High Impulsivity Predicts the Switch to Compulsive Cocaine-Taking

Abstract

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...

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