Drug addiction is increasingly viewed as the endpoint of a series of transitions from initial drug use--when a drug is voluntarily taken because it has reinforcing, often hedonic, effects--through loss of control over this behavior, such that it becomes habitual and ultimately compulsive. Here we discuss evidence that these transitions depend on interactions between pavlovian and instrumental learning processes. We hypothesize that the change from voluntary drug use to more habitual and compulsive drug use represents a transition at the neural level from prefrontal cortical to striatal control over drug seeking and drug taking behavior as well as a progression from ventral to more dorsal domains of the striatum, involving its dopaminergic innervation. These neural transitions may themselves depend on the neuroplasticity in both cortical and striatal structures that is induced by chronic self-administration of drugs.

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Impulsivity is the tendency to act prematurely without foresight. Behavioral and neurobiological analysis of this construct, with evidence from both animal and human studies, defines several dissociable forms depending on distinct cortico-striatal substrates. One form of impulsivity depends on the temporal discounting of reward, another on motor or response disinhibition. Impulsivity is commonly associated with addiction to drugs from different pharmacological classes, but its causal role in human addiction is unclear. We characterize in neurobehavioral and neurochemical terms a rodent model of impulsivity based on premature responding in an attentional task. Evidence is surveyed that high impulsivity on this task precedes the escalation subsequently of cocaine self-administration behavior, and also a tendency toward compulsive cocaine-seeking and to relapse. These results indicate that the vulnerability to stimulant addiction may depend on an impulsivity endophenotype. Implications of these findings for the etiology, development, and treatment of drug addiction are considered.

Stimulant addiction is often linked to excessive risk taking, sensation seeking, and impulsivity, but in ways that are poorly understood. We report here that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine (DA) function before drug exposure. Using positron emission tomography, we demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of DA release. These data demonstrate that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.Accumulating evidence suggests that certain personality traits, including sensation (or novelty) seeking, impulsivity, and antisocial conduct disorder, may predispose humans to drug abuse and addiction (1-4). However, from studies of human drug addicts alone, it is difficult to determine whether comorbid impulsivity and cognitive dysfunction (5, 6) pre-

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...