Stimulation of glutamate, aspartate and gamma-aminobutyric acid release from synaptosomes by hyperforin

Hyperforin is one pharmacologically active constituent of the medicinal her b Hypericum perforatum. The mechanism of its antidepressant-like activity i s currently considered to be the inhibition of synaptic reuptake of neurotr ansmitters. Here, we will demonstrate that it also stimulates the release o f glutamate from rat cortical synaptosomes, and that this effect is precede d by an increase in their free calcium [Ca2+](i) levels. These hyperforin-r elated effects were also observed in the absence of Ca2+ in the medium. Alt hough we noted enhanced glutamate, aspartate and GABA release under the inf luence of hyperforin, the release of various other amino acids was not enha nced. In contrast, reserpine did not influence the release of any of the am ino acids studied. Adding hyperforin to synaptosomal suspension decreased t heir pHi, which returned to basal levels under certain incubation condition s. It also prevented the generation of ATP-incluced pH gradients of isolate d synaptic vesicles, and preformed pH-gradients were reversed by it. We wil l discuss the implications of our studies in understanding the mechanisms o f hyperforin activity in relation to current findings on its pharmacologica l activity profile. our observations suggest that neurotransmitter release stimulation from synaptosomes and the previously reported reuptake inhibito ry properties of hyperforin are consequences of its effects on synaptosomal ionic homeostasis, and that it is not a reserpine-like agent.