Posted by sdb on June 27, 2006, at 17:24:57
There are many studies that prove hypericum effective as an antidepressant with anxiolitic properties. It remains controversial and for me I can not come to a final point. I am pretty sure that the drug industry had influence to play down positive effects. It is sad that there are only very limited studies about specific disorders, so you could be able to paint a clearer picture.
Maybe I will post some more studies because I think
it is positive to discuss this under experienced users and what other pbabblers say.
I will listen carefully.Take care
sdb
See Maze study below
Effects of Hypericum perforatum and paroxetine on rat performance in the elevated T-maze
Venessa Beijamini and Roberto AndreatiniCorresponding Author Contact Information, E-mail The Corresponding Author
Departamento de Farmacologia, Laboratório de Fisiologia e Farmacologia do Sistema Nervoso Central, Setor de Ciências Biológicas, Centro Politécnico, Universidade Federal do Paraná, P.O. Box 19031, Curitiba 81531-990, PR, Brazil
Accepted 7 March 2003. ; Available online 21 May 2003.
AbstractHypericum perforatum extract exhibits an antidepressant effect and since several antidepressant drugs are also effective on generalised anxiety disorder (GAD) and panic disorders (PD), H. perforatum may possess some anxiolytic/antipanic effect. Thus, the aim of the present study was to evaluate the putative antipanic/anxiolytic effect of standardised H. perforatum extract (LI 160) on rats tested in the elevated T-maze, an animal model of innate (panic) and learned (generalised) anxiety, at doses that exhibit antidepressant-like activity. H. perforatum (150, 300 and 500 mg/kg, administered orally 24, 18 and 1 h before the test) decreased the immobility time in the forced swim test. Rats were treated orally with H. perforatum (150 or 300 mg/kg) or paroxetine (5 mg/kg) 24, 18, and 1 h before being tested in the elevated T-maze (subacute treatment). Immediately after this test, the animals were submitted to the open field to evaluate locomotor activity. Paroxetine was used as a positive control, since it was clinically effective in GAD and PD. Other groups of animals were submitted to the same drug treatment for 7 days (subchronic treatment). Paroxetine (5 mg/kg) impaired inhibitory avoidance after subacute treatment, while subchronic administration increased one-way escape latency. Subacute treatment with H. perforatum (300 mg/kg) exerts a partial anxiolytic-like effect in the inhibitory avoidance task. Repeated administration of H. perforatum (300 mg/kg) induced an anxiolytic effect (decreased inhibitory avoidance) and an antipanic effect (increased one-way escape). No effect on locomotor activity was found with any treatment. Thus, the results suggest that H. perforatum extract could exert an anxiolytic and antipanic effect.
Author Keywords: Animal model; Anxiety; Antidepressant; Forced swim; Panic; Paroxetine; Phytotherapy
Article Outline
1. Introduction
2. Material and methods2.1. Animals
2.2. Drugs
2.3. Apparatus
2.4. Procedures2.4.1. Experiment 1—effects of H. perforatum on the forced swimming test
2.4.2. Experiment 2—effects of subacute (three times over 24 h) H. perforatum or paroxetine treatment on the elevated T-maze test
2.4.3. Experiment 3—effects of subchronic (7-day) treatment with H. perforatum or paroxetine on the elevated T-maze2.5. Statistical analysis
3. Results
3.1. Experiment 1—effects of H. perforatum on the forced swimming test
3.2. Experiment 2—effects of subacute (three times over 24 h) H. perforatum or paroxetine treatment on the elevated T-maze test
3.3. Experiment 3—effects of subchronic (7-day) treatment with H. perforatum or paroxetine on the elevated T-maze
3.4. Open-field results4. Discussion
Acknowledgements
References1. Introduction
Pathological anxiety comprises several kinds of disorders such as generalised anxiety disorder, panic disorder and obsessive-compulsive disorder, although for a long time animal models of anxiety considered anxiety as a single disorder. However, in the last few years, some investigators have developed animal models that try to separate these different types of anxiety. For example, the elevated T-maze, which was derived from the elevated plus-maze by suppression of one closed arm, has been proposed to evaluate two types of anxiety in the same animal, i.e. learned (or conditioned) anxiety, represented by inhibitory avoidance behaviour, and innate (or unconditioned) fear, represented by one-way escape [1, 2 and 3]. Inhibitory avoidance is the increased latency to leave a closed arm along three successive trials. This task was impaired by treatment with diazepam, ipsapirone, buspirone, ritanserin and chronic imipramine [4 and 5], treatments that were effective in generalised anxiety disorder (GAD) [6]. Thus, the learned nature and its pharmacological sensitivity suggest that this behaviour is related to GAD [5, 6 and 7]. On the other hand, one-way escape, which is tested by measuring the latency of the animal to flee from one open arm, was increased by chronic treatment with imipramine and fluoxetine ( [5], Poltronieri et al., personal communication), treatments that were effective on PD. On the other hand, anxiolytic drugs that were ineffective on PD (e.g. low to moderate dose of diazepam, buspirone, ipsapirone) did not impair one-way escape [4 and 6]. Thus, based on the assumption that innate fear is related to PD [5] and on the pharmacological sensitivity of PD, one-way escape is supposed to represent panic anxiety [1, 2, 3 and 5].
The extract of Hypericum perforatum L. (H. perforatum), popularly called St John’s Wort, has been used in folk medicine to treat depressive disorders [8]. Many clinical studies have suggested that the H. perforatum extract is effective in the treatment of mild to moderate depression (for review, see [7, 9, 10, 11 and 12]; but see also [13]). Moreover, the antidepressive effects of H. perforatum and its underlying mechanisms have been widely studied using animal models of depression [14, 15 and 16]. St John’s Wort has numerous biologically active constituents, including naphthodianthrones (e.g. hipericin), phloroglucinols (e.g. hyperforin) and flavonoids (e.g. biapigenin). Among these, the most important seems to be hyperforin, which is able to inhibit in vitro the uptake of monoamines, glutamate and γ-aminobutyric acid—GABA [17 and 18]. Chronic treatment with H. perforatum extract leads to adaptive changes in β-adrenoceptors in the frontal cortex [19], as observed with conventional antidepressive drugs.
However, few recent studies have shown that H. perforatum may also exert an anxiolytic effect. Considering clinical studies, H. perforatum treatment reduced the number of panic attacks in a patient with a possible panic disorder diagnosis [20] and three case reports suggest an anxiolytic effect of the extract [21]. Moreover, H. perforatum extract exerted a beneficial effect on patients with obsessive-compulsive disorder in an open study [22] and reduced anxiety and depression scores in the Hospital Anxiety and Depression Scale in patients with fatigue of unexplained origin [23]. Studies with animal models of anxiety strengthen the suggestion of an anxiolytic effect of this extract. It was found that H. perforatum extract without hyperforin increases the time spent in the open arms of the elevated plus-maze, suggesting an anxiolytic-like effect [24], although pure hyperforin also induces an anxiolytic effect on the elevated plus-maze [25]. Our group observed that acute treatment with H. perforatum extract decreased the marble-burying behaviour of mice but did not increase locomotor activity (Skalisz et al., unpublished results). Furthermore, H. perforatum impaired the acquisition of inhibitory avoidance in the light–dark test [26], an effect that is blocked by pre-treatment with flumazenil, a benzodiazepine receptor antagonist. H. perforatum extract also increases locomotor activity in the open field [26]. Moreover, chronic treatment with H. perforatum increased the time spent in the light compartment in the light/dark test [27]. Acute, but not chronic, H. perforatum treatment impaired inhibitory avoidance in the elevated T-maze [27]. Furthermore, Indian H. perforatum Linn extract (administered once daily for 3 days) also showed an anxiolytic-like effect on elevated plus-maze, elevated zero-maze, novelty-induced suppressed feeding latency and social interaction [28]. On the other hand, chronic treatment with H. perforatum extract reduced some flight behaviours in the Mouse Defense Test Battery, which has been suggested to be primarily sensitive to anti-panic agents [29].
Since (a) antidepressant drugs (ADs) were the main drug treatment for PD, (b) AD were also effective on GAD, and (c) H. perforatum exhibits an antidepressive effect, it was hypothesized that H. perforatum might posses antipanic and/or anxiolytic effect. Thus, the aim of the present study was to evaluate the effect of subacute and subchronic treatment with H. perforatum extract on rats tested in the elevated T-maze at the dose that exhibited antidepressive-like effect (determined in the forced swimming test) but did not change locomotor activity.
2. Material and methods
2.1. AnimalsThe subjects were adult male albino Wistar rats (250–320 g) from our own breed. They were housed in groups of five in polypropylene cages with wood shavings as bedding under controlled conditions of light (12 h light–dark cycle, light on at 7.00 a.m.) and temperature (22±1 °C). Tap water and food pellets were available ad libitum throughout the experiment.
2.2. DrugsThe dry standardized extract of aerial parts of H. perforatum (LI 160) was supplied by Eurofarma (coming from Indena, Milan, Italy; extraction solvent: methanol; herb-extract ratio 7:1). The amount of hypericin (0.3%) and hyperforin (3.3%) was quantified by high performance liquid chromatography and fluorescence detection by Indena. The H. perforatum extract was suspended in distilled water and sonicated for 20 min before oral administration. Paroxetine (Eurofarma, São Paulo, Brazil) was dissolved in distilled water. Both drugs were prepared on the same day of the experiment. The control group received physiological saline. All drugs were administered orally by gavage in a final volume of 2 ml/kg body weight.
2.3. ApparatusThe elevated T-maze was made of black painted wood and had three arms of equal dimensions (50 cm×10 cm). One arm, enclosed by 40 cm high walls, was perpendicular to two opposed open arms. To prevent the rats from falling down, the open arms were surrounded by a wood rim 1 cm high. The whole apparatus was elevated 50 cm above the floor. The experiments were performed with an observer inside the experimental room.
The open-field apparatus was a circular metal arena (1 m in diameter), divided into 6 central and 12 peripheral units (20 cm×20 cm), positioned under a bright light.
2.4. Procedures
2.4.1. Experiment 1—effects of H. perforatum on the forced swimming testThe procedure was a modification of the Porsolt et al. method, as described in a previous report [30 and 31]. Briefly, the rat was placed in a glass aquarium (20 cm×20 cm×40 cm) containing 15 cm deep cold water (24±1 °C) for 15 min followed by a 5-min retest (test session) 24 h later. Immobility time was recorded during the test session: the rat was judged immobile whenever it stopped swimming and remained floating in the water, with its head just above water level. The water was changed after each rat. Following the test, the animals were dried in a heated enclosure. The vehicle (control group) or H. perforatum extract (150, 300 and 500 mg/kg, p.o.) was administered three times (24, 18 and 1 h) before a test session. This test was performed to determine the antidepressive-like doses of H. perforatum used in the subsequent experiments.
2.4.2. Experiment 2—effects of subacute (three times over 24 h) H. perforatum or paroxetine treatment on the elevated T-maze testOne day before the elevated T-maze test, all animals were exposed to one of the open arms of the elevated T-maze for 30 min [5]. Wood barriers mounted on the border of the maze central area isolated the arms of the elevated T-maze.
In the elevated T-maze test, the rat was placed at the end of the enclosed arm facing the intersection of the arms. The latency to leave the enclosed arm with the four paws in three successive trials was recorded (standard measure proposed by Graeff et al. [1]). Additionally, the latency to enter one of the open arms was also recorded (modified measure proposed by our group). This procedure adds to the latency measured, the time spent by the rat in the junction area and in additional entries into the closed arm before the entry into any open arm. The first trial was designated as basal latency (baseline) and represented the learning inhibitory avoidance behaviour. The other trials were designated avoidance 1 and 2, respectively. The interval between trials was 30 s, during which the animal was placed in a Plexiglas box identical to its home cage. Thirty seconds after the last trial of inhibitory avoidance, the rat was placed at the end of one open arm and the latency to leave this arm with its four paws (one-way escape form open arm, standard measure proposed by Graeff et al. [1]) and the latency to enter the enclosed arm (one-way escape into enclosed arm, modified measure proposed by our group) were recorded (Escape 1). The same measurement was repeated after 30 s (Escape 2). This modification adds to the escape latency the time spent in the junction area and in other entries into open arms before entry into the closed arm. A cut-off time of 300 s was established for both measures (inhibitory avoidance and one-way escape).
Immediately after the elevated T-maze test, each rat was placed in the middle of the open field and its behaviour was evaluated for 5 min. Peripheral and central locomotion (number of units crossed) and rearing, time spent in grooming and immobility, and number of faecal boli were recorded [32].
The open field and the elevated T-maze were washed with a water–alcohol solution (5%) after each animal was tested. The experiments were performed at the same time of day (8:00–13:00 h).
The vehicle, paroxetine (5 mg/kg, p.o., positive control) and H. perforatum extract (150 or 300 mg/kg, p.o.) were administered as in experiment 1, three times (24, 18 and 1 h) before the test session.
2.4.3. Experiment 3—effects of subchronic (7-day) treatment with H. perforatum or paroxetine on the elevated T-mazeFor the subchronic study, animals were injected with vehicle, paroxetine (5 mg/kg, p.o.) or H. perforatum extract (150 or 300 mg/kg, p.o.) for 7 days, once a day. On the 6th day, all rats were exposed to one of the open arms of the elevated T-maze for 30 min. On this day, either drugs or vehicle were administered 30 min after pre-exposure. On the 7th day, rats were tested in the elevated T-maze 1 h after the last injection treatment. As in the experiment 2, the animals were submitted to the open-field test immediately after the elevated T-maze test.
2.5. Statistical analysisData were represented as mean±standard error of mean (S.E.M.) or as median±semi-inter-quartile range (SIR) as indicated in figures and table. One-way analysis of variance (ANOVA) was used to analyse the forced swimming test data. Significantly different data were further analysed by the post hoc Newman–Keuls test for individual group comparisons. The elevated T-maze data were analysed by non-parametric tests, i.e. Friedman ANOVA followed by the Wilcoxon matched pair test when appropriate for inhibitory avoidance results, and Kruskal–Wallis ANOVA followed by the Mann–Whitney U-test when appropriate for one-way escape results. The open-field parameters were evaluated by one-way ANOVA followed by the Newman–Keuls test for individual group comparisons (locomotor activity and immobility time) or by Kruskal–Wallis ANOVA followed by the Mann–Whitney U-test when appropriate (rearing, grooming and faecal boli). Differences were considered statistically significant when P≤0.05.
3. Results
3.1. Experiment 1—effects of H. perforatum on the forced swimming testThe effect of subacute treatment with H. perforatum extract on behavioural despair is illustrated in Fig. 1. ANOVA showed that there was a statistically significant effect of treatment (F3,42=6.089, P<0.002). Post hoc analysis revealed that all doses of H. perforatum extract (150, 300 and 500 mg/kg) significantly decreased immobility time when compared to the control group (P<0.05).
Enlarge Image (21K)Fig. 1. Effects of subacute administration (24, 18, and 1 h before the test) of H. perforatum extract 150 mg/kg (Hype 150, n=11), 300 mg/kg (Hype 300, n=12), 500 mg/kg (Hype 500, n=9) and vehicle (n=14) on the immobility time of rats submitted to the forced swimming test. Data represent mean±S.E.M. *P≤0.02 compared with the vehicle group.
3.2. Experiment 2—effects of subacute (three times over 24 h) H. perforatum or paroxetine treatment on the elevated T-maze test
Since we did not found statistically significant difference between groups on the latency to enter the open arm (modified procedure) in the inhibitory avoidance, these data will not be shown.
The results of the latency to leave enclosed arm (standard procedure) are showed in Fig. 2. Acute treatment did not affect the baseline latency (first withdrawal) in the inhibitory avoidance task (H3,48=5.38, P>0.10). As illustrated in Fig. 2, the control group showed inhibitory avoidance acquisition (χ2r=18.65, P<0.001) when evaluated by the latency to leave enclosed arm. The Wilcoxon matched pair test revealed that there were statistically significant differences between baseline and avoidance 1 (T=18.5, P<0.05), baseline and avoidance 2 (T=0.0, P<0.001) and between avoidance 1 and 2 (T=2.0, P<0.01). A similar profile was found for H. perforatum 150 (χ2r=15.82, P<0.001): statistically significant differences between baseline and avoidance 1 (T=1.5, P<0.01), baseline and avoidance 2 (T=1.0, P<0.01) and between avoidance 1 and 2 (T=1.0, P<0.01). The treatment with H. perforatum 300 and paroxetine 5 changed this profile: H. perforatum 300 (χ2r=14.11, P<0.001): statistically significant differences between baseline and avoidance 1 (T=2.0, P<0.01) and baseline and avoidance 2 (T=0.0, P<0.01), but not between avoidance 1 and 2 (T=1.5, 0.06>P>0.05); and paroxetine 5 (χ2r=16.05, P<0.001): statistically significant differences between baseline and avoidance 2 (T=0.0, P<0.01) and between avoidance 1 and 2 (T=0.0, P<0.01), but not between baseline and avoidance 1 (T=10.0, 0.07>P>0.05).
Enlarge Image (12K)Fig. 2. Effects of subacute administration (24, 18, and 1 h before the test) of H. perforatum extract 150 mg/kg (Hype 150, n=13) and 300 mg/kg (Hype 300, n=10), paroxetine 5 mg/kg (Paro 5, n=10), and vehicle (n=15) on the latency to leave the enclosed arm in the elevated T-maze. Data represent the mean±S.E.M. *P≤0.05 compared with baseline latency within the group; **P≤0.05 compared with avoidance 1 latency within the group.
In contrast to inhibitory avoidance, one-way escape was not affected by the treatments. Kruskal–Wallis ANOVA showed that there were no statistically significant differences between treatment groups in Escape 1A [vehicle: 30±12, Hype 150: 14±3, Hype 300: 43±29, Paro 5: 25±6, mean±S.E.M.; H(3,48)=2.24, NS], Escape 1B [vehicle: 43±12, Hype 150: 43±22, Hype 300: 69±28, Paro 5: 25±6; H(3,48)=3.00, NS], Escape 2A [vehicle: 32±10, Hype 150: 15±3, Hype 300: 22±11, Paro 5: 20±4; H(3,48)=1.81, NS] and Escape 2B [vehicle: 76±16, Hype 150: 60±20, Hype 300: 48±13, Paro 5: 91±27; H(3,48)=3.03, NS].
3.3. Experiment 3—effects of subchronic (7-day) treatment with H. perforatum or paroxetine on the elevated T-mazeSince we did not found statistically significant difference between groups on the latency to enter the open arm (modified procedure) for inhibitory avoidance, these data will not be shown.
Fig. 3 (top) shows the results of subchronic treatment on the latency to leave the enclosed arm (standard procedure). Like in the acute experiment, 7-day treatment did not affect the baseline latency in the inhibitory avoidance task (H3,48=2.49, P>0.10). Friedman ANOVA revealed an increasing latency of inhibitory avoidance along trials in the control group (χ2r=18.56, P<0.001), in the group treated with H. perforatum 150 (χ2r=9.7, P<0.01) and in the paroxetine 5 group (χ2r=15.82, P<0.001). Post hoc analysis showed statistically significant differences in the control group: between baseline and avoidance 1 (T=1.0, P<0.01), baseline and avoidance 2 (T=0.0, P<0.01) and avoidance 1 and 2 (T=1.0, P<0.05); in the H. perforatum 150 group: between baseline and avoidance 1 (T=14.0, P<0.05), baseline and avoidance 2 (T=1.0, P<0.01) and avoidance 1 and 2 (T=4.0, P<0.05); and in the paroxetine 5 group: between baseline and avoidance 1 (T=6.5, P<0.01), baseline and avoidance 2 (T=1.0, P<0.01) and between avoidance 1 and 2 (T=0.0, P<0.01). On the other hand, the H. perforatum 300 group did not acquire inhibitory avoidance learning (χ2r=4.66, NS).
Enlarge Image (21K)Fig. 3. Effects of subchronic (7 days) administration of H. perforatum extract 150 mg/kg (Hype 150, n=13) and 300 mg/kg (Hype 300, n=11), paroxetine 5 mg/kg (Paro 5, n=12) and vehicle (n=12) on rat behaviour in the elevated T-maze. Data represent mean±S.E.M. Top: Latency to leave enclosed arm. *P≤0.05 compared with baseline latency within the group; **P≤0.05 compared with avoidance 1 latency within the group. Bottom: one-way escape from the open arm (Escape 1A and 2A) and one-way escape into the enclosed arm (Escape 1B and 2B). #P≤0.05 compared with the vehicle group.
Results of one-way escape are shown in Fig. 3 (bottom; A: one-way escape from open arm, B: one-way escape into the enclosed arm). The subchronic treatment changed Escape 1A [H(3,48)=9.3, P<0.05], Escape 1B [H(3,48)=14.58, P<0.01] and Escape 2B [H(3,48)=12.35, P<0.01], but did not affect Escape 2A [H(3,48)=4.38, NS], as indicated by Kruskal–Wallis ANOVA. The one-way escape from open arm (standard measure) showed a statistically significant effect of paroxetine 5 when compared to vehicle on Escape 1A (U=24.5, P<0.01). The one-way escape into enclosed arm (modified measure) detected that H. perforatum 300 and paroxetine 5 increased the escape latency when compared to the control group in Escape 1B (U=30.5, P<0.05; U=13, P<0.001, respectively). Moreover, there was a statistically significant difference between paroxetine 5 and vehicle in Escape 2B (U=17, P<0.01).
3.4. Open-field resultsTable 1 summarises the open-field behaviour results. The subacute treatment did not change the central locomotor activity [F(3,44)=0.152, NS], peripheral locomotor activity [F(3,44)=0.675, NS], immobility time [F(3,44)=0.354, NS], grooming [H(3,48)=1.510, NS], rearing [H(3,48)=15.019, P<0.01] or faecal boli [H(3,48)=1.978, NS].
Table 1. Effects of subacute and subchronic treatment with H. perforatum extract, paroxetine or vehicle on parameters for rats tested in the open field
Full Size TableHype 150 and Hype 300: H. perforatum extract 150 mg/kg (n=13) and 300 mg/kg (n=10), Paro 5: paroxetine 5 mg/kg (n=10), and vehicle (n=15).
In the same way as the subacute treatment, no statistically significant differences were found with subchronic treatment in central locomotor activity [F(3,44)=2.61, 0.07>P>0.05], peripheral locomotor activity [F(3,44)=0912, NS], immobility time [F(3,44)=1.119, NS] or faecal boli [H(4,58)=4.12, NS]. Additionally, rearing was not affected by the treatment [H(3,48)=4.540, NS], but there was a statistically significant effect on grooming [H(4,58)=8.015, P<0.05]. A posteriori analysis revealed a statistically significant difference between H. perforatum 300 and paroxetine 5 (U=27, P<0.05) and between H. perforatum 300 and H. perforatum 150 (U=22, P<0.01).
4. DiscussionTreatment with three doses of H. perforatum extract significantly reduced the immobility time of rats submitted to the forced swimming test, suggesting an antidepressive-like effect. This result is in accordance with the antidepressive-like activity of H. perforatum in animal models [14, 15, 16, 33, 34 and 35]. Particularly in studies on rats submitted to the forced swimming test, H. perforatum exerted an anti-immobility time effect at doses (per oral) between 125 and 1000 mg/kg [15 and 35]. Thus, the results obtained in the present study for the effect of H. perforatum on FST agree with literature data and the extract doses of 150 and 300 mg/kg were chosen for use in the subsequent experiments.
Regarding the results of inhibitory avoidance in the elevated T-maze, subacute treatment with H. perforatum extract 300 mg/kg and paroxetine 5 mg/kg impaired avoidance 2 and avoidance 1 performance, respectively. These results suggest a partial anxiolytic effect (partial blockade of inhibitory avoidance acquisition) at doses that did not affect locomotor activity since did not affect square crossing in the open field and baseline latency in the elevated T-maze. However, the results with H. perforatum could be due to a higher avoidance behaviour exhibited in avoidance 1 plus a greater variability of data. On the other hand, paroxetine 5 mg data could be viewed as a delay in inhibitory avoidance acquisition, which would be an indication of anxiolytic-like effect. After subchronic administration (7 days), only the highest dose of extract impaired the development of inhibitory avoidance but did not impair the locomotor activity, which is interpreted as an anxiolytic-like effect.
Pre-clinical studies with paroxetine on animal models of anxiety have presented variable results. In the four-plate test, acute paroxetine administration induced an anxiolytic effect that was increased by buspirone pre-treatment [36 and 37]. An anxiolytic effect of acute paroxetine administration was also seen on the ultrasonic isolation calls of rat pups [38] and shock-induced ultrasonic vocalization [39]. In the social interaction test, acute treatment with paroxetine did not change animal behaviour while chronic treatment increased significantly the time spent in social interaction [40 and 41]. On the other hand, paroxetine induced an anxiogenic effect in the elevated plus-maze after acute administration [42, 43, 44 and 45] but an anxiolytic effect after repeated administration [42]. However, there is a suggestion that this acute effect of paroxetine could be due to an anti-exploratory action rather than to a true anxiogenic effect [45]. Thus, contradictory results were found with acute treatment, but a consistent anxiolytic-like effect was seen with repeated treatment. These last results correlate with clinical evidence showing that generalised anxiety disorder is improved by repeated treatment with paroxetine [46 and 47]. In the present study, we also observed this variable effect of paroxetine, but additional studies (with wide range dose and longer treatment) are need to evaluate the sensitivity of this procedure to paroxetine treatment.
Our results with H. perforatum extract agree with some clinical studies that indicated a putative anxiolytic effect for this phytomedicine [20, 21, 22 and 23], although the cited studies did not address directly this matter and had methodological flaws. However, animal studies with the light–dark test [26 and 27], elevated T-maze [27], elevated plus-maze [24 and 48] and marble-burying behaviour test [Skalisz et al., unpublished data] indicated an anxiolytic-like effect for H. perforatum, supporting the hypothesis of a putative anxiolytic clinical effect. Moreover, pure hyperforin exerted a clear anxiolytic-like effect on rat behaviour in the elevated plus-maze [25].
Regarding one-way escape, a measure related to innate anxiety, subacute H. perforatum and paroxetine administration did not change escape latency from the open arms in the elevated T-maze. However, subchronic treatment with paroxetine increased Escape 1A, 1B and 2B at a dose that did not change locomotor activity. Our data agree with clinical studies that showed an antipanic effect of paroxetine only after repeated administration [49, 50 and 51]. Chronic treatment with fluoxetine and imipramine, effective drugs for panic disorder, also increases the one-way escape latency in the elevated T-maze ( [5], Poltronieri et al., personal communication). On the other hand, benzodiazepines, 5-HT1A agonists and 5-HT2 antagonists, drugs with an anxiolytic effect but ineffective in panic disorder, did not modify this parameter [4]. These results lead to the suggestion that one-way escape could be a useful measure of antipanic drugs [4 and 5]. Thus, the present results with paroxetine provide additional data for the predictive validity of one-way escape as a model of panic anxiety.
H. perforatum extract only increased one-way escape into enclosed arm (Escape 1B), showing the possibility of an antipanic effect. In regard to H. perforatum, there is a case report that suggests this effect [20]. The reduction of flight behaviours in the Mouse Defense Test Battery is a further indication that H. perforatum may possess a potential antipanic effect [29]. Nevertheless, chronic treatment (21 days) with H. perforatum extract did not increase the escape latency from the open arms in the same model [27]. However, it is worth to note that Flausino et al. evaluated one-way escape from open arm (named A in the present study—Escape 1A and 2A), which was not influenced by H. perforatum treatment in the present study (Fig. 3, bottom). Results from our laboratory with clonazepam, a clinically antipanic drug, suggested that the one-way escape into enclosed arm (modified method) can be more sensitive to antipanic drugs than one-way escape from open arm, which can explain the contradiction between our data and Flausino et al. [27]. However, by permitting the animal to explore the apparatus a bit more (e.g. central platform), it could be said that the additional procedure used in the present study introduces a behavioural change that alters the results and validity of the model. However, data from our laboratory [Bazzi et al., unpublished data] have shown that, at least in numerical terms, there is no difference between undrugged animals tested only by the standard method and animals tested by the modified method.
Both paroxetine and H. perforatum extract, like fluoxetine and imipramine, inhibit serotonin reuptake, a fact that might explain in part their similar profile observed in elevated T-maze. However, as described before, the H. perforatum extract has many actions on neurotransmitter systems that could explain its effects on rats tested in the elevated T-maze. Thus, additional studies are needed to delineate its anxiolytic/antipanic effects.
In conclusion, the present results suggest an anxiolytic and antipanic effect of H. perforatum extract on rats tested in the elevated T-maze at doses that induce an antidepressive effect in the forced swimming test and do not change locomotor activity. However, since the results of the present study could be seen as smaller than observed in previous studies, further research is needed to corroborate the putative antipanic effect of H. perforatum. In addition, the present data supports the one-way escape as a model of panic anxiety and provide additional evidence that the modified method used to record latency escape from the open arm can be more sensitive to the antipanic effect of drugs than the standard method.
Acknowledgements
This study was supported by CAPES and CNPq, Brazil. We wish to thank Eurofarma (Brazil) for the supply of the H. perforatum extract and paroxetine. Silvia Nardi Cordazzo Genari and Cezar Augusto Harres for their technical assistance.
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