Abstract
BackgroundAssessing the relative value of cocaine and how it changes with chronic drug use represents a long-standing goal in addiction research. Surprisingly, recent experiments in rats – by far the most frequently used animal model in this field – suggest that the value of cocaine is lower than previously thought.Methodology/Principal FindingsHere we report a series of choice experiments that better define the relative position of cocaine on the value ladder of rats (i.e., preference rank-ordering of different rewards). Rats were allowed to choose either taking cocaine or drinking water sweetened with saccharin – a nondrug alternative that is not biologically essential. By systematically varying the cost and concentration of sweet water, we found that cocaine is low on the value ladder of the large majority of rats, near the lowest concentrations of sweet water. In addition, a retrospective analysis of all experiments over the past 5 years revealed that no matter how heavy was past cocaine use most rats readily give up cocaine use in favor of the nondrug alternative. Only a minority, fewer than 15% at the heaviest level of past cocaine use, continued to take cocaine, even when hungry and offered a natural sugar that could relieve their need of calories.Conclusions/SignificanceThis pattern of results (cocaine abstinence in most rats; cocaine preference in few rats) maps well onto the epidemiology of human cocaine addiction and suggests that only a minority of rats would be vulnerable to cocaine addiction while the large majority would be resilient despite extensive drug use. Resilience to drug addiction has long been suspected in humans but could not be firmly established, mostly because it is difficult to control retrospectively for differences in drug self-exposure and/or availability in human drug users. This conclusion has important implications for preclinical research on the neurobiology of cocaine addiction and for future medication development.
Highlights
The immediate reward value of cocaine, especially if it is rapidly delivered to the brain following smoking or intravenous injection, is widely thought to be higher than that of most natural or sociallyvalued rewards – a difference that would contribute to explain its addictive potential [1,2,3,4,5]
Twenty-nine rats from 2 independent cohorts were first trained on alternate daily sessions to lever press to self-administer either water sweetened with saccharin (0.2%) or intravenous cocaine (0.25 mg) under a fixed-ratio 1 (FR) schedule
Rats had concurrent access for 45 min to the lever associated with cocaine and to the lever associated with water sweetened with saccharin but responding on either lever had no programmed consequence
Summary
The immediate reward value of cocaine, especially if it is rapidly delivered to the brain following smoking or intravenous injection, is widely thought to be higher than that of most natural or sociallyvalued rewards – a difference that would contribute to explain its addictive potential [1,2,3,4,5]. This assumption is largely based on retrospective self-reports from current or ex-cocaine addicts or on evidence from experimental animals given access to cocaine selfadministration with no behavioral alternative available. Recent experiments in rats – by far the most frequently used animal model in this field – suggest that the value of cocaine is lower than previously thought
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