Treatment of cocaine addiction is hampered by high rates of relapse even af
ter prolonged drug abstinence. This relapse to compulsive cocaine use can b
e triggered by re-exposure to cocaine(1), by re-exposure to stimuli previou
sly associated with cocaine(2) or by exposure to stress(3). In laboratory r
ats, similar events reinstate cocaine seeking after prolonged withdrawal pe
riods', thus providing a model to study neuronal mechanisms underlying the
relapse to cocaine. The endocannabinoid system has been implicated in a num
ber of neuropsychiatric conditions, including drug addiction(7,8). The acti
ve ingredient of marijuana, Delta9-tetrahydrocannabinol, activates the meso
limbic dopamine (DA) reward system(9,10) and has rewarding effects in precl
inical models of drug abuse(8,11,12). We report here that the synthetic can
nabinoid agonist, HU210 (ref. 13), provokes relapse to cocaine seeking afte
r prolonged withdrawal periods. Furthermore, the selective CB1 receptor ant
agonist, SR141716A (ref. 14), attenuates relapse induced by re-exposure to
cocaine-associated cues or cocaine itself, but not relapse induced by expos
ure to stress. These data reveal an important role of the cannabinoid syste
m in the neuronal processes underlying relapse to cocaine seeking, and prov
ide a rationale for the use of cannabinoid receptor antagonists for the pre
vention of relapse to cocaine use.