Neuropeptide infusion into CSF is a potentially important pharmacotherapeutic modality. There are few preliminary studies investigating its feasibility, however. The studies described here will assess the dynamics of neuropeptide clearance from cerebrospinal fluid (CSF) and evaluate the effects of long-term peptide infusion by implanted pump in experimental animals. Somatostatin, arginine vasopressin, and beta-endorphin have been chosen because of their implications for human disease; CSF somatostatin and arginine vasopressin are deficient in Alzheimer's disease; and CSF beta-endorphin deficiencies are associated with some painful states. The experiments will use models established in this laboratory for studying CSF-plasma relationships in awake sheep and anesthetized rabbits. Lumbar, ventricular, and cisternal CSF will be sampled simultaneously to determine physiological concentrations at these sites. Ventriculo-cisternal perfusion in rabbits will test the hypothesis that these peptides are cleared by an active transport system rather than simply by bulk flow, and autoradiography will establish sites of brain bound peptide. In the major part of the work, a chronically implanted pump will be used to infuse peptides by either ventricular or lumbar routes. This will test the hypotheses that lumbar infusion is a satisfactory method of achieving steady state ventricular and cisternal concentrations, will give predictable dose response relationships, and will not lead to gross behavioral, electroencephalographic, hormonal, or structural changes if concentrations are kept close to physiological range. The goal of these studies is to determine the mechanisms of CSF clearance for these peptides and to provide data for possible applications of chronic CSF infusion of peptides in patients.
