Effects of oxytocin and a derivative (Z-prolyl-D-leucine) on morphine tolerance/withdrawal are mediated by the limbic system.

Recent data indicate that the neurohypophyseal hormone oxytocin (OXT) and Z-prolyl-D-leucine (Z-Pro-D-Leu), a synthetic dipeptide derived from the C-terminal part of OXT, attenuate the development of tolerance to and dependence on morphine in the mouse. Biochemical and behavioral data raise the possibility that these effects of the peptides might be associated with their effects on the central nervous system and in particular on limbic brain structures. The present results confirm this hypothesis, since intracerebroventricular (i.c.v., 50 ng) and local (0.5 ng) injections of OXT and Z-Pro-D-Leu into the dorsal hippocampus and the mesolimbic nucleus accumbens attenuate morphine tolerance/dependence, similarly to systemic injections of these peptides in higher amounts (5-50 micrograms). Local injections of these peptides into other brain sites (e.g. the nucleus caudatus, ventral tegmental area and the external cortical surface) are without effect. Lesion of the nucleus accumbens by the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) completely prevents the effects of Z-Pro-D-Leu and partially those of OXT on morphine tolerance/dependence. The data point to the role of limbic structures as mediators of the effects of neuropeptides on morphine addiction.