A great number of studies have shown the presence of physiological interactions between brain neurotransmitter systems in behavioural responses. This is the case for opioid, cholecystokinin (CCK) and dopamine systems. However, so far the role that the CCK system may play in vulnerability to consumption of drugs of abuse is not clear. This was investigated in this study using Lewis rats that are more sensitive to the reinforcing properties of drugs of abuse than Fischer rats. The extraneuronal CCK8 levels and brain CCK2 receptors were found higher in Fischer than in Lewis rats in the nucleus accumbens, one of the most important structures involved in drug consumption. Moreover, pharmacological modulation of the CCK system by administration of a selective CCK2 agonist blocked, in the conditioned place preference, the reinforcing effects of morphine in Lewis rats, whereas a selective CCK2 antagonist revealed reinforcing effects of the alkaloid in Fischer rats. These results obtained following systemic administrations of the CCK ligands were confirmed following microinjection into the nucleus accumbens. Thus, a low level of CCK efflux in the nucleus accumbens could be one of the many factors involved in drug reinforcing effects, whereas a high level of CCK efflux could attenuate it.