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...