To test the effect of chronic hyperinsulinemia on cerebrospinal fluid (CSF) insulin concentrations in the obese (fafa) Zucker rat, obese and heterozygote lean (Fafa) rats were infused peripherally with insulin or vehicle for 6 days. Both basal levels and the increase of plasma immunoreactive insulin (IRI) were greater in fafa (increase = 713 microU/ml) than in Fafa (increase = 392 microU/ml) rats, P less than 0.0001. Vehicle-infused fafa rats had higher CSF IRI levels than did vehicle-infused Fafa rats (4.3 +/- 1.2 microU/ml vs. 1.5 +/- 0.4 microU/ml, P less than 0.01). CSF IRI was elevated in both insulin-infused groups (P less than 0.001). After insulin infusion Fafa rats had higher CSF IRI levels than did fafa rats (Fafa: 10.0 +/- 1.8 microU/ml vs. fafa: 7.1 +/- 0.1 microU/ml). In contrast to the effect of insulin infusion on plasma IRI, the increase of CSF IRI was greater in Fafa rats (8.5 microU/ml) than in fafa rats (4.0 microU/ml, P less than 0.001). Uptake of insulin from the periphery to the CSF therefore appears to be reduced in obese fafa Zucker rats compared to lean Fafa controls.