Department of Pharmacological Sciences and Experimental Medicine, University of Camerino, 62032 Camerino (MC), Italy,
1 Department of Pharmacology and Toxicology, Military Institute of Hygiene and Epidemiology, Kozielska 4, 01-163 Warsaw, Poland and
2 Institute of Legal Medicine, University of Macerata, 62100 Macerata, Italy
Received 31 August 2000; in revised form 7 December 2000; accepted 9 January 2001
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ABSTRACT |
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INTRODUCTION |
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At present, the active principle(s) and the mechanism(s) of action responsible for these effects of HPE are unknown; however, several studies have proposed that hypericin (Suzuki et al., 1984; Butterweck et al., 1998
) and hyperforin (Bhattacharya et al., 1998
; Chatterjee et al., 1998a
, b
; Laakmann et al., 1998
; Muller et al., 1998
; Kaehler et al., 1999
; Singer et al., 1999
) may represent major active principles for effects on the central nervous system.
The present study was aimed at evaluating in Marchigian Sardinian alcohol-preferring (msP) rats the effects on alcohol intake of two extracts of HPE with different content of hyperforin and hypericin: a methanolic extract containing 0.3% hypericin and 3.8% hyperforin (HPE1), and a CO2 extract (HPE2) with 24.33% hyperforin and very low hypericin content. In some experiments, the effects of the two extracts were also evaluated in the FST.
It is well known that HPE inhibit 5-hydroxytryptamine (5-HT) reuptake (Perovic and Muller, 1995; Bennett et al., 1998
), and show high affinity for sigma receptors (Raffa, 1998
). In this regard, a previous study by our group (Panocka et al., 2000
) had suggested that increased synaptic levels of 5-HT, as well as stimulation of sigma receptors, may be involved in the antidepressant-like effect of HPE1, but not in its effect on ethanol intake. To confirm these findings and to extend them to HPE2, the present study evaluated the effects of HPE2 in rats pretreated with the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) (Baumgarten et al., 1981
), as well as with the selective sigma-1 receptor antagonist NE-100 (Matsuno et al., 1996
).
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MATERIALS AND METHODS |
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Drugs
Two extracts provided by Indena (Milan, Italy) were employed: a methanolic extract with 0.3% hypericin and 3.8% hyperforin (HPE1) and a CO2 extract (HPE2) with 24.33% hyperforin and very low hypericin content. HPE1 was suspended in tap water, whereas HPE2 was emulsified in 0.1% Tween 80 and tap water. 5,7-DHT and desipramine (desmethylimipramine; RBI, Natick, MA, USA) were dissolved in 0.9% (w/v) NaCl. Ascorbic acid (0.1%) was added to the solution of 5,7-DHT as an antioxidant. Nomifensine (RBI, Natick, MA, USA) was suspended in distilled water (5 mg/ml) immediately before intraperitoneal (i.p.) injection. Fluoxetine (Lilly Research Laboratories, Indianapolis, IN, USA) and the selective sigma-1 receptor antagonist NE-100 (Matsuno et al., 1996) were dissolved in distilled water immediately before i.p. injection.
Intragastric surgery
All animals used in the present study had been implanted with intragastric (i.g.) catheter before experiments began. This procedure was adopted to avoid any possible disturbance to the animal during HPE administration. Rats were anaesthetized by i.p. injection of 100150 µl/100 g body weight of a solution containing ketamine (86.2 mg/ml) and acepromazine (1.3 mg/ml). A polyethylene catheter (PE-50; Clay Adams, Parsippany, NJ, USA) was permanently implanted into the stomach, according to the method of Lukas and Moreton (1979). The PE tubing was run subcutaneously to reach the skin between the scapulae, where it was exteriorized.
Pretreatment with 5,7-DHT
Under ketamine/acepromazine anaesthesia, rats were implanted with a stainless-steel cannula for infusion of 5,7-DHT into the lateral ventricle. Coordinates, taken from the stereotaxic atlas of Paxinos and Watson (1986), were: 1 mm posterior and 2 mm lateral to bregma, 2 mm ventral from the surface of the skull.
After a week of recovery, animals were slightly anaesthetized and infused into the lateral ventricle through an injector (2.5 mm longer than the guide cannula) with 5,7-DHT, 150 µg/rat, or with an equal volume of vehicle. To protect dopaminergic and noradrenergic neurons (Lipska et al., 1992), rats received i.p. pretreatment with the dopamine reuptake blocker nomifensine (15 mg/kg, divided into two doses, 50 and 30 min before infusion) and the noradrenaline reuptake blocker desipramine (15 mg/kg, divided into two doses, 60 and 40 min before infusion). The infusion was carried out at a rate of 4 µl/min (total volume 20 µl).
After the end of the experiments (5 weeks after 5,7-DHT infusion) rats were killed, brains were removed and frozen at 80°C until analysis. The tissue concentration of 5-HT in the medial prefrontal cortex, striatum and hippocampus was determined by high-pressure liquid chromatography (HPLC) with electrochemical detection.
Forced swimming test
The swimming sessions of the FST were conducted in individual glass cylinders 60 cm high and with a diameter of 30 cm, containing water at the temperature of 2325°C. Water was 30 cm deep rather than 18 cm, as reported in the original method of Porsolt et al. (1977). This change was adopted according to the suggestions of Detke and Lucki (1995); at this water depth, rats could touch the bottom of the jar with their tail, but they could not support themselves with their hindlimbs. The first 15-min swimming session (pretest) was conducted between 10:00 and 12:00; 24 h later, rats were placed again in water for the 5-min test. Test sessions were video-taped and analysed by means of a Panasonic (NV-HD650EG) videocassette recorder. The immobility time (i.e. time in which rats were making only small movements necessary to keep their head above water) was measured by an experienced observer, who was blind to the treatment conditions. The rats employed did not have access to ethanol for 2 weeks before the FST, since, in msP rats, ethanol itself produces an anti-immobility effect in the test (Ciccocioppo et al., 1999).
Experimental procedure
Experiment 1. Effects of HPE1 and HPE2 on ethanol intake.
Rats were offered 10% ethanol 2 h/day at the beginning of the dark phase. HPE1 or HPE2 was given i.g. 1 h before access to ethanol. Food and water were freely available during the day, but were removed from the rat's cage immediately before i.g. treatment with either HPE or vehicle, and offered again 1 h later together with 10% ethanol. The experiment concerning HPE1 was carried out according to a within-subject design at intervals of 45 days. The experiment concerning HPE2 was carried out according to a between-subject design in different groups of rats. In the present, as well as in the following experiments, the intakes of water and 10% ethanol were measured 15, 30, 60, 90 and 120 min following access to them. Food intake was measured 30, 60, 90 and 120 min after the beginning of the experiment.
Experiment 2. Effect of HPE2 on BAL.
At 09:00, different groups of rats received an i.g. intubation of HPE2 or vehicle. One hour later, all the rats employed received an i.g. administration of 0.7 g/kg of ethanol, as a 10% solution; this is the amount voluntarily ingested by msP rats shortly (25 min) after access to 10% ethanol, when this solution is offered 2 h/day (Ciccocioppo et al., 1999). Blood samples (50100 µl) were taken from the tail vein 15, 30, 60 and 120 min after ethanol administration. Blood-alcohol levels (BAL) and blood-acetaldehyde levels were measured by gas chromatography (Cingolani et al., 1991
).
Experiment 3. Influence of pretreatment with 5, 7-DHT on the effects of HPE2.
In this experiment, only HPE2 was used, since a previous study by our group (Panocka et al., 2000) had already evaluated the influence of 5,7-DHT on the effects of HPE1 on alcohol intake and on immobility time in the FST. Experiments in 5,7-DHT-pretreated rats began 10 days following central infusion of the neurotoxin. Different groups of animals were used for the experiments on ethanol intake from those on immobility in the FST.
For ethanol intake studies, HPE2 were given by single i.g. administration 1 h before access to ethanol. The experiment was carried out according to a within-subject design at intervals of 45 days. To behaviourally validate 5,7-DHT pretreatment, after completion of the experiment, the same rats were tested for the effect on ethanol intake of i.p. treatment with the selective serotonin reuptake inhibitor fluoxetine, 5 mg/kg.
For studies in the FST, different groups of rats received either vehicle or HPE2 three times: 24, 12 and 1 h before the test. This dosing regime was employed, since a single administration of HPE is not enough to exert an antidepressant-like effect (Perfumi et al., 1999). Behavioural validation of 5-HT depletion with fluoxetine treatment was not possible in the FST, in which the rat can be used just once (Borsini et al., 1989
; De Pablo et al., 1989
; West, 1990
).
Experiment 4. Influence of pretreatment with the sigma-1 receptor antagonist, NE-100, on the effects of HPE1 and HPE2. For ethanol intake studies, a single i.p. dose (0.25 mg/kg) of NE-100 was given 30 min before i.g. administration of both extracts. The experiment was carried out according to a within-subject design at intervals of 45 days. The NE-100 dose of 0.25 mg/kg was chosen on the basis of preliminary experiments.
For the FST, different groups of rats received either vehicle or HPE1 or HPE2 on three occasions: 24, 12 and 1 h before the test. NE-100 (0.25 mg/kg) was injected i.p. 30 min before each treatment.
Statistical analysis
The results of the experiments on ethanol intake were analysed by multifactorial analysis of variance (ANOVA), either split-plot, with between-group comparisons for drug treatment and within-group comparisons for time, or with repeated measures. Pairwise comparisons were made by means of the Dunnett's test. The results of the other experiments were analysed by one-way ANOVA, followed by NewmanKeuls test. Statistical significance was set at P < 0.05.
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RESULTS |
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In the 2-h test, rats showed frequent episodes of feeding; the cumulative food intake of controls was between 9.4 and 11.9 g/kg. The doses of HPE1 or HPE2 that reduced ethanol intake did not significantly modify food intake in the 2-h test (Table 1).
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Experiment 2. Effect of HPE2 on BAL
The mean BAL in controls and in HPE2-treated rats, following i.g. administration of 0.7 g/kg of ethanol, are reported in Fig. 2. The overall ANOVA revealed a statistically significant effect of HPE2 treatment [F(4,29) = 20.9; P < 0.001]. Pairwise comparisons showed a statistically significant reduction in BAL at 31.2 mg/kg and higher doses, whereas a 15.6 mg/kg dose did not have a significant effect.
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Experiment 3. Influence of pretreatment with 5,7-DHT on the effects of HPE2
5,7-DHT produced >85% reduction in 5-HT levels in the brain areas investigated (medial frontal cortex, striatum and hippocampus, data not shown).
Figure 3 shows the influence of 5,7-DHT pretreatment on the effect of HPE2 on ethanol intake. The overall ANOVA revealed a highly significant treatment effect [F(3,20) = 19.6, P < 0.001]; pairwise comparisons revealed a statistically significant effect of HPE2 both in rats pretreated with 5,7-DHT or in rats not pretreated with the neurotoxin. HPE2 (125 mg/kg) reduced 10% ethanol intake in rats pretreated with 5,7-DHT vehicle to a similar extent as in rats pretreated with 5,7-DHT, and no statistically significant difference between the two groups was observed. On the other hand, pretreatment with 5,7-DHT completely abolished the reduction of ethanol intake induced by a 5 mg/kg dose of fluoxetine (data not shown).
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Experiment 4. Influence of pretreatment with the sigma-1 receptor antagonist, NE-100 on the effects of HPE1 and HPE2
Figure 4 (upper panel) shows the influence of i.p. pretreatment with NE-100, 0.25 mg/kg, on the effect of HPE1 on ethanol intake. The overall ANOVA revealed a highly significant effect [F(3,15) = 52.3, P < 0.001]. NE-100 did not modify ethanol intake in comparison to controls receiving i.p. vehicle. HPE1, 250 mg/kg, reduced 10% ethanol intake in rats pretreated with NE-100 to the same extent as in rats pretreated with i.p. vehicle. Thus, NE-100 had no effect on HPE1 inhibition of ethanol intake.
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Figure 5 (upper panel) shows the effect of HPE1 on the immobility time in the FST in rats pretreated with NE-100, 0.25 mg/kg. The overall ANOVA revealed a statistically significant treatment effect [F(3,28) = 7.2; P < 0.01]. In control rats pretreated with vehicle, HPE1 significantly (P < 0.01) reduced the immobility time. However, in NE-100-pretreated rats, the immobility time after i.g. HPE1 was not significantly different from that of controls (P > 0.05).
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DISCUSSION |
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The doses of the two extracts which reduced ethanol intake did not significantly modify food intake in the 2-h test. Water intake was very low both in controls and treated rats, and a trend was observed towards an increase in water intake in HPE-treated rats, but the increase did not compensate for the reduced ingestion of ethanol solution. However, it should be considered that msP rats usually ingest very low amounts of water; moreover, they had free access to water during the entire day, therefore lower intake of ethanol solution in the 2-h test does not necessarily require a simultaneous increase in water intake for homeostatic reasons.
Hypericin and hyperforin have been proposed to mediate several effects of HPE. The present study shows that HPE2 is about eight times more potent than HPE1 in inhibiting ethanol intake in msP rats. HPE2 has 24.33% hyperforin and very low hypericin content, whereas HPE1 contains 3.8% hyperforin and 0.3% hypericin. Thus, the potency of the two extracts in reducing ethanol intake parallels the hyperforin, but not the hypericin, content. These observations suggest that hyperforin may have a greater role than hypericin in attenuating ethanol intake. Hyperforin is readily bioavailable following oral administration, is able to cross the bloodbrain barrier (Ostrowski, 1998), influences neurochemical systems in the central nervous system and is responsible for behavioural effects of HPE (Bhattacharya et al., 1998
; Chatterjee et al., 1998a
, b
; Laakmann et al., 1998
; Muller et al., 1998
; Kaehler et al., 1999
; Singer et al., 1999
). However, it cannot be excluded that the effects of HPE on ethanol intake may result from the combined action of several components of the extract, as suggested for its antidepressant effect (see Chatterjee et al., 1998b). Moreover, the site of action for the effect of HPE on ethanol intake remains to be determined. The availability of pure hyperforin will be needed for these purposes.
Several data indicate that HPE increase serotonergic neurotransmission (Perovic and Muller, 1995; Cott, 1997
; Muller et al., 1997
; Nahrstedt and Butterweck, 1997
; Calapai et al., 1999
; Kaehler et al., 1999
; Neary and Bu, 1999
) by reducing 5-HT reuptake and inhibiting MAO activity. Hypofunction of the serotonergic system is thought to play an important role in the pathogenesis of depressive disorders (Maes and Meltzer, 1995
; Bennett et al., 1998
) and in ethanol misuse (Wong and Murphy, 1989
; Overstreet et al., 1992
; Sellers et al., 1992
; McBride et al., 1993
). However, the results of the present study with HPE2 and of our previous study with HPE1 (Panocka et al., 2000
) suggest that their effect on ethanol intake is not mediated by inhibition of 5-HT reuptake or inhibition of enzymatic degradation of 5-HT, since it was not modified by 5,7-DHT. On the other hand, the anti-immobility effect of HPE1 and HPE2 was lower in rats pretreated with 5,7-DHT, in comparison to rats with unchanged 5-HT levels. Thus, an increase in 5-HT extracellular levels is apparently not involved in the effect of HPE1 and HPE2 on ethanol intake, but may have a role in their antidepressant-like effect. Since components of HPE have been reported to bind to several subtypes of 5-HT receptors, such as 5-HT1A and 5-HT2A (Cott, 1997
; Teufel-Mayer and Gleitz, 1997
), 5-HT3/5, 5-HT4 (Chatterjee et al., 1998b
), 5-HT6 and 5-HT7 (Simmen et al., 1999
), we cannot exclude a possible involvement of postsynaptic 5-HT receptors in the effect of HPE on ethanol intake.
Moreover, the present study indicates that the sigma-1 receptor antagonist NE-100 does not influence the effect of HPE1 and HPE2 on 10% ethanol intake, but completely abolishes their effect in the FST. These findings are in accordance with those of our previous study (Panocka et al., 2000) with the less selective sigma receptor antagonist rimcazole, and suggest that sigma-1 receptors may mediate the antidepressant-like effect of HPE. This is consistent with reports that sigma-1 receptors may be involved in the action of antidepressant drugs (Matsuno et al., 1996
; Matsuno and Mita, 1998
) and in the relief of behavioural despair in the FST (Matsuno et al., 1996
). In the literature, hypericin has been reported to bind to sigma-1 receptors (Raffa, 1998
), but no data are available on the affinity of hyperforin for these receptors.
At present, we cannot suggest which neurochemical systems may mediate the effect of HPE on ethanol intake. Several studies have documented that pharmacological manipulations of central dopaminergic, serotonergic, opioidergic, GABAergic and glutamatergic mechanisms can influence ethanol consumption (Weiss and Koob, 1991) and HPE has been reported to influence these neurochemical systems (Butterweck et al., 1997
, 1998
; Muller et al., 1997
; Chatterjee et al., 1998b
).
The findings obtained with BAL following administration of HPE deserve several comments. First, HPE2 sharply reduced BAL at doses of 31.2 mg/kg, whereas a dose of 15.6 mg/kg, which reduced ethanol intake, did not significantly modify BAL. In our opinion, these findings support the view that reduction of ethanol intake induced by HPE2 and reduction of BAL are different, independent effects. Moreover, HPE1 did not modify BAL at a dose of 250 mg/kg, which produced a marked reduction in ethanol intake (Perfumi et al., 1999
). Our working hypothesis is that the effect of HPE on ethanol intake might be mediated centrally, whereas the effect on BAL might be due to influence on ethanol absorption and to a greater degradation of ethanol by gastric alcohol dehydrogenase. This hypothesis also relies on the consideration that a reduction of BAL per se should not decrease, but rather increase ethanol consumption by rats in order to experience the expected effects of ethanol. Second, it is of interest that HPE2, at doses that reduce ethanol intake, also reduces BAL; thus HPE2 in addition to lowering ethanol intake may reduce the systemic effects of the amounts of ethanol ingested. Third, blood-acetaldehyde levels were never increased in response to HPE2 administration, thus excluding a possible disulfiram-like effect.
In conclusion, the present results confirm that HPE reduce ethanol intake in alcohol-preferring rats and suggest that hyperforin may have a greater role than hypericin in this respect. Sigma-1 receptors and increased synaptic serotonin levels may mediate the antidepressant-like effect of HPE, but apparently do not mediate the effect on ethanol intake. Several reports have shown comorbidity between depression and alcohol dependence (Deykin et al., 1988; Neighbors et al., 1992
; Grant and Harford, 1995
; Baving and Olbrich, 1996
; Merikangas et al., 1998
; Swensden et al., 1998
), and similar changes in the regulation of central neurotransmitters (Markou et al., 1998
). However, the findings of the present and of our previous study (Panocka et al., 2000
) suggest that, in msP rats, the antidepressant-like effects of HPE and its effect on ethanol intake are mediated by different neurochemical systems.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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