The distinctions between drugs in the induction and expression of sensitization indicate that behavioral sensitization can arise from multiple neuroadaptations in multiple brain nuclei. This is not only the result of distinct molecular targets for the drugs, but may also include a differential involvement of learned associations. It is postulated that the relatively more robust pharmacological capacity of amphetamine to release dopamine may induce a form of sensitization that is more dependent on adaptations in mesoaccumbens dopamine transmission compared with cocaine and morphine sensitization.

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Compulsive drug use in the face of adverse consequences is a hallmark feature of addiction, yet there is little preclinical evidence demonstrating the actual progression from casual to compulsive drug use. Presentation of an aversive conditioned stimulus suppressed drug seeking in rats with limited cocaine self-administration experience, but no longer did so after an extended cocaine-taking history. In contrast, after equivalent extended sucrose experience, sucrose seeking was still suppressed by an aversive conditioned stimulus. Persistent cocaine seeking in the presence of signals of environmental adversity after a prolonged cocaine-taking history was not due to impaired fear conditioning, nor to an increase in the incentive value of cocaine, and may reflect the establishment of compulsive behavior.

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Impulsivity and compulsivity represent useful conceptualizations that involve dissociable cognitive functions, mediated by neuroanatomically and neurochemically distinct components of cortico-subcortical circuitry. The constructs were historically viewed as diametrically opposed, with impulsivity being associated with risk-seeking and compulsivity with harm-avoidance. However, they are increasingly recognized to be linked by shared neuropsychological mechanisms involving dysfunctional inhibition of thoughts and behaviors. In this paper, we selectively review new developments in the investigation of the neurocognition of impulsivity and compulsivity in humans, in order to advance our understanding of the pathophysiology of impulsive, compulsive and addictive disorders and indicate new directions for research.

ARTICLESTreatment of cocaine addiction is hampered by high rates of relapse even after prolonged drug abstinence. This relapse to compulsive cocaine use can be triggered by re-exposure to cocaine 1 , by re-exposure to stimuli previously associated with cocaine 2 or by exposure to stress 3 . In laboratory rats, similar events reinstate cocaine seeking after prolonged withdrawal periods 4-6 , thus providing a model to study neuronal mechanisms underlying the relapse to cocaine. The endocannabinoid system has been implicated in a number of neuropsychiatric conditions, including drug addiction 7,8 . The active ingredient of marijuana, ∆9-tetrahydrocannabinol, activates the mesolimbic dopamine (DA) reward system 9,10 and has rewarding effects in preclinical models of drug abuse 8,11,12 . We report here that the synthetic cannabinoid agonist, HU210 (ref. 13), provokes relapse to cocaine seeking after prolonged withdrawal periods. Furthermore, the selective CB1 receptor antagonist, SR141716A (ref. 14), attenuates relapse induced by re-exposure to cocaine-associated cues or cocaine itself, but not relapse induced by exposure to stress. These data reveal an important role of the cannabinoid system in the neuronal processes underlying relapse to cocaine seeking, and provide a rationale for the use of cannabinoid receptor antagonists for the prevention of relapse to cocaine use.To study the role of the cannabinoid system in relapse to cocaine seeking, we used a 'reinstatement model' 15 in which we tested rats for relapse behavior induced by drug or non-drug stimuli, following extinction of the drug-taking behavior that was previously maintained by cocaine. This preclinical model simulates the human situation in which cocaine addicts relapse to compulsive drug use after prolonged withdrawal periods [1][2][3] . First we evaluated whether activation of cannabinoid receptors by the synthetic cannabinoid agonist, HU210, would reinstate cocaine seeking after a prolonged withdrawal period. In daily two-hour sessions, rats were trained to nose poke for intravenous (i.v.) cocaine self-administration. Subsequently, responding for cocaine was extinguished in the absence of the drug for at least 14 days. Rats were then tested under extinction conditions (that is, cocaine was not available) for reinstatement of drug seeking induced by systemic injections of HU210 or its vehicle. We found that HU210 reinstates cocaine seeking in a dose-dependent manner (Fig. 1a). This effect was reversed with the selective CB1 receptor antagonist SR141716A. When given alone, the cannabinoid antagonist did not modify baseline response rates (Fig. 1b). These data indicate that the 'relapse' provoking effect of HU210 is mediated by CB1 receptors. The biphasic dose-effect curve with HU210 observed here is similar to that observed in previous studies on the behavioral effects of this and related compounds 8,12 . There is a general agreement that the central effects of the endocannabinoids anandamide and 2-arachidonylglycerol are mediated by CB1 receptors 8,1...

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Through association with the interoceptive effects of drugs of abuse, neutral environmental stimuli can gain motivational properties themselves, becoming conditioned reinforcers that can evoke craving and relapse to drug seeking. Nucleus accumbens dopamine (DA) neurotransmission plays an important role in the reinforcing effect of cocaine itself, but, unlike nucleus accumbens glutamate, it seems not to mediate the conditioned reinforcing properties of cocaine-paired stimuli. Dorsal striatal DA transmission, in contrast, has been shown to be enhanced during cocaine seeking under a second-order schedule of reinforcement, which depends on the conditioned reinforcing properties of cocaine-associated stimuli. Therefore, the aim of the present study was to evaluate the role of DA and glutamate transmission in the dorsal striatum in cue-controlled cocaine seeking. Infusion of the DA receptor antagonist ␣-flupenthixol into the dorsal striatum decreased cocaine seeking under a second-order schedule of reinforcement. In addition, intradorsal striatal infusion of the AMPA/kainate (KA) receptor antagonist LY293558 (3SR, 4aRS, 6RS, 8aRS-6-[2-(iH-tetrazol-5-yl)ethyl]-1,2,3,4,4a,5,6,7,8,8adecahydroiso-quinoline-3-carboxylic acid), but not the NMDA receptor antagonist AP-5, also decreased cue-controlled cocaine seeking. These data show that stimulation of DA and AMPA/KA receptors in the dorsal striatum is critical for well established drug seeking that depends on the reinforcing effects of cocaine-associated stimuli. In addition, given the importance of the dorsal striatum in stimulusresponse habit learning, these data suggest that the habitual or compulsive quality of persistent drug seeking depends on dorsal striatal mechanisms.