Influence of Z-Prolyl-D-Leucine on alpha-MPT-induced catecholamine utilization in specific mouse brain nuclei.

The synethetic dipeptide Z-Prolyl-D-Leucine (Z-Pro-D-Leu) inhibits the development of tolerance to and dependence on morphine in mice. The possible mode of action of the dipeptide was studied by measuring the alpha-MPT-induced disappearance of noradrenaline (NA) and dopamine (DA) either by a spectrofluorimetric assay in major brain areas (lower brainstem, striatum) or by a radioenzymatic assay in specific brain nuclei. For the latter purpose, mouse brain nuclei containing mainly the cell body areas (nucl. tractus solitarii, locus coeruleus, substantia nigra, area tegmentalis ventralis) or some selected terminal projections (nucl. caudatus, nucl. accumbens, gyrus dentatus hippocampi, nucl. raphe dorsalis) of major NA- and DA-containing pathways were selected. In the lower brainstem studied as a whole, the dipeptide did not affect the utilization of either NA or DA. Analysis of the data on the NA utilization in specific brain nuclei, however, revealed that the dipeptide affected NA disappearance in some mesencephalic-limbic nuclei which receive noradrenergic innervation from the dorsal noradrenergic bundle (e.g., nucl. raphe dorsalis, area tegmentalis ventralis, gyrus dentatus). NA utilization in the cell body region of the same pathway (locus coeruleus), however, was not affected by the dipeptide. The dipeptide facilitated DA utilization in the main terminal area of the mesolimbic DA-ergic projection (nucl. accumbens), whereas the same treatment inhibited DA utilization in the main terminal region of the nigro-striatal DA-ergic pathway (nucl. caudatus). The data suggest that localized changes in NA and DA utilization following Z-Pro-D-Leu might be important for peptide-induced changes in morphine tolerance and dependence.