Older age is associated with diminished symptomatic and cardiovascular response to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). We hypothesized that circulating concentrations of endogenous CCK-4 and/or CCK-8 are increased in later life, possibly due to decreased enzymatic degradation, and that this is associated with desensitization of CCK-B receptors. The study group consisted of 20 healthy subjects aged 18-30 years and 20 healthy subjects aged 65-85 years. The two groups were compared on fasting basal plasma concentrations of CCK-4, sulfated CCK-8 (CCK-8s) and nonsulfated CCK-8 (CCK-8 ns), and on binding capacity of lymphocyte CCK-B receptors. Under single-blind (to subject) conditions, subjects were then administered an intravenous bolus of placebo, followed 50 min later by an intravenous bolus of 50 micro g of CCK-4. Plasma concentrations of total CCK (CCK(T)) were measured 2 min before and 2, 5, 10, and 15 min after each injection. Compared with younger subjects, older subjects had a significantly higher basal plasma concentration of CCK-8s and significantly diminished binding capacity of CCK-B receptors. Following injection of placebo, plasma CCK(T) concentrations did not significantly change from baseline in either age group, but the elderly had significantly higher concentrations than the young at 2, 5, and 10 min. Following injection of CCK-4, the plasma concentration of CCK(T) was highest at 2 min and declined after that. The elderly had significantly higher CCK(T) concentrations (ie. a slower decline in CCK(T)) than the young at 5, 10, and 15 min. These findings are consistent with our hypothesis and suggest that age-related changes in the CCK system could contribute to the diminished panicogenic response to exogenous CCK-4 in older persons.