Choosing Under the Influence: A Drug-Specific Mechanism by Which the Setting Controls Drug Choices in Rats.

Ample evidence shows that the setting can control drug choices in both humans and animals. Here we reveal in rats that a major mechanism of this control involves a regulation of the drug influence on other competing options at the time of choice. Briefly, rats were offered a choice between a drug dose (cocaine or heroin) and a brief access to water sweetened with saccharin in two different settings. In one setting, choosing under the influence was not possible and rats largely preferred saccharin over either cocaine or heroin. In contrast, when the same rats were shifted to a setting where choosing under the influence was possible, they chose the drug either nonexclusively or exclusively depending on whether the drug enhanced or suppressed sweet reward, respectively. Thus, when rats were under the orexigenic influence of heroin at the time of choice, they more frequently chose saccharin in alternation with heroin. In contrast, when rats were under the anorexic influence of cocaine, they stopped choosing saccharin and continued taking cocaine exclusively. These setting- and drug-specific changes in preference were rapid and reversible, and could be induced by passively administering cocaine or heroin before choice. Finally, rats behaved as if they were oblivious to the drug influence on their choices. This behavior could explain why rats are vulnerable to harm themselves, sometimes to the point of death, in settings where choices are made under the drug influence, notably if this influence excludes other important options or, conversely, enhances harmful ones.

Extended heroin access increases heroin choices over a potent nondrug alternative.

Epidemiological research shows that the proportion of drug users who become addicted to heroin is higher than to cocaine. Here we tested whether this difference could be due to a difference in the addiction liability between the two drugs. Addiction liability was assessed under a discrete-trials choice procedure by measuring the proportion of rats that prefer the drug over a potent alternative reward (ie, water sweetened with saccharin). Previous research on choice between self-administration of i.v. cocaine or sweet water showed that the proportion of cocaine-preferring rats remains relatively low and invariable (ie, 15%), even after extended drug access and regardless of past drug consumption (ie, total drug use before choice testing). By contrast, the present study shows that under similar choice conditions, the proportion of heroin-preferring rats considerably increases with extended heroin access (6-9 h per day for several weeks) and with past heroin consumption, from 11 to 51% at the highest past drug consumption level. At this level, the proportion of drug-preferring rats was about three times higher with heroin than with cocaine (51% vs 15%). This increase in the rate of heroin preference after extended heroin access persisted even after recovery from acute heroin withdrawal. Overall, these findings show that choice procedures are uniquely sensitive to different drugs and suggest that heroin is more addictive than cocaine. This higher addiction liability may contribute to explain why more drug users become addicted to heroin than to cocaine in epidemiological studies.

Cocaine is low on the value ladder of rats: possible evidence for resilience to addiction.

BACKGROUND: Assessing 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 FINDINGS: Here 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/SIGNIFICANCE: This 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.

Intense sweetness surpasses cocaine reward.

BACKGROUND: Refined sugars (e.g., sucrose, fructose) were absent in the diet of most people until very recently in human history. Today overconsumption of diets rich in sugars contributes together with other factors to drive the current obesity epidemic. Overconsumption of sugar-dense foods or beverages is initially motivated by the pleasure of sweet taste and is often compared to drug addiction. Though there are many biological commonalities between sweetened diets and drugs of abuse, the addictive potential of the former relative to the latter is currently unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that when rats were allowed to choose mutually-exclusively between water sweetened with saccharin-an intense calorie-free sweetener-and intravenous cocaine-a highly addictive and harmful substance-the large majority of animals (94%) preferred the sweet taste of saccharin. The preference for saccharin was not attributable to its unnatural ability to induce sweetness without calories because the same preference was also observed with sucrose, a natural sugar. Finally, the preference for saccharin was not surmountable by increasing doses of cocaine and was observed despite either cocaine intoxication, sensitization or intake escalation-the latter being a hallmark of drug addiction. CONCLUSIONS: Our findings clearly demonstrate that intense sweetness can surpass cocaine reward, even in drug-sensitized and -addicted individuals. We speculate that the addictive potential of intense sweetness results from an inborn hypersensitivity to sweet tastants. In most mammals, including rats and humans, sweet receptors evolved in ancestral environments poor in sugars and are thus not adapted to high concentrations of sweet tastants. The supranormal stimulation of these receptors by sugar-rich diets, such as those now widely available in modern societies, would generate a supranormal reward signal in the brain, with the potential to override self-control mechanisms and thus to lead to addiction.