Changes in the basal brain bilateral morphologic, neurochemical and/or functional patterns may be partly responsible for some brain disorders such as those involving mood. WKY and SHR strains as well as 6-hydroxydopamine (6-OHDA)-lesioned animals are validated models for the study of mood disorders. Because dopamine and enkephalins are involved in anxiety-related behaviors, the aim of our study was to analyze enkephalinase activity, assayed as aminopeptidase M activity, in the left and right medial prefrontal cortex (mPFC) of WKY and SHR treated with saline (sham group) or following left or right intrastriatal injections of the neurotoxic 6-OHDA. Sham left and sham right WKY exhibited a significant left predominance. Left 6-OHDA-lesioned rats inverted the left predominance of sham to right predominance. In right 6-OHDA-lesioned rats, the left predominance in sham right rats disappeared. Sham left as well as sham right SHR did not show any bilateral differences. In contrast, while the left lesion demonstrated a highly significant left predominance, the right lesion showed a slight but significant right predominance. A significant negative correlation between enkephalinase activity of the right mPFC and blood pressure and heart rate was observed only in left-lesioned SHR. Our results demonstrate that unilateral nigrostriatal injections of 6-OHDA influence the bilateral distribution of enkephalinase activity depending on both the side of the lesion and the strain analyzed. These results support the hypothesis that DA pathways may interact asymmetrically with enkephalins in the mPFC and that enkephalinase activity may play a role in the regulatory mechanisms underlying this interaction.