Extracts of the medicinal plant St. John's wort (Hypericum perforatum) are widely used for the treatment of mild to moderate depression. Hyperforin, a constituent of St. John's wort, is known to inhibit the sodium-dependent uptake of catecholamines and amino acids into synaptic nerve endings, probably by interference with mechanisms controlling the synaptic sodium concentration. Because de novo synthesis of acetylcholine (ACh) is dependent on sodium-dependent highaffinity choline uptake, we studied the effect of hyperforin on choline (Ch) uptake in vitro and on striatal ACh release in vivo using microdialysis. In rat brain synaptosomes, hyperforin inhibited high-affinity choline uptake with an IC 50 of 8.5 M, whereas low-affinity uptake was not affected. Local infusion of hyperforin (100 M) via the dialysis probe caused a delayed reduction of ACh release and a concomitant increase of Ch levels. Infusion of a lower concentration of hyperforin (10 M), however, increased striatal ACh release and lowered Ch levels. Systemic administration of hyperforin (1-10 mg/kg i.p.) led to therapeutic plasma levels of hyperforin and caused a significant elevation of striatal ACh release. Behavioral testing revealed a reduction of locomotor activity in mice treated with high-dose (10 mg/kg) hyperforin. We conclude that low doses of hyperforin stimulate striatal ACh release by an unknown mechanism, whereas high doses inhibit synaptic choline uptake and ACh release. The results are discussed with respect to the therapeutic use of St. John's wort in patients with neurodegenerative disorders.
Choline (Ch) is an essential nutrient as the biosynthetic precursor of acetylcholine (ACh) and phospholipids. Under resting conditions, the intracellular accumulation of Ch (above 10-fold), which is positively charged, is governed by the membrane potential and follows the Nernst equation. Accordingly, in synaptosomes from adult rats during depolarization, we observed a linear relationship between release of free cytoplasmic Ch and KCl concentration (2.7-120 mM). The K + -evoked Ch release was Ca 2+ -independent and did not originate from ACh or phospholipid hydrolysis. In superfused brain slices of adult rats, however, a K + -induced Ch efflux was absent. Also, under in vivo conditions, 30-60 mM KCl failed to increase the extracellular Ch level as shown by microdialysis in adult rat hippocampus. On the contrary, in brain slices from 1-week-old rats, high K + as well as 4-aminopyridine evoked a marked Ch efflux in a concentration-dependent fashion. This phenomenon faded within 1 week. Hemicholinium-3 (HC-3, 1 and 10 lM), a blocker of cellular choline uptake, caused a marked efflux of choline from adult rat slices but no or significantly less release from immature slices. We conclude that depolarization of synaptic endings causes a Ca 2+-independent release of free cytoplasmic Ch into the extracellular space. In adult rat brain, this elevation of Ch is counteracted by a homeostatic mechanism such as uptake into brain cells.
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