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 could therefore be interesting to study behavioral changes induced by chronic local stimulation of neuropeptide receptors. With this aim poly(lactide-co-glycolide) microspheres loaded with a highly potent, peptidase-resistant, cholecystokinin (CCK)-B-selective CCK peptidomimetic agonist (pBC 264) were prepared by a water in oil in water emulsion solvent evaporation method and stereotaxically implanted into the anterior part of the rat nucleus accumbens. Two different kinds of loaded polymeric microspheres differing only by the stabilizing agent [ovalbumin (OVA) or Pluronic F 68] added to the inner emulsion were used. The histological and behavioral studies done 24 h and 8 days after implantation of nonloaded microspheres in the nucleus accumbens indicated that the microspheres were well tolerated. The in vivo release of the selective CCK-B agonist pBC 264 (associated with a tracer dose of [3H]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 formulation with Pluronic F 68 after 24 h. Eight days after implantation 36% of pBC 264 had diffused from the microspheres, and 8% (approximately 30 pmol) was still present in the brain concentrated around the site of administration. In all cases the released material was found to correspond to intact pBC 264, thus demonstrating the possibility of obtaining a slow controlled release of peptide in vivo. This method opens up interesting perspectives to study the long-term effects of neuropeptides.
Blanco-Príeto
M J
MJ
Département de Pharmacochimie Moléculaire et Structurale, U. 266 INSERM-URA D 1500 CNRS, Université René Descartes, UFR des Sciences Pharmaceutiques et Biologiques, Paris, France.
Durieux
C
C
Daugé
V
V
Fattal
E
E
Couvreur
P
P
Roques
B P
BP
D000818:Animals; D001672:Biocompatible Materials; D002766:Cholecystokinin / Q000008:administration & dosage / Q000819:agonists* / Q000031:analogs & derivatives*; D003692:Delayed-Action Preparations; D019344:Lactic Acid; D008856:Microscopy, Fluorescence; D008863:Microspheres; D009714:Nucleus Accumbens / Q000187:drug effects*; D010446:Peptide Fragments / Q000008:administration & dosage*; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D051381:Rats
C084553:BC 264; D001672:Biocompatible Materials; D003692:Delayed-Action Preparations; D010446:Peptide Fragments; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D002766:Cholecystokinin