The co-localization of serotonin (5-hydroxytryptamine, 5HT) and neuroactive peptides in the same neuron points to the importance of interactions between serotonergic and peptidergic systems in maintaining body homeostasis. In this work, we used an original genetic rat model to search for possible interrelations between 5HT system functioning and the activities of aminopeptidases, i.e. enzymes which are the key regulators of (neuro)peptides level/function. The activities of three cytosolic exopeptidases: alanyl aminopeptidase (alanyl-AP), arginyl aminopeptidase (arginyl-AP) and dipeptidyl peptidase III (DPP III) were measured in brains and peripheral tissues of the sublines of rats with constitutionally upregulated/downregulated 5HT transporter activity. These rat sublines, termed as high-5HT and low-5HT subline, have been obtained previously by selective breeding for the extreme values of platelet 5HT level and velocity of 5HT uptake. Besides in the periphery they show marked alterations also in brain 5HT function, indicating the differences in central 5HT transmission/homeostasis. In this study, we have found that animals from the high-5HT subline have significantly lower activity of brain alanyl-AP (p<0.05) and arginyl-AP (p<0.01) as compared to control animals. No other differences were noticed regardless of the 5HT subline, investigated organ or analyzed aminopeptidase. Results suggest that the constitutional upregulation of serotonergic activity may be related to a lowered brain cytosolic aminopeptidase activity which may have an influence on the cleavage of their physiological substrates.