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.
Striatal cholinergic interneurons are stimulated by glutamatergic inputs from thalamus and cortex via NMDA receptors. The present microdialysis study was designed to characterize the role of nitric oxide (NO) in this process and to identify the NO synthase (NOS) isoform responsible for this effect. For this purpose, we studied the effects of NMDA and 3-morpholino sydnonimine (SIN-1) perfusions on the release of acetylcholine (ACh) in mouse striatum. In wild-type C57/Bl6 mice, perfusion of NMDA (100 lM) induced a two-fold stimulation of ACh release. This effect was attenuated in mice lacking endothelial NOS but was completely absent in mice lacking neuronal NOS. Local perfusion of SIN-1 (300 lM), an NO donor, increased ACh release by more than two-fold in all three mouse lines. We conclude that NO synthesized by neuronal NOS provides a nitrergic link in the glutamatergic stimulation of striatal cholinergic interneurons.
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