Repeated administration of drugs of abuse is thought to induce a variety of persistent changes in both behavior and brain morphology, including modifications of neurons from the brain regions involved in addiction. We have studied the morphology of the basal dendritic arbor of cortical pyramidal neurons in addiction-resistant Fischer 344 strain rats that self-administered morphine. Pyramidal neurons in the prelimbic and motor cortex were intracellularly injected with Lucifer Yellow in fixed tissue and they were reconstructed in three dimensions using Neurolucida software. Morphine self-administration did not produce significant changes in the structure of the dendritic arbors or in the spine density of pyramidal neurons in either the prelimbic or motor cortex of F344 rats. Moreover, pyramidal cell morphology did not differ in these two cortical areas in saline self-administered animals. However, when the structure of these cortical pyramidal cells from Fischer 344 rats was compared with that previously reported in addiction-prone Lewis rats in the same cortical areas, significant morphological differences were found between both strains. Indeed, these differences were not only observed following morphine self-administration but also in saline self-administered control animals. We suggest that strain differences in the structure of pyramidal cells in certain cortical areas might represent an anatomical substrate for the distinct vulnerability to the reinforcing effects of morphine exhibited by Fischer 344 and Lewis rats in operant self-administration paradigms.