Abstract

Using high performance liquid chromatography with electrochemical detection, we attempted to find among L-dopa-related analogs a competitive antagonist against L-dopa-induced facilitation of impulse (2 Hz)-evoked endogenous norepinephrine (NE) release from rat hypothalamic slices. At the first screening in the presence of cocaine and 3-hydroxybenzylhydrazine (NSD-1015), a L-aromatic amino acid decarboxylase inhibitor, L-dopa (1-100 nM) concentration-dependently facilitated NE release. L-dopa (1 microM) reduced NE release. D-dopa, L-phenylalanine, 3-O-methyl-dopa, 3,4-dihydroxyphenylacetic acid or L-dopa-phosphate at 1 to 1000 nM, and carbidopa (1-10 nM), did not mimic L-dopa. L-dopa methyl ester (0.3-10 nM) concentration-dependently decreased NE release, suggesting that it is antagonistic, whereas L-threo-3,4-dihydroxyphenylserine (0.001-1 nM) concentration-dependently mimicked L-dopa. At the second screening in the additional presence of S-sulpiride, L-dopa (1-1000 nM) concentration-dependently facilitated NE release. Maximum effect was seen at 0.3 to 1 microM. Pretreatment with carbidopa (0.1-10 nM) or L-dopa phosphate (0.01-0.1 nM) was somewhat antagonistic. L-Dopa methyl ester (3-30 nM) in a concentration-dependent manner shifted the concentration-facilitation curve for L-dopa to the right: Schild plots gave a straight line with a slope of 1.00 and pA2 was 8.9, whereas l-propranolol (1-100 nM) concentration-dependently reduced maximal effect of L-dopa without rightward shift of the curve. L-Dopa methyl ester and some large neutral amino acids inhibited uptake of [3H]-L-dopa into slices in the presence of NSD-1015.(ABSTRACT TRUNCATED AT 250 WORDS)