behavior. A fixed-ratio (FR5) reinforcement schedule was used to model goal-directed behavior and a variable-interval (VI30) schedule was used to model habitual behavior. Results As predicted, NTX reduced fluid deliveries earned by the FR5-alcohol group significantly more than all other groups. However, NTX reduced lever presses during self-administration sessions in VI30-trained rats without reducing earned deliveries, due to the low contingency between rate of pressing and fluid deliveries under that schedule. Interestingly, when fluid delivery was withheld (extinction), NTX reduced reward-seeking in all rats. Finally, NTX blocked reinstatement of reward-seeking upon presentation of 0.2ml alcohol or sucrose and associated cues in the FR5-trained but not VI30-trained rats. Discussion NTX reduced goal-directed alcohol drinking compared to other operant conditions. In addition, NTX blocked reinstatement of reward-seeking in rats trained on the goal-directed FR5 reinforcement schedule but not in rats trained on the habit-like VI30 reinforcement schedule. However, NTX also exerted nonspecific effects on reward-seeking that were revealed under low-effort contingency conditions or absence of reward. Together, the data support the hypothesis that NTX is less effective in conditioning models that are more habit-associated.

Habitual alcohol seeking: Modeling the transition from casual drinking to addiction

“…Excitingly, recent work has shown that naltrexone has differential effects on alcohol seeking in animals that are trained on habit-promoting schedules. Specifically, it was observed that the ability of naltrexone to reduce cue-mediated ethanol seeking and ethanol consumption in rats was greater in rats that were trained on a ratio schedule, thought to maintain goal-directed behavior, as compared to rats trained on a habitpromoting interval schedule (Hay et al, 2013). …”

“…However, a few studies looking at drug and ethanol habits in animals exist (Belin & Everitt, 2008; Miles, Everitt, & Dickinson, 2003; Zapata, Minney, & Shippenberg, 2010). Several labs have published on habitual ethanol seeking using a lithium chloride devaluation paradigm (Barker et al, 2014; Barker, Torregrossa, Arnold, & Taylor, 2010; Dickinson, Wood, & Smith, 2002), specific satiety devaluation (Corbit et al, 2012; Hay, Jennings, Zitzman, Hodge, & Robinson, 2013) or contingency degradation (Barker et al, 2014) but to our knowledge, no outcome inflation data have been published related to alcohol seeking habits. Importantly, ethanolseeking habits differ from food seeking habits in that the transition from actions to habits occurs more readily (Corbit et al, 2012; Dickinson et al, 2002).…”

Comparison of dehydroepiandrosterone (DHEA) and pregnanolone with existing pharmacotherapies for alcohol abuse on ethanol- and food-maintained responding in male rats

“…Nevin et al, 1983). Although interpreted differently, naltrexone produced similar results in a study by Hay, Jennings, Zitsman, Hodge, & Robinson (2013).…”

Translational Research on Habit and Alcohol

“…In another study, mice chronically exposed to ethanol vapor and then trained to operantly self-administer ethanol were insensitive to ethanol devaluation compared to mice without the previous exposure [150]. Other studies have reported habitual alcohol seeking, but either did not compare ethanol to sucrose self-administration [53] or did not detect differences [55, 56]; however, these studies did not include a prior ethanol exposure period, but only ethanol self-administered in the operant chamber. Taken together, these studies demonstrate that alcohol self-administration can transition from a goal-directed to a habitual behavior in rodents, and that a history of alcohol exposure can promote the speed of this transition.…”