Anxiolytic effect of berberine on exploratory activity of the mouse in two experimental anxiety models: Interaction with drugs acting at 5-HT receptors

Abstract

The aim of this study was to assess the anxiolytic effect of berberine (abbrev. BER) using two experimental anxiety models in the mouse. In the black and white test of anxiety, berberine (100, 500 mg/kg) produced an increase in the first time entry, time spent in the white section, and total changes between two compartments. On the other hand, in the elevated plus-maze test, berberine (100, 500 mg/kg) produced an increase in the time spent and arm entries in the open arms, and a decrease in the time spent and arm entries in the closed arms. Berberine (500 mg/kg) decreased locomotor activity in mice. Furthermore, BER at 100, 500 mg/kg decreased concentrations of NE, DA and 5-HT, and increased the concentrations of VMA, HVA and 5-HIAA in the brain stem. BER also attenuated the anxiogenic effect of WAY-100635, 8-OH DPAT and DOI and enhanced the anxiolytic effect of BUS, p-MPPI and RIT in the elevated plus-maze. These results suggested that berberine at 100 mg/kg had a significant anxiolytic-like effect, which was similar to that observed with 1 mg/kg diazepam and 2 mg/kg buspirone. The anxiolytic mechanism of BER might be related to the increase in turnover rates of monoamines in the brain stem and decreased serotonergic system activity. Moreover, BER decreased serotonergic system activity via activation of somatodendritic 5-HT1A autoreceptors and inhibition of postsynaptic 5-HT1A and 5-HT2 receptors.

Introduction

Anxiety, a state of excessive fear, is characterized by motor tension, sympathetic hyperactivity, apprehension and vigilance syndromes (Sadock and Sadock, 2003). Anxiety may interfere with intelligence, psychomotor function and memory (Pine et al., 1999). The benzodiazepines are considered the drug of choice in the treatment of anxiety. Unfortunately, there are several side effects such as tolerance, amnestic effect, etc. (Barbee, 1993). Thus, we had hopes of finding a natural plant that possessed anxiolytic activity but did not impair memory.

Berberine (abbreviated as BER) is an active ingredient isolated from Coptis chinensis Franch (Ranunculaceae). In recent studies, BER has been shown to have multiple pharmacological actions including anticerebral ischemic effect, inhibition of thromboxane A2 synthesis (Huang et al., 2002), and a partial agonist of platelet alpha 2 adrenoceptor (Hui et al., 1991). Furthermore, we found that BER (500 mg/kg, p.o.) improved scopolamine-induced amnesia by increasing peripheral and central cholinergic neuronal system activity (Peng et al., 1997). On the other hand, Coptis rhizome was used to cure anxiety by clinical traditional physicians. Thus, it was worth-while to investigate the anxiolytic effect of BER.

It is well known that changes and control of emotion are related to changes in levels of monoamines and its metabolites in the brain stem (Vander et al., 1994). The reduction of serotonergic system activity in the brain produces anxiolytic effects (Gardner, 1986). Moreover, MAO-A preferentially oxidizes norepinephrine and serotonin, and monoamine oxidase inhibitors (MAOIs) after long-term administration are used to treat anxiety disorders (Naoi and Nagatsu, 1986, Liebowitz et al., 1992, Versiani et al., 1992, Atmaca et al., 2002). Recently, BER was found to inhibit MAO-A (Kong et al., 2001). However, the anxiolytic effect of BER had never been studied. We therefore undertook studies to determine 1) whether BER posessed anxiolytic effects by using the plus-maze and black and white tests in mice with diazepam and buspiron as positive controls, 2) the relationship between the anxiolytic effect of BER and the concentrations of monoamines in the brain stem.