Environment-dependent behavioral traits and experiential factors shape addiction vulnerability.

The transition from controlled drug use to drug addiction depends on an interaction between a vulnerable individual, their environment and a drug. Here we tested the hypothesis that conditions under which individuals live influence behavioral vulnerability traits and experiential factors operating in the drug taking environment to determine the vulnerability to addiction. The role of behavioral vulnerability traits in mediating the influence of housing conditions on the tendency to acquire cocaine self-administration was characterized in 48 rats housed in either an enriched (EE) or a standard (SE) environment. Then, the influence of these housing conditions on the individual vulnerability to develop addiction-like behavior for cocaine or alcohol was measured in 72 EE or SE rats after several months of cocaine self-administration or intermittent alcohol drinking, respectively. The determining role of negative experiential factors in the drug taking context was further investigated in 48 SE rats that acquired alcohol drinking to self-medicate distress in a schedule-induced polydipsia procedure. The environment influenced the acquisition of drug intake through its effect on behavioral markers of resilience to addiction. In contrast, the initiation of drug taking as a coping strategy or in a negative state occasioned by the contrast between enriched housing conditions and a relatively impoverished drug taking setting, facilitated the development of compulsive cocaine and alcohol intake. These data indicate that addiction vulnerability depends on environmentally determined experiential factors, and suggest that initiating drug use through negative reinforcement-based self-medication facilitates the development of addiction in vulnerable individuals. SIGNIFICANCE STATEMENT: The factors that underlie an individual's vulnerability to switch from controlled, recreational drug use to addiction are not well understood. We showed that in individuals housed in enriched conditions, the experience of drugs in the relative social and sensory impoverishment of the drug taking context, and the associated change in behavioral traits of resilience to addiction, exacerbate the vulnerability to develop compulsive drug intake. We further demonstrated that the acquisition of alcohol drinking as a mechanism to cope with distress increases the vulnerability to develop compulsive alcohol intake. Together these results demonstrate that experiential factors in the drug taking context shape the vulnerability to addiction.

High locomotor reactivity to novelty is associated with an increased propensity to choose saccharin over cocaine: new insights into the vulnerability to addiction.

Drug addiction is associated with a relative devaluation of natural or socially-valued reinforcers that are unable to divert addicts from seeking and consuming the drug. Before protracted drug exposure, most rats prefer natural rewards, such as saccharin, over cocaine. However, a subpopulation of animals prefer cocaine over natural rewards and are thought to be vulnerable to addiction. Specific behavioral traits have been associated with different dimensions of drug addiction. For example, anxiety predicts loss of control over drug intake whereas sensation seeking and sign-tracking are markers of a greater sensitivity to the rewarding properties of the drug. However, how these behavioral traits predict the disinterest for natural reinforcers remains unknown. In a population of rats, we identified sensation seekers (HR) on the basis of elevated novelty-induced locomotor reactivity, high anxious rats (HA) based on the propensity to avoid open arms in an elevated-plus maze and sign-trackers (ST) that are prone to approach, and interaction with, reward-associated stimuli. Rats were then tested on their preference for saccharin over cocaine in a discrete-trial choice procedure. We show that HR rats display a greater preference for saccharin over cocaine compared with ST and HA whereas the motivation for the drug was comparable between the three groups. The present data suggest that high locomotor reactivity to novelty, or sensation seeking, by predisposing to an increased choice toward non-drug rewards at early stages of drug use history, may prevent the establishment of chronic cocaine use.

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.