Effects of the putative polyamine antagonists diethylenetriamine and 1,10-diaminodecane on N-methyl-D-aspartic acid-stimulated [3H]norepinephrine release from rat hippocampal slices.
N-Methyl-D-aspartic acid (NMDA, 500 microM) stimulated the net release of [3H]norepinephrine from rat hippocampal slices. The putative polyamine inverse agonist 1,10-diaminodecane (DA10) dose-dependently inhibited NMDA-stimulated release with a calculated IC50 value of 33 microM. The putative polyamine competitive antagonist diethylenetriamine (DET) partially inhibited (maximum effect 40%) NMDA-stimulated release at 1 mM which was the highest concentration tested. DET (1 mM) but not DA10 also partially inhibited potassium-stimulated release of norepinephrine from hippocampal slices. Neither DET or DA10 significantly altered the nonstimulated basal efflux of neurotransmitter. The inhibition of NMDA-stimulated release produced by 100 microM DA10 or 1 mM DET was not attenuated by addition of the polyamines spermine or spermidine up to 1 mM. In addition, the IC50 value for DA10-induced inhibition of NMDA-stimulated neurotransmitter release was not altered by the addition of DET (100-1000 microM). The combination of the glycine antagonist 7-chlorokynurenic acid (3 microM) and DA10 (100 microM) inhibited NMDA-stimulated release by approximately 70%. The addition of the glycine agonist D-serine (3-100 microM) partially attenuated the inhibition produced by these two compounds. No further enhancement was observed when D-serine was added in the presence of spermine or spermidine. Finally, the NMDA open channel blocker (+)-5-methyl-10,11- dihydro-5H-dibenzo[1,d]cyclo-hepten-5,10-imine maleate dose-dependently inhibited NMDA-stimulated release with an IC50 value of 25 nM. The inhibitory potency of (+)-5-methyl-10,11- dihydro-5H-dibenzo[1,d]cyclo-hepten-5,10-imine maleate was not significantly altered by the presence of either DET (100 microM) or DA10 (30 or 100 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
Woodward
J J
JJ
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond.
Cueto
S
S
D000818:Animals; D003959:Diamines / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D011073:Polyamines / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
C065351:1,10-diaminodecane; D003959:Diamines; D011073:Polyamines; C005391:diethylenetriamine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D009638:Norepinephrine