Subchronic and chronic exposure to d-fenfluramine dose-dependently enhances splenic immune functions in young and old male Fischer-344 rats

Abstract

Serotonin (5-HT) has been shown to modulate various arms of the rodent immune system in an age- and sex-dependent fashion. Thus, only young (5–6 months) male and old (21–23 months) female Fischer-344 (F344) rats demonstrated an elevation in ex vivo assessed basal and IL-2 stimulated splenic NK activity as well as CON-A induced T cell proliferation after subchronic (30–44 days) administration of low doses (0.6–1.8 mg/kg per day, p.o.) of the 5-HT releaser and reuptake inhibitor, d-fenfluramine (d-FEN). In the present study when young male F344 rats were administered higher doses of d-FEN (3–9 mg/kg per day, p.o.) for 30–39 days, there was a dose-dependent decrease in basal NK activity which returned to control levels after overnight incubation with IL-2. Further, only the rats receiving 6 mg/kg per day of d-FEN exhibited an elevation (40%) in CON-A mitogenesis compared to controls. When 15-month-old male rats were treated with d-FEN (0.6 mg/kg per day, p.o.) for 8 months, their NK and T cell activities at 23 months were not statistically different from young (7 months old) control animals. Importantly, neither the old rats treated with d-FEN nor the young control animals evidenced splenic or hepatic hypertrophy and lesions. In contrast, the old control animals showed increased NK activity (250%) and decreased T cell mitogenesis (300%) which correlated with a high incidence of splenic pathology. Thus, long-term exposure to d-FEN appears to maintain the NK and T cell arms of the immune system at youthful levels and prophylactically reduce the splenic pathology associated with advancing age. These results suggest that long-term exposure to increased levels of 5-HT may be beneficial to the immune system of the aging male F344 rat.