Functional interdependence between mesencephalic dopaminergic pathways is an emerging concept. Using in vivo voltammetry and acute manipulation of dopaminergic transmission with pharmacological agents, we have previously reported the existence of a preferentially left lateralized functional interdependence between the entorhinal cortex and the nucleus accumbens. The aim of the present work was to test if this phenomenon is only a dynamic process or if compensation occurs when interdependent functioning is considered in a more long-term perspective. In this study 6-OHDA lesions of the dopamine terminals of the entorhinal cortex were performed separately in the left and right hemispheres. Spontaneous and (+)-amphetamine stimulated locomotor activity were recorded 3 weeks after unilateral interventions in the Ent. Variations in DA and DOPAC levels were measured in the nucleus accumbens 5 weeks after the lesion. The following results were obtained. After unilateral 6-OHDA in the left Ent, DA and DOPAC tissue contents as well as the DOPAC/DA ratio were found significantly changed in nucleus accumbens in the two hemispheres. After dopaminergic destruction in the right Ent only the DOPAC/DA ratio in the left Acc was found statistically elevated. No differences in spontaneous or (+)-amphetamine-stimulated locomotor activity were observed after either left or right lesions. These data confirm those previously obtained with the voltammetric approach and further support the existence of an asymmetrical functional interdependence between mesencephalic DAergic pathways reaching the Ent and the Acc. These results may provide new insights in the pathophysiology of schizophrenic psychoses.