Chronic leptin administration in developing rats reduces stress responsiveness partly through changes in maternal behavior

In adult rodents, leptin has been shown to significantly alter the activity of several neuroendocrine functions, including the activity of the hypotha lamic-pituitary-adrenal (HPA) axis. Leptin is generally believed to be inhi bitory to HPA activity in adults. Developing rat pups have high circulating levels of leptin, which begs the question of leptin's physiological role i n controlling basal and stress-induced adrenocortical activity in neonatal rats. In this study, we treated rat pups daily from days 2-9 (or 6-10) of l ife with either vehicle or leptin (1 or 3 mg/kg body wt, ip) and determined the effects on body weight gain, fat pad deposits, and HPA activity in 10- day-old pups. We measured hypothalamic CRF mRNA levels in vehicle- and lept in-treated pups by in situ hybridization and determined plasma ACTH, cortic osterone, and leptin concentrations under basal conditions or following exp osure to a 3-min ether stress. Because leptin activates sympathetic activit y and energy expenditure in adults and possibly also in rat pups, and becau se litter temperature is an important determinant of maternal behavior, we also investigated whether chronic leptin administration would modify aspect s of maternal care that are important for the maintenance of HPA function. Chronic leptin treatment increased circulating levels of leptin and had sig nificant dose-related metabolic effects, including reduced body weight gain and fat pad weight in 10-day-old pups. Basal expression of CRF mRNA in the PVN or secretion of ACTH and corticosterone was not modified by leptin tre atment. In contrast, chronically elevated leptin concentrations during the neonatal period significantly lowered CRF expression in the PVN 60 min afte r stress and reduced the duration of the ACTH response to stress in pups, s uggesting that glucocorticoid feedback on the HPA axis might be altered by this treatment. In addition, mothers caring for pups injected with leptin d isplayed longer bouts of anogenital licking of pups than mothers of vehicle -treated rats. Given that this particular type of pup stimulation has been shown to influence stress responsiveness, it is possible that the maternal response modulates the effects of exogenous leptin treatment. In conclusion , our results demonstrate that the leptin signal is functional during the e arly developmental period and that leptin can modulate the hormonal respons e to stress in young rats either by a direct effect on the HPA axis or indi rectly through changing some aspects of maternal behavior. (C) 2000 Academi c Press.