L-dopa facilitates the release of endogenous norepinephrine and dopamine via presynaptic beta 1- and beta 2-adrenoceptors under essentially complete inhibition of L-aromatic amino acid decarboxylase in rat hypothalamic slices.
In rat hypothalamic slices, L-aromatic amino acid decarboxylase (AADC) was assayed, and the actions of L-DOPA on impulse (2 Hz)-evoked norepinephrine (NE) and dopamine (DA) release were studied under inhibition of AADC. Slices were incubated with L-DOPA, and DA and NE produced by conversion of the precursor were analyzed by high performance liquid chromatography with electrochemical detection (HPLC-ECD). In the slices, the Km and Vmax of AADC were 131 microM and 122 pmol/min/mg protein, respectively. NSD-1015, an AADC inhibitor, caused a noncompetitive type of inhibition, and the K1 value was 0.086 microM. In the presence of 20 microM NSD-1015, which was expected to cause 99.6% inhibition of AADC, L-DOPA (0.01-100 nM) concentration-dependently facilitated the release of NE from the superfused slices, and the L-DOPA (10 nM)-induced facilitation was antagonized by 100 nM ICI 89,406 and 100 nM ICI 118,551, a selective beta 1- and beta 2-adrenoceptor antagonist, respectively. This action of L-DOPA was not modified by 30 microM tropolone, an inhibitor of catechol-O-methyl-transferase. L-DOPA at 0.01-1 nM similarly facilitated the release of DA. A quantitative analysis revealed that the L-DOPA-induced increase in NE and DA release was much higher by a factor of 3 to 4 orders than was the amount of DA and NE converted from L-DOPA. These results add further support to the hypothesis that L-DOPA itself acts as a neuroactive substance in the rat central nervous system.
Goshima
Y
Y
Department of Pharmacology, Yokohama City University School of Medicine, Japan.
Nakamura
S
S
Misu
Y
Y
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D004298:Dopamine / Q000096:biosynthesis*; D004558:Electric Stimulation; D006834:Hydrazines / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D066298:In Vitro Techniques; D007700:Kinetics; D007980:Levodopa / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000096:biosynthesis*; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D006834:Hydrazines; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; C026777:ICI 118551; C004297:3-hydroxybenzylhydrazine; C025716:ICI 89406; D004298:Dopamine; D009638:Norepinephrine