Serge H. Ahmed

Neurobiological mechanisms in the transition from drug use to drug dependence

Drug addiction is a chronic relapsing disorder characterized by compulsive drug intake, loss of control over intake, and impairment in social and occupational function. Animal models have been developed for various stages of the addiction cycle with a focus in our work on the motivational effects of drug dependence. A conceptual framework focused on allostatic changes in reward function that lead to excessive drug intake provides a heuristic framework with which to identify the neurobiologic mechanisms involved in the development of drug addiction. Neuropharmacologic studies in animal models have provided evidence for the dysregulation of specific neurochemical mechanisms in specific brain reward and stress circuits that provide the negative motivational state that drives addiction. The allostatic model integrates molecular, cellular and circuitry neuroadaptations in brain motivational systems produced by chronic drug ingestion with genetic vulnerability, and provides a new opportunity to translate advances in animal studies to the human condition.

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.

Neurobiological evidence for hedonic allostasis associated with escalating cocaine use

A paradoxical aspect of the transition to drug addiction is that drug users spend progressively more time and effort to obtain drug hedonic effects that continually decrease with repeated experience. According to the hedonic allostasis hypothesis, increased craving for and tolerance to the hedonic effects of drugs result from the same chronic alteration in the regulation of brain reward function (allostasis). Here we show in rats that repeated withdrawals from prolonged cocaine self-administration produces a persistent decrease in brain reward function that is highly correlated with escalation of cocaine intake and that reduces the hedonic impact of cocaine.

Persistent increase in the motivation to take heroin in rats with a history of drug escalation

The transition from stable to escalated levels of cocaine self-administration has been shown to depend upon drug availability. The generality of this phenomenon is assessed here by studying the effects of availability on heroin self-administration. Two groups of rats were trained on a 1-h continuous schedule of self-administration, after which, access to heroin (40 μg/injection) was increased to 11 h in one group (long access or LgA rats) or kept to 1 h in the other group (short access or ShA rats). After 18 sessions on this regimen, both ShA and LgA rats were tested for extinction and stress-induced reinstatement of heroin-seeking behavior. In LgA rats, both total and first hour intake gradually escalated over time. After escalation, LgA rats were slower to extinguish heroin-seeking behavior and responded more to the reinstating effect of stress after extinction. These findings show that: (1) the escalation process in drug consumption is common to both opiate and stimulant self-administration; (2) escalation in heroin consumption is associated with a persistent increase in the motivation for taking heroin.

Long-lasting increase in the set point for cocaine self-administration after escalation in rats

Abstract Rationale: When access time to a continuous schedule of drug self-administration is restricted, animals tend to limit intake to a certain level over time and across doses. This observation suggests an endogenous constraint or set point that determines the individual’s preferred level of pharmacological effects. Objectives: To assess whether the transition to increased levels of drug intake is associated with a change in set point. Methods: Two groups of rats were trained on a 1-h continuous schedule of cocaine self-administration (250 µg/injection), after which access to cocaine was increased to 6 h in one group (Long Access or LgA rats) or kept to 1 h in the other group (Short Access or ShA rats). After 22 sessions on this regimen, different doses of cocaine were tested (31.25, 62.5, 125, and 250 µg/injection). For each dose, the post-response time-out period was reduced to 4 s to reduce any temporal limitations on self-injections and subjects were tested several times. Results: In LgA rats, the first hour intake escalated over time and eventually reached a level 200% greater than that of ShA rats. Though all rats maintained relatively constant intake across doses, LgA rats took nearly two times as much cocaine than ShA rats. When access to cocaine for LgA rats was reduced to 1 h, intake returned very slowly toward pre-escalation levels but was still elevated even after 2 months of reduced availability. Conclusions: These data suggest that the transition to escalated levels of intake is associated with a long-lasting change in cocaine set point.

Cocaine- but not food-seeking behavior is reinstated by stress after extinction

Abstract Reinstatement of drug-seeking behavior after extinction constitutes a potential animal model of relapse to drug abuse. In a typical reinstatement experiment, previously drug-trained rats undergo extinction during which responding is no longer followed by drug delivery. After significant extinction is observed, rats are then exposed to an event expected to reinstate drug-seeking behavior. Using this procedure, it has been recently reported that footshock stress leads to reinstatement of drug-seeking in heroin-trained, presently drug-free rats. The purpose of the present study was to assess the generality of this effect of stress. Here we report that 15 min of intermittent footshock (0.86 mA; 0.5 s on, with a mean off period of 40 s) reinstated selectively cocaine-seeking behavior after 14 extinction sessions (rats were previously trained on a FR1 TO 20 s to obtain cocaine at a dose of 0.25 mg/infusion). In contrast, under similar experimental conditions, the same stressor did not reinstate food-seeking in food-trained rats after seven extinction sessions (rats were previously trained on a FR1 TO 20 s to obtain six food pellets). Rather, when the basal level of responding was sufficiently high, footshock stress induced a significant suppression of the instrumental performance. These data are discussed in light of several behavioral mechanisms which may explain the specificity of stress in reinstating drug-seeking behavior and not food-seeking behavior.

Transition to drug addiction: a negative reinforcement model based on an allostatic decrease in reward function

RationaleThe transition from initial drug use to drug addiction has been proposed to result from an allostatic decrease in reward function driven by an overactivation of brain antireward processes.ObjectivesHow decreased reward function explains compulsive drug use is not entirely clear at present, and is still a subject for debate.MethodsWe present a quantitative model of cocaine self-administration that integrates pharmacokinetic, pharmacodynamic, and motivational factors to address this question. The model assumes that reward system responsivity is a homeostatically regulated process where the desired level of responsivity (called the reward set point) is initially different from the baseline level. The reduction or correction of this difference or error in reward function would drive cocaine self-administration.ResultsTheoretical data obtained by computer simulation fit the experimental data obtained in animals self-administering cocaine (i.e., the within-session pattern of self-injections, the shape and curvature of the dose-injection function, the nonlinear relationship between drug intake and regulated drug effects). Importantly, simulation of an allostatic decrease in reward system responsivity exacerbates the initial error that drives self-administration, thereby increasing both the intake of, and the motivation for, the drug. This allostatic change manifests as a vertical shift in the dose-injection function similar to that seen in animals with escalating cocaine self-administration.ConclusionsThe present model provides a satisfactory explanation of escalated drug intake and suggests a novel negative reinforcement view of addiction based on an allostatic decrease in reward function.

Dissociation of Psychomotor Sensitization from Compulsive Cocaine Consumption

The transition from drug use to drug addiction is associated with a process of escalation, whereby drug use becomes excessive and difficult to control. Several mechanisms have been advanced to explain escalating patterns of drug use as opposed to nonescalating patterns. Although current evidence favors hedonic tolerance, there remains some dispute about the contribution of behavioral sensitization to cocaine intake escalation. Here, we concurrently assessed the ability of cocaine to induce psychomotor sensitization and drug-seeking behavior in animals with 1-h (short access or ShA) vs 6-h (long access or LgA) access to intravenous (i.v.) cocaine self-administration. As expected, cocaine intake by LgA rats escalated over time and became excessive compared to cocaine intake by ShA rats, which remained low and stable. Despite escalated levels of cocaine consumption, however, LgA rats were not more sensitized to cocaine than ShA rats. The dose–effect function for cocaine-induced locomotion (0.125–1 mg, i.v.) was shifted to the left in LgA rats by the same amount as in ShA rats after cocaine self-administration. In contrast, LgA rats were much more responsive than ShA rats to the motivational effects of cocaine, as measured by the ability of i.v. cocaine to reinstate extinguished drug-seeking behavior. This study demonstrates a dissociation of psychomotor sensitization from the change in motivation underlying the transition to compulsive cocaine consumption, and therefore suggests that responsiveness to the motivational effects of the drug, not psychomotor sensitization, would represent a specific behavioral marker of the transition to and maintenance of compulsive cocaine use.

Validation crisis in animal models of drug addiction: Beyond non-disordered drug use toward drug addiction

In standard drug self-administration settings, animals have no choice than drug use. As a result, serious doubt exists about the interpretation of drug use in experimental animals. Is it symptomatic of an underlying addiction state or merely an expectable response to lack of choice? This incertitude in turn casts a shadow over many behavioral and neurobiological changes that have been well documented in animals following extended drug self-administration. Do they reflect pathological dysfunctions or normal neurobiological adaptations? Here I address these questions by focusing on intravenous cocaine self-administration in the rat as a paradigm example. Overall, available evidence shows that when a valuable behavioral option, even a biologically or physiologically inessential one, is made available during access to cocaine self-administration, most rats readily abstain from cocaine use in favor of the alternative reward regardless of the amount of past cocaine use. Only a small minority of rats continue to self-administer the drug despite the opportunity of making a different choice. This pattern of results (i.e., abstinence in most rats; cocaine preference in few rats) maps well onto what is currently known about the epidemiology of human cocaine addiction. It is thus possible that the minority of cocaine-preferring rats would be homologous to the minority of human cocaine users with a diagnosis of addiction while the remaining majority of abstinent rats would be resilient to cocaine addiction. Choice could represent an objective method of selection of addicted animals for future research on the neurobiological dysfunctions that are hypothesized to underlie cocaine addiction. Other competing interpretations of the same pattern of results are also discussed at the end of this review.

The science of making drug-addicted animals.

Research involving animal models of drug addiction can be viewed as a sort of reverse psychiatry. Contrary to clinicians who seek to treat addicted people to become and remain abstinent, researchers seek to make drug-naïve animals addicted to a drug with known addictive properties in humans. The goals of this research are to better understand the neuroscience of drug addiction and, ultimately, to translate this knowledge into effective treatments for people with addiction. The present review will not cover the vast literature that has accumulated over the past 50 years on animal models of drug addiction. It is instead more modestly devoted to recent research spanning the past decade on drug self-administration-based models of addiction in the rat (the animal species most frequently used in the field), with a special focus on current efforts to model compulsive cocaine use as opposed to nonaddictive use. Surprisingly, it turns out that modeling compulsive cocaine use in rats is possible but more difficult than previously thought. In fact, it appears that resilience to cocaine addiction is the norm in rats. As in human cocaine users, only few individual rats would be vulnerable. This conclusion has several important implications for future research on the neuroscience of cocaine addiction and on preclinical medication development.