N-methyl- d-aspartate (NMDA) stimulates release of α-MSH from the rat hypothalamus through release of nitric oxide

Superfusion of rat hypothalamic slices with 10 −4 M N-methyl- d-aspartic acid (NMDA) resulted in increased release of α-melanocyte-stimulating hormone (α-MSH). Peptide release was blocked by 10 −6 M N G-nitro- l-arginine methyl ester ( l-NAME) a specific competitive inhibitor of nitric oxide synthase but not by the inactive enantiomer d-NAME at 10 −6 M. The inhibition by l-NAME was reversed by the addition of 10 −5 M l-arginine, an excess of enzyme substrate. Release of nitric oxide products into tissue superfusates was stimulated by a 50 mM concentration of potassium ions and by 10 −4 M NMDA. Potassium-stimulated release was blocked by l-NAME. Basal, potassium-stimulated and NMDA-stimulated release of nitric oxide products were significantly inhibited by the NMDA-receptor antagonist d-(−)-2-amino-5-phosphopentanoic acid (AP5) at 10 −4 M and by the NMDA-channel blocker ketamine at 10 −4 M. We conclude that nitric oxide mediates the stimulatory action of glutamic acid ont he release of α-MSH from the rat hypothalamus.