Effect of D-fenfluramine on neuropeptide Y concentration and release in the paraventricular nucleus of food-deprived rats

Abstract

Recent evidence indicates that Neuropeptide Y (NPY) is an important signal in the hypothalamic neural circuitry that stimulates feeding in the rat. Administration of d-fenfluramine (FEN) has been shown to rapidly inhibit feeding in the rat. Because food deprivation increases the levels and release of NPY in the paraventricular nucleus (PVN) of the hypothalamus, the aim of this study was to investigate whether the rapid anorectic effects of FEN in food-deprived (FD) rats are associated with alterations in the hypothalamic NPYergic system. In the first experiment, the effect of FEN (10 mg/kg) on NPY concentrations in nine microdissected hypothalamic sites was assessed by radioimmunoassay (RIA) in rats either food deprived for 3 days or fed ad lib during the experimental period. In response to food deprivation, NPY concentrations increased significantly in the PVN and arcuate nucleus, but NPY levels remained unchanged in the remaining seven hypothalamic sites. In control rats maintained on ad lib food supply, FEN injection produced little effect on NPY concentration in hypothalamic sites. However, FEN suppressed NPY levels selectively in the PVN of FD rats, so that NPY concentrations measured in the nucleus were within the range found in satiated control rats. In the second experiment, the effect of FEN on NPY release in the PVN was examined in FD rats by the push-pull cannula (PPC) technique. NPY levels in the PPC perfusate were unchanged in FD rats during the period 30–120 min after saline or FEN injection. Also, the mean rate of NPY release was similar in vehicle- and FEN-treated FD rats. These results raise the possibility that the immediate anorectic effects of FEN may not be due to decreased NPY release in the PVN, but may be due to either suppression of postsynaptic NPY action and/or activation of neural systems that inhibit feeding behavior. However, the decrease in NPY concentration seen selectively in the PVN implies that FEN may eventually affect NPY secretion in FD rats.