Neuropeptide Y: localization in the central nervous system and neuroendocrine functions


*Laboratoire d'endocrinologie moléculaire, URA CNRS 650, UA INSERM, Université de Rouen, 76134 Mont-Saint-Aignan, France


Summary— Neuropeptide Y (NPY) is a 36-amino acid peptide first isolated and characterized from porcine brain extracts. A number of immunocytochemical investigations have been conducted to determine the localization of NPY-containing neurons in various animal species including both vertebrates and invertebrates. These studies have established the widespread distribution of NPY in the brain and in sympathetic neurons. In the rat brain, a high density of immunoreactive cell bodies and fibers is observed in the cortex, caudate putamen and hippocampus. In the diencephalon, NPY-containing perikarya are mainly located in the arcuate nucleus of the hypothalamus; numerous fibers innervate the paraventricular and suprachiasmatic nuclei of the hypothalamus, as well as the paraventricular nucleus of the thalamus and the periaqueductal gray. At the electron microscope level, using the pre- and post-embedding immunoperoxidase techniques, NPY-like immunoreactivity has been observed in neuronal cell body dendrites and axonal processes. In nerve terminals of the hypothalamus, the product of the immunoreaction is associated with large dense core vesicles. In lower vertebrates, including amphibians and fish, neurons originating from the diencephalic (or telencephalic) region innervate the intermediate lobe of the pituitary where a dense network of immunoreactive fibers has been detected. At the ultrastructural level, positive endings have been observed in direct contact with pituitary melanotrophs of frog and dogfish. These anatomical data suggest that NPY can act both as a neurotransmitter (or neuromodulator) and as a hypophysiotropic neurohormone.

In the rat a few NPY-containing fibers are found in the internal zone of the median eminence and high concentrations of NPY-like immunoreactivity are detected in the hypothalamo-hypophyseal portal blood, suggesting that NPY may affect anterior pituitary hormone secretion. Intrajugular injection of NPY causes a marked inhibition of LH release but does not significantly affect other pituitary hormones. Passive immunoneutralization of endogenous NPY by specific NPY antibodies induces stimulation of LH release in female rats, suggesting that NPY could affect LH secretion at the pituitary level. However, NPY has no effect on LH release from cultured pituitary cells or hemipituitaries. In addition, autoradiographic studies show that sites for 125I-labeled Bolton-Hunter NPY or 125I-labeled PYY (2 specific ligands of NPY receptors) are not present in the adenohypophysis, while moderate concentrations of these binding sites are found in the neural lobe of the pituitary. It thus appears that the inhibitory effect of NPY on LH secretion must be mediated at the hypothalamic level. This hypothesis is supported by the following observations: i), intracerebroventricular injection of NPY causes a reduction in plasma LH; ii), NPY fibers have been observed in contact with LHRH neurons in the preoptic region; iii), the organum vasculosum of the lamina terminalis, where LHRH neurons are located, lacks a blood-brain barrier (NPY injected peripherally can thus reach LHRH neurons in this area). The fact that intracerebroventricular injection of NPY in 5,7-dihydroxytryptamine treated rats causes stimulation of LH release (instead of an inhibition in control animals) also suggests that the effect of NPY may in part be mediated via serotoninergic neurons.

In amphibians, the existence of a NPY-neuronal system originating from the hypothalamus and terminating in the pars intermedia suggest that NPY may play a role in the control of pituitary melanotrophs. In vitro data show that NPY induces a marked inhibition of α-melanotropin (α-MSH) release in frog and toad. The biologically active determinant of NPY is located in the C-terminal region of the molecule. Experiments conducted with acutely dispersed pituitary cells and electrophysiological data using the patch-clamp technique indicate that NPY exerts a direct effect on pituitary melanotrophs. Administration of NPY in black background-adapted toads causes aggregation of dermal melanophores. Taken together, these data indicated that in amphibians NPY can be considered as a melanotropin-release inhibiting factor (MIF).

From these studies, it is concluded that NPY was: i), a neurotransmitter which mediates a number of processes in the brain and in sympathetic nerves; and ii), a hypophysiotropic neurohormone which regulates the secretion of various pituitary hormones such as LH in mammals and α-MSH in amphibians.