Effects of depletion of brain catecholamines during the development of morphine dependence on precipitated withdrawal in rats

Summary The significance of long term depletion of brain catecholamines (CAs) for the development of morphine dependence and for the expression of morphine withdrawal was studied in rats which were implanted with morphine pellets for 10 days. CAs were depleted by inhibition of tyrosine-hydroxylase with alpha-methyl-tyrosine (AMT) or by destruction of catecholaminergic nerve terminals with 6-hydroxydopamine (6-OHDA). In the acute experiments these drugs were applied within 24 hrs before precipitation of withdrawal; in the chronic experiments drug administration was started before the first implantation and in the case of AMT, continued repeatedly thereafter.With either method, acute depletion of brain CAs resulted in reduced intensity of withdrawal. When CAs were kept low through the whole time of morphine exposure and also at the time of withdrawal, the intensity of withdrawal was normal in the case of 6-OHDA administration and only slightly decreased in the case of AMT. When AMT administration was discontinued 40 hrs before precipitation of withdrawal the withdrawal pattern occurred with unchanged intensity.Our experimental data are compatible with the assumption that long lasting depletion of brain CAs is compensated for by induction of neuronal supersensitivity for noradrenaline (NA) and dopamine (DA). While both CAs play an important role in the full expression of the withdrawal syndrome their possible involvement in mechanisms leading to dependence seems to be unlikely although final statements cannot be made by the presented experiments.