Recent evidence suggest that the endocannabinoid system might be a component of the brain reward system and, then, play a role, not only in cannabinoid tolerance/dependence, but also in dependence/withdrawal to other drugs of abuse. However, there are not many studies that compare the changes in endocannabinoid ligands and/or receptors in brain regions (particularly in those areas related to reinforcement processes) during dependence to opiates, cocaine or alcohol. The present study addressed this objective, by examining the changes in CB(1) receptor binding (measured by [3H]-CP55,940 autoradiography) and its mRNA levels (measured by in situ hybridization) in different brain regions of animals chronically exposed to morphine, cocaine or ethanol. The results showed that these three drugs produced different changes in CB(1) receptor binding and mRNA levels, a finding that precludes the existence of a common alteration of the endocannabinoid system during dependence states to these habit-forming drugs. Thus, chronic ethanol exposure was usually uneffective in altering both CB(1) receptor binding and mRNA levels in all regions examined. In contrast, chronic cocaine exposure produced significant changes only at the level of CB(1) receptor mRNA, with decreases of the transcript levels in the ventromedial hypothalamic nucleus and the superficial and deep layers of the cerebral cortex, but no changes in the hippocampal, motor and limbic structures. Finally, chronic morphine exposure increased the density of CB(1) receptors in the medial caudate-putamen, but decreased their mRNA levels in this region and also in the lateral caudate-putamen and the cerebellum. In limbic structures, chronic morphine exposure increased both binding and mRNA levels for CB(1) receptors in the septum nuclei. Binding was also increased in the nucleus accumbens, but reduced in the basolateral amygdala. In hippocampal structures, chronic morphine exposure reduced CB(1) receptor binding in the dentate gyrus, although mRNA levels were unaffected in this region, but increased in the CA2 subfield of the Ammon's horn. The results indicate that mechanisms of dependence for alcohol, cocaine and morphine are different in terms of their impact on the endocannabinoid system. Alcohol did not produce any effects on CB(1) receptor binding and mRNA levels, whereas cocaine only affected transcript levels in selected regions and morphine produced divergent and region-dependent effects.