Release of endogenous norepinephrine from rat hypothalamus by stimulation of N-methyl-D-aspartic acid receptors

Release of endogenous dopamine and norepinephrine (NE) from rat hypothalamic slices superfused with Mg⁺⁺-free medium in the presence of nomifensine and tyrosine was measured by high-performance liquid chromatography coupled to an electrochemical detector. Superfusion with L- glutamic acid or N-methyl-D-aspartic acid elicited a concentration-dependent release of NE but not of dopamine. The release of NE was transient, returning toward basal values despite the continued presence of the amino acid. Superfusion with 20 mM K⁺ caused a release of NE that declined at a slower rate. Mg⁺⁺, DL-2-amino-5-phosphonopentanoic acid and MK-801 {D-5-methyl- 10,11,dihydro-5H-dibenzo[a,d] cyclohepten-5-10-imine maleate}, but not 6- cyano-7-nitroquinoxaline-2,3-dione, inhibited the L-glutamic acid-evoked release of NE. The release of NE by L-glutamic acid was virtually abolished by tetrodotoxin and by elimination of Ca⁺⁺ from and inclusion of 2 mM ethylene glycol bis(β-aminoethyl ether)-N,N'-tetraacetic acid in the superfusion medium. Repeated L-glutamic acid applications displayed a decreased response, whereas repeated exposure to 20 mM K⁺ did not. Exposure to L-glutamic acid in the absence of Ca⁺⁺ (plus 2 mM ethylene glycol bis(β-aminoethyl ether)-N,N'-tetraacetic acid) or in the presence of DL-2- amino-5-phosphonopentanoic acid did not reduce the effects seen on subsequent exposure to L-glutamic acid. Exposure to L-glutamic acid in the absence of Mg⁺⁺ reduced the effect of a subsequent exposure to L-glutamic acid. These observations provide evidence for an indirect modulation of rat hypothalamic endogenous NE by the N-methyl-D-aspartate receptor.