Increasing experimental evidences suggest that genetic factors play an important role in the vulnerability to drug addiction. Genetic animal models provide a valuable tool to investigate how genetic factors affect the sensitivity to the reinforcing and addictive properties of drugs of abuse. Two inbred strains of rats suitable for this kind of studies are the Lewis and Fischer 344 rats known to be differently sensitive to drugs of abuse as well as to stress. The aim of this research is to identify likely neurochemical differences at the level of the mesolimbic dopaminergic system, known to be involved in the reinforcing and motivational properties of drugs of abuse. By means of brain microdialysis it has been observed that Lewis rats, who are more or selectively sensitive, compared to Fischer 344 rats, to the rewarding effects of drugs of abuse in self-administration and conditioned place preference paradigms, appear to have a mesolimbic dopaminergic system more responsive to the properties of drugs of abuse to increase extracellular dopamine in the nucleus accumbens (in both shell and core compartment) compared to Fischer 344 rats (Cadoni and Di Chiara, 2007). It is worth noting that Lewis rats showed a dopaminergic transmission responsiveness in the nucleus accumbens core similar to that of outbred rats sensitized to drugs of abuse (morphine, cocaine, amphetamine, nicotine). Further studies in order to clarify the effect of repeated exposures to drugs of abuse are in progress.