Much research suggests that certain personality traits predispose humans to drug abuse and addiction, including sensation- (or novelty-) seeking, risk-taking, impulsivity and antisocial conduct disorder. However, from studies of human drug addicts alone, it is difficult to determine whether co-morbid impulsivity and cognitive dysfunction pre-date the onset of drug use or emerge as a consequence of chronic drug use. Accumulating evidence from studies in animals suggests that distinct behavioural and physiological traits predict individual differences in drug-taking behaviour. Of these the best characterized is the HR (high responder) rat described by Piazza PV et al. (1989). Science 245, 1511-1513, which show high levels of locomotor activity in a novel environment and increased propensity to self-administer low doses of psychostimulant drugs such as d-amphetamine and cocaine. A key neural substrate underlying individual differences in drug vulnerability is thought to involve the brain dopamine (DA) systems, in particular the nigrostriatal, mesolimbic and mesocortical DA pathways innervating the dorsal striatum (caudate and putamen), nucleus accumbens and prefrontal cortex. A recent positron emission tomography (PET) study in non-human primates has indicated that low DA D2 receptor availability in the striatum inversely predicts subsequent levels of intravenous cocaine self-administration (Nader MA et al. (2006). Nat Neurosci 9, 1050-1056). However, it is not clear how D2 receptor availability in the striatum relates to a specific behavioural endophenotype that confers vulnerability to drug addiction. This symposium considers the relevance of a spontaneously occurring form of impulsivity in outbred rats to intravenous cocaine self-administration and to underlying changes in striatal D2 receptor function, as measured by PET (see Dalley JW et al. Science Mar 2^nd 2007). Rats were screened for trait high impulsivity (HI) using a 5-choice serial reaction time task (5-CSRTT) of sustained visual attention (Robbins TW 2002. Psychopharmacology 15 617-634). Impulsivity was defined as high levels of anticipatory responses made before the presentation of a food-predictive, brief light stimulus, a trait which is present in roughly 7% of subjects screened. We found that HI rats show a clear increase in their rate of intravenous cocaine self-administration as well as a vertical shift in the cocaine dose-response function compared with non-impulsive (NI) rats. We also found using PET and the selective high-affinity DA D2/3 receptor antagonist [18F]fallypride that D2/3 receptor availability is significantly reduced in the nucleus accumbens, but not dorsal striatum, of cocaine-naïve HI rats compared with cocaine-naïve NI rats. As there were no accompanying changes in DA release in the nucleus accumbens the most likely explanation for the significant reduction in D2/3 receptor availability in HI rats was a reduction in Bmax. In a final experiment, we investigated the consequences of intravenous cocaine self-administration on pre-trained 5-CSRTT performance. Intriguingly, prolonged exposure of HI rats to cocaine dramatically, and selectively, reduced impulsive responding on the 5-CSRTT. Overall, therefore, these findings expand on previous findings in abstinent human cocaine addicts (Volkow et al. (1993. Synapse 14, 169-177) by demonstrating that decreased D2 receptor availability in the striatum may be a pre-disposing neurobiological trait and not only a consequence of chronic cocaine exposure. They also highlight an important causal relationship between trait impulsivity and susceptibility to drug taking. Thus, these findings may be consistent with the hypothesis that stimulant drug addiction represents a transition from initial impulsivity mediated by DA dysfunction in the nucleus accumbens to the emergence of compulsive habitual drug responding mediated by the dorsal striatum.