Although the voluntary intake of drugs of abuse is a behavior largely preserved throughout phylogeny, it is currently unclear whether pathological drug use ("addiction") can be observed in species other than humans. Here, we report that behaviors that resemble three of the essential diagnostic criteria for addiction appear over time in rats trained to self-administer cocaine. As in humans, this addiction-like behavior is present only in a small proportion of subjects using cocaine and is highly predictive of relapse after withdrawal. These findings provide a new basis for developing a true understanding and treatment of addiction.

Both impulsivity and novelty-seeking have been suggested to be behavioral markers of the propensity to take addictive drugs. However, their relevance for the vulnerability to compulsively seek and take drugs, which is a hallmark feature of addiction, is unknown. We report here that whereas high reactivity to novelty predicts the propensity to initiate cocaine self-administration, high impulsivity in contrast predicts the development of addiction-like behavior in rats, including persistent or compulsive drug taking in the face of aversive outcomes. This study provides experimental evidence that a shift from impulsivity to compulsivity occurs during the development of addictive behavior, thereby providing important insights into the genesis and neural mechanisms of drug addiction.Compulsive cocaine use has been hypothesized to result from a failure in top-down executive control over maladaptive habit learning (1, 2). In neural terms this may reflect the diminishing influence of prefrontal cortical function, as behavioral control devolves from ventral to dorsal striatum (1). In behavioral terms, we predict that the development of addiction reflects a shift from impulsivity to compulsivity (3).Human studies have implicated individual differences in different forms of impulsivity and sensation-seeking in vulnerability to drug use and abuse (4-6). However, whether the enhanced impulsivity observed in drug addicts (7,8) pre-dates the onset of compulsive drug use or is a consequence of protracted exposure to drugs has not been fully established. In addressing this issue experimentally, we operationalized these human traits in experimental animals as an inability to wait before performing an appropriate response, one phenotype of impulsivity (9) measured as premature responses in a 5-choice serial reaction-time task (5-CSRTT) of sustained visual attention (10), as distinct from locomotor reactivity to a novel environment, a sensation-seeking phenotype (11). These animal models support the existence of a "vulnerable phenotype" that predisposes to drug addiction. Thus outbred rats exhibiting high levels of novelty-induced locomotor activity, called high responder (HR), show increased sensitivity to the reinforcing effects of addictive drugs and self-administer lower doses of psychostimulants than low responder (LR) littermates (11). Impulsivity, on the other hand, correlates with ethanol intake (12) and predicts instead the escalation of cocaine self-administration (10, 13), which may be more indicative of a necessary stage in the transition to compulsive drug-seeking. Whilst these studies have addressed the initiation of drug taking, they have not captured the essential feature of addiction, namely the persistence of drug seeking in the face of negative consequences, a characteristic (14) to investigate the contrasting contribution of high impulsivity (HI) and high reactivity to novelty (HR) to the development of compulsive drug-taking.In this model we have operationally defined three addiction-like criteria in r...

We hypothesize that drug addiction can be viewed as the endpoint of a series of transitions from initial voluntary drug use through the loss of control over this behaviour, such that it becomes habitual and ultimately compulsive. We describe evidence that the switch from controlled to compulsive drug seeking represents a transition at the neural level from prefrontal cortical to striatal control over drugseeking and drug-taking behaviours as well as a progression from ventral to more dorsal domains of the striatum, mediated by its serially interconnecting dopaminergic circuitry. These neural transitions depend upon the neuroplasticity induced by chronic self-administration of drugs in both cortical and striatal structures, including long-lasting changes that are the consequence of toxic drug effects. We further summarize evidence showing that impulsivity, a spontaneously occurring behavioural tendency in outbred rats that is associated with low dopamine D 2/3 receptors in the nucleus accumbens, predicts both the propensity to escalate cocaine intake and the switch to compulsive drug seeking and addiction.

A neuroanatomical principle of striatal organization has been established through which ventral domains, including the nucleus accumbens, exert control over dorsal striatal processes mediated by so-called "spiraling," striato-nigro-striatal, circuitry. We have investigated the functional significance of this circuitry in the control over a cocaine-seeking habit by using an intrastriatal disconnection procedure that combined a selective, unilateral lesion of the nucleus accumbens core and infusion of a dopamine receptor antagonist into the contralateral dorsolateral striatum, thereby disrupting striato-midbrain-striatal serial connectivity bilaterally. We show that this disconnection selectively decreased drug-seeking behavior in rats extensively trained under a second-order schedule of cocaine reinforcement. These data thereby define the importance of interactions between ventral and dorsal domains of the striatum, mediated by dopaminergic transmission, in the neural mechanisms underlying the development and performance of cocaine-seeking habits that are a key characteristic of drug addiction.