The primary objective of this work was to investigate how in vivo administration of depolarizing agents increases extracellular concentrations of 5-hydroxytryptamine (5-HT) and simultaneously decreases levels of its chief metabolite 5-hydroxyindole-3-acetic acid (5-HIAA). To this end the effects of a number of agents on extracellular levels of 5-HT and 5-HIAA in cat spinal cord were determined by microdialysis and high-pressure liquid chromatography with electrochemical detection. The semipermeable portion of the dialysis probe was centered in the dorsal horn. Artificial cerebrospinal fluid containing elevated K+ or drugs was introduced into the dorsal horn via the dialysis probe. Increases in recovered 5-HT were assumed to reflect increased levels in the extracellular fluid due to release, reduced reuptake and/or reduced metabolism. Depolarizing agents (K+, veratridine and aconitine) increased 5-HT, but dramatically decreased 5-HIAA levels. Extracellular 5-HT returned to near base-line levels with removal of the depolarizing agents. The reduction in 5-HIAA was transient after potassium infusion, but outlasted the infusion of veratridine or aconitine by several hours. Reduction of 5-HIAA could be blocked or reversed with the Na+ channel blockers, lidocaine and tetrodotoxin. Evidently, the decrease in 5-HT metabolism followed activation of sodium channels. Parachloroamphetamine caused an increase in 5-HT levels, presumably reflecting increased 5-HT release, but did not change 5-HIAA levels. Although fluoxetine increased 5-HT, it reduced 5-HIAA, presumably through blockade of 5-HT reuptake leading to a secondary reduction in metabolism. The monoamine oxidase (MAO) inhibitors, pargyline and clorgyline, also caused increases in 5-HT and reductions in 5-HIAA, results expected from inhibition of MAO. Prior administration of fluoxetine or MAO inhibitors did not prevent the decrease in 5-HIAA caused by depolarizing agents. The changes in 5-HT and 5-HIAA produced by local application of depolarizing agents were attributed to release of 5-HT and and independent reduction in its metabolism.
|Original language||English (US)|
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jan 1 1991|
ASJC Scopus subject areas
- Molecular Medicine