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...

The present study was designed to evaluate the relationship between reinstatement of drug-seeking behaviour following long-term extinction of intravenous (i.v.) drug self-administration (an animal model for craving) and long-term behavioural sensitization. Rats were allowed to self-administer heroin (50 microg/kg per inj., 14 daily sessions), cocaine (500 microg/kg per inj., 10 daily sessions) or saline. Following a 3-week extinction period, reinstatement tests were performed to evaluate priming effects of amphetamine, cocaine and heroin on nonreinforced drug-seeking behaviour. In addition, the occurrence of long-term behavioural sensitization in rats with a history of heroin or cocaine self-administration was determined. Heroin-seeking behaviour was reinstated by heroin (0.25 mg/kg), amphetamine (1.0 mg/kg) and cocaine (10 mg/kg). In addition, animals with a history of heroin self-administration displayed locomotor sensitization to both heroin and amphetamine. Cocaine-seeking behaviour was reinstated by cocaine and amphetamine, but not by heroin. Interestingly, locomotor sensitization to amphetamine, but not heroin, was observed in animals with a history of cocaine self-administration. In other words, the induction of drug-seeking behaviour following a prolonged drug-free period was found to be associated with the expression of long-term behavioural sensitization. These data provide experimental evidence for a role of behavioural sensitization in the incentive motivation underlying drug-seeking behaviour. If drug hyperresponsiveness would indeed be a crucial factor in drug-induced craving in human addicts, pharmacological readjustment of the neuroadaptations underlying drug sensitization may prevent relapse to drug use long after detoxification.

Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.

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Methylphenidate is the first-choice treatment for attention-deficit/hyperactivity disorder (ADHD), but its mechanism of action is incompletely understood. The cognitive effects of methylphenidate have been extensively studied, but little is known about its effects on spontaneous social behavior. During adolescence, rats display a characteristic, highly vigorous form of social behavior, termed social play behavior, which is of critical importance for social and cognitive development. We investigated the neurobehavioral mechanisms by which methylphenidate affects social play behavior in rats. Methylphenidate (0.3-3.0 mg/kg, s.c. or p.o.) abolished social play behavior, without altering general social interest. This effect of methylphenidate did not depend upon the baseline level of social play and was not secondary to changes in locomotion. Furthermore, the play-suppressant effect of methylphenidate was not subject to tolerance or sensitization. Methylphenidate blocked both the initiation to play and the responsivity to play initiation. The effect of methylphenidate was mimicked by the noradrenaline reuptake inhibitor atomoxetine, which is also used for the treatment of ADHD, and was blocked by an a-2 adrenoceptor antagonist. In addition, combined administration of subeffective doses of methylphenidate and atomoxetine suppressed social play. However, blockade of a-1 adrenoceptors, b-adrenoceptors, or dopamine receptors did not alter the effect of methylphenidate. These data show that methylphenidate selectively blocks the most vigorous part of the behavioral repertoire of adolescent rats through a noradrenergic mechanism. We suggest that the effect of methylphenidate on social play is a reflection of its therapeutic effect in ADHD, that is, improved behavioral inhibition. However, given the importance of social play for development, these findings may also indicate an adverse side effect of methylphenidate.

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The differences between direct and indirect agonists indicate a clear, but complex, involvement of DA in drug-seeking behaviour long after detoxification. Moreover, the results show an important role of D2 receptor activation in the persistence of cocaine- but not heroin-seeking behaviour. Finally, the results from both studies suggest a relationship between drug-induced reinstatement and drug hyperresponsiveness in long-term abstinent rats.

The results show that the reinforcing and motivational effects of heroin and heroin-paired stimuli are mediated, at least in part, by activation of cannabinoid CB1 receptors. Therefore, the present study provides a rationale for the use of cannabinoid antagonists in the treatment of opiate addiction.