Neuropeptide-dopamine interactions. V. Cyclo(His-Pro) regulation of striatal dopamine transporter complex

Cyclo(His-Pro) (CHP) is a cyclic dipeptide that is ubiquitously distributed through the central nervous system, including striatum. Many biologic effects of CHP seem to be mediated through a dopaminergic mechanism. To further examine the mechanism of action of this peptide, we have studied effects of chronic CHP treatment on the properties of nigro-striatal dopaminergic neurons in rats. Chronic CHP administration elicited significant increase in both KD and Bmax of striatal mazindol-binding sites (labelling DA transporter complex), but no change in either D1- or D2-type DA receptors. Chronic treatment with DA uptake blockers (e.g., benztropine, GBR 12909, bupropion, and mazindol) also produced changes in striatal mazindol-binding sites that were similar to that of chronic CHP. Furthermore, CHP led to a dose-dependent inhibition of [3H]-DA uptake by striatal synaptosomes, reaching to maximal inhibition of uptake (30%) at CHP dosage of 10 nM. The dose-response curve for CHP inhibition of DA uptake, unlike DA uptake blockers that led to a total inhibition, was partial and V-shaped. Again unlike DA uptake blockers, CHP did not inhibit the binding of [3H]-mazindol to striatal membranes. On the basis of these data we hypothesize that while CHP may inhibit DA uptake by modifying mazindol-binding locus at DA transporter complex, its primary action may be at a site other than mazindol-binding site.