Anxiolytic effects of yokukansan, a traditional Japanese medicine, via serotonin 5-HT1A receptors on anxiety-related behaviors in rats experienced aversive stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Yokukansan, a traditional Japanese medicine (Kampo), has been reported in the treatment of behavioral and psychological symptoms of dementia (BPSD) such as aggression, anxiety and depression in patients with Alzheimer's disease and other forms of senile dementia. AIMS OF THE STUDY: In the present study, we investigated the anxiolytic effects of yokukansan on anxiety-related behaviors in rats that have experienced aversive stress. MATERIALS AND METHODS: We used male Wistar/ST rats which received an electrical footshock as aversive stress. Yokukansan at a dose of 1.0 g/kg was administered orally once a day for 14 or 16 day before behavioral tests. To evaluate the anxiolytic effects, we used the contextual fear conditioning (CFC) test and elevated plus-maze (EPM) test. And we also investigated effects of yokukansan on locomotor activity in the Open-field (OF) test and on the change in plasma corticosterone after CFC stress, in rats that had experienced footshock stress. RESULTS: In the CFC test, rats that had experienced footshock showed significant freezing behavior on re-exposure to the box 14 day after footshock stress. Yokukansan significantly suppressed freezing behavior in the CFC test. In the EPM test on the 16th day after the CFC test, yokukansan significantly increased the time spent in open arms after footshock stress compared to control rats. However, repeated administration of yokukansan on the 14th day did not affect the decrease in locomotor activity and the increase in plasma corticosterone by re-exposure to the box 14 day after footshock stress in the OF test and determination of serum corticosterone, respectively. These anxiolytic effects by yokukansan were antagonized by WAY-100635, a selective 5-HT(1A) receptor antagonist, in the CFC test, but not the EPM test. Furthermore, 5-HT(1A) receptor agonist buspirone significantly suppressed freezing behavior in the CFC test; however, buspirone induced no change in the time spent in open arms in the EPM test. CONCLUSION: These findings suggested that yokukansan has anxiolytic effects on anxiety-like behaviors induced by both innate fear and memory-dependent fear. In particular, yokukansan produced anxiolytic effects via 5-HT(1A) receptors in memory-dependent fear induced by aversive stress. Furthermore, yokukansan could be useful as one of the therapeutic drugs for the treatment of anxiety disorders and various mental disorders that have comorbid anxiety.

Regulation of cerebral blood flow in the hippocampus by neuronal activation through the perforant path: relationship between hippocampal blood flow and neuronal plasticity.

Although changes in regional cerebral blood flow (rCBF) have been used as an index of neuronal activity, the effects of long-term potentiation (LTP) in the hippocampus, widely assumed to be an electrophysiological basis of learning and memory, on the changes in rCBF by neuronal activity remain unclear. Hence, to elucidate whether the effects of LTP in the hippocampus reflect in the correlation between neuronal activity and co-occurring changes in rCBF, we investigated the effects of LTP on the responses of hippocampal blood flow (HBF) to the electrical stimulation of the perforant path in vivo. We continuously measured HBF using Laser-Doppler flowmetry, and systemic blood pressure and heart rate were measured from the femoral artery during electrical stimulations in halothane-anesthetized rats. The results showed that the reactivity of HBF to neuronal activation was potentiated by a tetanic stimulation that induces LTP, although the tetanic stimulation did not affect baseline of HBF values. These results suggest that the presence of the plasticity between neuronal activity and the rCBF in the perforant path-dentate pathway, and the neuronal plasticity can be reflected in the transient changes in rCBF when the brain region is activated but not in the steady state.