SLOW DELIVERY OF THE SELECTIVE CHOLECYSTOKININ AGONIST PBC-264 INTO THE RAT NUCLEUS-ACCUMBENS USING MICROSPHERES

Neuropeptides have been shown to play a critical role in adaptational processes, probably by long-term modulation of neuronal pathways. It c ould therefore be interesting to study behavioral changes induced by c hronic local stimulation of neuropeptide receptors. With this aim poly (lactide-co-glycolide) microspheres loaded with a highly potent, pepti dase-resistant, cholecystokinin (CCK)-B-selective CCK peptidomimetic a gonist (pBC 264) were prepared by a water in oil in water emulsion sol vent evaporation method and stereotaxically implanted into the anterio r part of the rat nucleus accumbens. Two different kinds of loaded pol ymeric microspheres differing only by the stabilizing agent [ovalbumin (OVA) or Pluronic F 68] added to the inner emulsion were used. The hi stological and behavioral studies done 24 h and 8 days after implantat ion of nonloaded microspheres in the nucleus accumbens indicated that the microspheres were well tolerated. The in vivo release of the selec tive CCK-B agonist pBC 264 (associated with a tracer dose of [H-3] pBC 264) from microspheres prepared with OVA was very fast (92% after 6 h ), whereas only 26% (88 pmol) of pBC 264 was released from the formula tion with Pluronic F 68 after 24 h. Eight days after implantation 36% of pBC 264 had diffused from the microspheres, and 8% (similar to 30 p mol) was still present in the brain concentrated around the site of ad ministration. In all cases the released material was found to correspo nd to intact pBC 264, thus demonstrating the possibility of obtaining a slow controlled release of peptide in vivo. This method opens up int eresting perspectives to study the long-term effects of neuropeptides.