Comparison of hypericum extracts with imipramine and fluoxetine in animal models of depression and alcoholism
Introduction
Clinical evidence suggests that hypericum extracts (Hypericum perforatum L., St. John’s wort) have antidepressive properties and may offer an interesting alternative for the treatment of mood disorders (for review, see: Linde et al., 1996; Volz, 1997). Thus far, however, it remains unclear to what extent the antidepressive efficacy of hypericum extracts compares to that of standard antidepressants, such as the tricyclics (e.g., imipramine), or the selective serotonin reuptake inhibitors (SSRIs; e.g., fluoxetine). Also in preclinical studies, antidepressant-like effects of hypericum extracts have been reported. Thus, indications for antidepressive efficacy were obtained in animal models based on stress-induced behavioral deficits, such as the mouse or rat forced swimming test, the mouse tail suspension test, or the rat learned helplessness test (Butterweck et al., 1997; Gambarana et al., 1996; Öztürk, 1997; Okpanyi and Weischer, 1987; Winterhoff et al., 1993, Winterhoff et al., 1995). Unfortunately, it remains difficult to evaluate such extracts with respect to potency and efficacy, as no dose–response data comparing different hypericum extracts with each other, and with standard antidepressants, have been reported in these preclinical studies. In addition, as it is well known that, similar to the clinical situation, repeated treatment is required for full development of antidepressive efficacy of tricyclics and SSRIs in these animal models of depression (e.g., De Vry and Schreiber, 1993), it remains to be demonstrated whether such a sensitization effect also occurs in the case of hypericum extracts. The only study on the effects of repeated treatment with a hypericum extract suggests that at least no tolerance appears to develop for the antidepressant-like effects of these compounds in the rat forced swimming test (Winterhoff et al., 1995). However, the lack of an appropriate control group in the latter study precludes any conclusion on the possible development of sensitization of the antidepressant-like effects.
Recent clinical studies have indicated that antidepressants, including the tricyclic imipramine, and the SSRI fluoxetine, may be of therapeutic benefit in the treatment of alcoholism, as these compounds may reduce alcohol craving and/or intake in particular subgroups of patients (Cornelius et al., 1993; Kranzler et al., 1995; Naranjo et al., 1990; Nunes et al., 1993; for review, see: Anton, 1996). Interestingly, it has been suggested that hypericum extracts may also be beneficial for the treatment of alcoholic patients (Anonymus, 1996; Krylov and Ibatov, 1993). Both fluoxetine (e.g., De Vry et al., 1996; Maurel et al., 1999b, Maurel et al., 1998; Zabik et al., 1982) and imipramine (de Beun et al., 1996b) have previously been reported to attenuate the intake of ethanol (EtOH) in particular animal models of alcoholism. Thus far, however, no comparative study on the effects of hypericum extract and these compounds in such a model has been reported.
It was the aim of the present study to compare the efficacy of the methanolic hypericum extract LI 160 (Jarsin), with that of the ethanolic hypericum extract Ze 117 (Remotiv), as well as, with that of imipramine and fluoxetine in animal models of depression and alcoholism. Therefore, the effects of different doses of these compounds were compared in the rat forced swimming model of depression, under a standardized application schedule (i.e., three applications in 24 h; De Vry and Schreiber, 1993; Porsolt et al., 1977). In order to investigate possible sensitization effects, repeated treatment for 1 week (nine applications, B.I.D.) with Ze 117, imipramine and fluoxetine was compared with administration of these compounds under the standardized application schedule, preceeded by the appropriate vehicle control applications. In order to assess the potential anti-alcohol effects of hypericum extract, the effects of acute treatment with Ze 117 was compared with that of imipramine and fluoxetine in alcohol-preferring cAA rats (Maurel et al., 1999a). These rats derive from the Finnish alcohol-preferring AA rats (for review, see: Sinclair et al., 1989) and have been used extensively for the characterization of novel pharmacotherapies of alcoholism (e.g., De Beun et al., 1996a, De Beun et al., 1996b; De Vry et al., 1996; Maurel et al., 1999b; Schreiber et al., 1993). In this model, effects on excessive EtOH intake and EtOH preference are compared with effects on food and total fluid intake under a standardized 12-h limited access, two-bottle (EtOH 10% v/v versus water) choice procedure. This allows for an assessment of the specificity of the anti-alcohol effect of a compound (i.e., the extent to which a reduction in EtOH intake coincides with a reduction in EtOH preference); as well as its selectivity (i.e., the extent to which a reduction in EtOH intake can be dissociated from a general reduction of food or fluid intake).
Section snippets
Animals
For the rat forced swimming test, male Wistar rats were purchased from Harlan-Winkelmann (Borchen, Germany). Body weight upon arrival at the laboratory was around 200 g. Rats were individually housed in Makrolon type three cages under a normal 12-h light/dark period (light on at 7:00 a.m.), with unrestricted access to food (standard pellets; Ssniff Spezialdiäten, Soest, Germany) and water ad libitum. Ambient temperature and relative humidity were maintained at 22±1°C and at 55±5%, respectively.
Acute experiment
Effects of acute administration of imipramine, fluoxetine (both: 3–30 mg/kg) and the hypericum extracts Ze 117 and LI 160 (both: 5–40 mg/kg) on immobility scores are shown in Fig. 1. The reference antidepressants, imipramine and fluoxetine, induced a dose-dependent reduction in immobility [imipramine: F(3,20)=11.41, P<0.001; fluoxetine: F(3,20)=26.59, P<0.001]; the maximal effect being 50% and 57% immobility reduction, for imipramine and fluoxetine, respectively. Fluoxetine appeared to be
Discussion
In the present study, it was found that treatment with the hypericum extracts Ze 117 and LI 160 reduces stress-induced immobility; with a potency comparable to, and an efficacy slightly less than that of the tricyclic imipramine and the SSRI fluoxetine. Direct comparison of Ze 117 and LI 160 in this animal model of depression indicated that both extracts were generally equipotent (same MED value of 20 mg/kg); whereas the former compound was slightly more effective than the latter (i.e.,
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