Acute and chronic actions of a dry methanolic extract of Hypericum perforatum and a hyperforin-rich extract on dopaminergic and serotonergic neurones in rat nucleus accumbens.
Dry hydroalcoholic extract of Hypericum perforatum L. is effective in the treatment of mild-to-moderate depression. Neither the mechanism of action nor the component or components of the extract responsible are known to date. In several in vitro and ex vivo models, the extract and hyperforin, one of its active components, cause changes similar to those of tricyclic antidepressants. Little is known about effects on a complex neuronal system relevant to antidepressant actions such as the mesolimbic system in the brain. In animal models of depression, the levels of dopamine were reduced in the nucleus accumbens, which is an important part of the mesolimbic system. These and other deficits were compensated by imipramine. We investigated the actions of the methanolic Hypericum extract LI 160 and a hyperforin-rich research extract in the shell region of the nucleus accumbens under in vivo conditions after acute administration, and after application repeated fourteen times. Both extracts induced an increase of dopamine (DA) and 5-hydroxytryptamine (5-HT) levels measured by in vivo microdialysis. The dose-response curve followed an inverse U-shape. Repeated application caused a rapid tolerance of DA but not of 5-HT neurones. Similar changes were observed after acute and repeated applications of imipramine. Several lines of evidence have suggested other active components in the Hypericum extract. The potency of hyperforin surpassed that of imipramine in the acute release of both DA and 5-HT by the nucleus accumbens. The effect of hyperforin correlated well with the inhibiting potency on high-affinity DA and 5-HT uptake. The missing effect of relatively high doses on DA and 5-HT levels as found in dose-response experiments may be explained by self-inhibition caused by the activation of autosomal receptors and by the inhibition by GABA. The inhibition of neuronal GABA transport occurs at somewhat higher concentrations of hyperforin. In conclusion, the findings demonstrate an imipramine-like effect of methanolic Hypericum extract LI 160 and of hyperforin on mesolimbic, dopaminergic and serotonergic neurones in acute and chronic experiments, which probably contributes to the antidepressant action of the medication. The methanolic Hypericum extract contains active compounds other than hyperforin.
Rommelspacher
H
H
Department of Clinical Neurobiology, Benjamin Franklin Hospital, Free University, Berlin, Germany. hrommel@zedat.fu-berlin.de
Siemanowitz
B
B
Mannel
M
M
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds; D004298:Dopamine / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D020902:Hypericum; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D000432:Methanol; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects*; D010696:Phloroglucinol / Q000031:analogs & derivatives; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000502:physiology; D012997:Solvents; D013729:Terpenes / Q000494:pharmacology*
D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D001643:Bridged Bicyclo Compounds; C422326:Hypericum extract LI 160; D010936:Plant Extracts; D012997:Solvents; D013729:Terpenes; D012701:Serotonin; D010696:Phloroglucinol; D007099:Imipramine; C001654:hyperforin; D004298:Dopamine; D000432:Methanol