The University of North Carolina School of Medicine at Chapel Hill, Medical Wing D, CB# 7240, Chapel Hill, NC 27599-7240, USA
Received 13 October 1998; in revised form 15 January 1999; accepted 4 March 1999
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ABSTRACT |
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INTRODUCTION |
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Alcoholism and depression have some common neurochemical substrates (Markou et al., 1998). It has been speculated that the pathophysiology of alcoholism and depression might involve pre-existing low brain serotonin levels that are increased transiently by alcohol consumption (Ballenger et al., 1979
; Rosenthal et al., 1980
). Serotonergic compounds have been shown to reduce pathologic drinking in experimental animals (Murphy et al., 1988
; Rezvani et al., 1991
; Sellers et al., 1992
; Overstreet et al., 1994
; Rezvani and Grady, 1994
; Tomkins et al., 1995) and heavy drinkers (Lawrin et al., 1986
; Naranjo et al., 1990
) and alleviate the symptoms of depressive disorders (Meltzer, 1990
). Because of this similarity in the pathogenesis of depression and alcoholism and the antidepressant properties of SJW, we postulated that the SJW may also reduce voluntary alcohol intake in alcohol-preferring rats. To test this hypothesis, we studied the effects of the SJW extract on voluntary alcohol intake in two different strains of alcohol-preferring rats: inbred alcohol-preferring fawn-hooded (FH) rats and selectively-bred high-alcohol drinking (HAD) rats.
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MATERIALS AND METHODS |
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Adult male rats were housed individually in wire mesh cages (26 x 34 x 20 cm) under a constant room temperature of 22 ± 1°C and a 12:12 light dark cycle (10:0022:00, dark). Animals were fed Agway Prolab Rat/Mouse/Hamster 3000 formula (Agway, Syracuse, NY) and water ad libitum.
Establishment of baseline alcohol intake
Alcohol intake was determined using the standard two-bottle choice method utilized in our and other laboratories for many years (Murphy et al., 1988; McBride et al., 1990
; Rezvani et al., 1990
, 1991
, 1997
). Animals were first given free access to water in a graduated Richter tube for 1 day. Next, they were given access only to a solution of 10% (v/v) ethanol for 3 consecutive days. During this period, rats became accustomed to drinking from Richter tubes and to the taste and pharmacological effects of alcohol (Waller et al., 1982
; Rezvani et al., 1997
). Thereafter, they were given free access to both water and a solution of 10% alcohol for at least 3 consecutive weeks and throughout the period of study. Treatments were administered orally in the morning (09:30). Water and alcohol intake were recorded at 6 and 24 h after the treatment, whereas food intake was measured at 24 h. Water and alcohol intakes were measured by reading the numbers on the graduated Richter tubes and subtracting them from the previous readings.
Preparation of agents
Solutions of SJW extract were prepared in distilled water. The volume of vehicle (distilled water) or SJW extract administered orally was 5 ml/kg body wt. The standardized compound (LI 160, batch no. 970201 provided by Lecthwer Pharma AG, Berlin) is an 80% methanolic extract of Hyperici herba and contained 0.22% total hypericin (sum of hypericin and pseudohypericin) measured by thin- layer chromatography and 4.05% hyperforin measured by high-performance liquid chromatography. These data were provided by Lecthwer Pharma AG, Berlin. Solutions of 10% alcohol were prepared from 95% grade ethanol and distilled water.
Experimental protocol
Acute administration.
After establishment of a stable baseline for alcohol, food, and water intake, FH (n = 810) and HAD (n = 8) rats were administered by gavage at 09:30 either the vehicle or one of the following doses of SJW extract: 100, 200, 400, and 800 mg/kg (for FH rats) and 100, 200, 400, and 600 mg/kg (for HAD rats) using a random treatment order. Each rat received the vehicle and all of the doses of SJW extract. The interval between treatments was at least 3 days. The solutions of extract were delivered slowly into the stomach through a special ball-tipped 16 gauge stainless steel gavage needle (Beckton Dickenson) (Rezvani et al., 1986).
Chronic administration. In another experiment, to determine the effect of chronic administration of SJW on alcohol intake, a group of FH rats (n = 9) was given orally once a day either the vehicle or 400 mg/kg of SJW extract for 15 consecutive days.
Statistical analysis of data
The results are presented as means ± SEM. Alcohol intake (g/kg) was calculated by multiplying the volume of alcohol consumed in ml by 10% and 0.7893 (ethanol density)/body wt in kg. Alcohol preference, expressed as a percentage, was calculated as follows (volume of alcohol consumed in ml/total fluid intake in ml) x 100 (Rezvani and Grady, 1994; Rezvani et al., 1997
). Statistical differences between drug-treated and control groups were determined by using ANOVA and Tukey Student's t-test for multiple comparison (GB-STAT, version 5.01, Dynamic Microsystems, Inc., Silver Spring, MD, USA).
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RESULTS |
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DISCUSSION |
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Suzuki et al. (1984) reported that hypericin inhibited both monoamine oxidase-(MAO) A and B; however, this finding could not be confirmed by other workers (Demisch et al., 1989; Bladt and Wagner (1994
). The latter group demonstrated that none of the fractions of Hypericum or their constituents tested in vitro showed significant MAO inhibition at pharmacologically relevant concentrations. Although some of the discrepancies could be the result of using different extracts that might be different in purity, existing data suggest that the pharmacological actions of SJW extract cannot be explained by MAO inhibition.
One may consider also whether SJW exerts its action on alcohol intake by interfering with alcohol metabolism. Although the present data do not address this possibility, other investigators have found that intragastric administration of the extract of SJW does not interfere with alcohol metabolism (Perfumi et al., 1999, personal communication).
It has been shown that the number of 5-HT1A and 5-HT2A receptors are significantly increased by 50% in Hypericum-treated rats (Teufel-Mayer and Gleitz, 1997). Interestingly, both 5-HT2 and 5-HT1A receptors have been implicated in excessive drinking in rats (McBride et al., 1993
; Overstreet et al., 1994
, 1997
). Thus, it is possible that SJW extract reduces voluntary alcohol intake by acting directly at these receptors and therefore altering 5-HT transmission.
The fact that SJW extract increases 5-HT2 receptors during chronic treatment (Teufel-Mayer and Gleitz, 1997) indicates that SJW may also be a novel antidepressant agent. Typically, antidepressant agents lead to the downregulation of 5-HT2 receptors (Maies and Meltzer, 1995
). However, chronic treatment with SJW extract leads to an increase in 5-HT2 receptors (Teufel-Mayer and Gleitz, 1997
) as well as an antidepressant effect (Ernst, 1995
). Indeed, we found that FH rats, which exhibit an innate high immobility in the forced swim test of depression (Rezvani et al., 1990
), became less immobile following chronic (15 consecutive days) treatment with SJW extract (Rezvani et al., 1998
). Others have also recently reported suppression of alcohol intake after acute administration of SJW extract and reduction in swim test immobility after chronic treatment (Perfumi et al., 1999
). Perhaps the downregulation of 5-HT2A receptors induced by chronic classic antidepressant treatment accounts for their relative lack of efficacy in the treatment of alcoholism (Litten et al., 1996
). Indeed, in contrast to the constant suppression of alcohol intake seen during chronic treatment with SJW extract, we have observed that tolerance develops to the suppressing effects of the serotonin reuptake inhibitor, fluoxetine, on alcohol intake (Rezvani et al., 1992
). It appears, therefore, that 5-HT2 receptors may not be involved in the alcohol-suppressant effects of SJW, but changes in these receptors may account for the lack of tolerance development following chronic treatment.
In conclusion, the present findings demonstrate that acute or repeated oral administration of the SJW extract induced a dose-dependent reduction in alcohol intake in alcohol-preferring rats. Although the antidepressant effect of SJW extract has been suggested to be associated with its serotonergic property, its effect on alcohol intake is probably linked to its broad spectrum of pharmacological properties, such as reducing the re-uptake of serotonin, DA, NA, and GABA transmitters in the brain. The exact mechanism of action of the extract on alcohol intake remains to be investigated systematically.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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REFERENCES |
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Bladt, S. and Wagner, H. (1994) Inhibition of MAO by fractions and constituents of Hypericum extract. Journal of Geriatric Psychiatry and Neurology 7 (Suppl. 1), 5759.
Butterweck, V., Wall, A., Lieflander-Wulf, U., Winterhoff, H. and Nahrsted, A. (1997) Effects of the total extract and fractions of Hypericum perforatum in animal assays for antidepressant activity. Pharmacopsychiatry 30 (Suppl.), 117124.[ISI][Medline]
Chatterjee, S. S., Bhattacharya, S. K., Wonnemann, M., Singer, A. and Muller, W. E. (1998) Hyperforin as a possible antidepressant component of Hypericum extracts. Life Sciences 63, 499510.[ISI][Medline]
Cott, J. M. (1997) In vitro receptor binding and enzyme inhibition by Hypericum perforatum extract. Pharmacopsychiatry 30 (Suppl.), 108112.[ISI][Medline]
Demisch, L., Holzl, J., Golnik, B. and Kaczmarczyk, P. (1989) Identification of selective MAO-type-A inhibitors in Hypericum perforatum L. (Hyperforat ®). Pharmacopsychiatry 22, 194.
DiChiara, G. and Imperato, A. (1985) Ethanol preferentially stimulates dopamine release in the nucleus accumbens of freely moving rats. European Journal of Pharmacology 115, 131132.[ISI][Medline]
Ernst, E. (1995) St John's wort, an anti-depressant? A systematic, criteria-based review. Phytomedicine 2, 6771.[ISI]
Hyytia, P. and Koob, G. F. (1995) GABAA receptor antagonism in the extended amygdala decreases ethanol self-administration in rats. European Journal of Pharmacology 283, 151159.[ISI][Medline]
Koob, G. F., Roberts, A. J., Schulteis, G., Parsons, L. H., Heyser, C. J., Hyytia, P. and Merlo-Pich, E. (1998) Neurocircuitry targets in ethanol reward and dependence. Alcoholism: Clinical and Experimental Research 22, 39.[ISI][Medline]
Lawrin, M. O., Naranjo, C. A. and Seller, E. M. (1986) Identification of new drugs for modulating alcohol consumption. Psychopharmacology Bulletin 22, 10101025.
LeMarquand, D., Pihl, R. O. and Benkelfat, C. (1994) Serotonin and alcohol intake, abuse and dependence: clinical evidence. Biological Psychiatry 36, 326337.[ISI][Medline]
Li, T.-K., and McBride, W. J. (1995) Pharmacogenetic models of alcoholism. Clinical Neuroscience 3, 182185.[ISI][Medline]
Litten, R. Z., Allen, J. and Fertig, J. (1996) Pharmacotherapies for alcohol problems: a review of research with focus on developments since 1991. Alcoholism: Clinical and Experimental Research 20, 859876.[ISI][Medline]
Maies, M. and Meltzer, H. Y. (1995) The serotonin hypothesis of major depression. In Psychopharmacology. The Fourth Generation of Progress, Bloom, F. E. and Kupfer, D. J. eds, pp. 933944. Raven Press, New York.
Markou, A., Kosten, T. R. and Koob, G. F. (1998) Neurobiological similarities in depression and drug dependence: a self-medication hypothesis. Neuropsychopharmacology 18, 135174.[ISI][Medline]
McBride, W. J., Murphy, J. M., Lumeng, L. and Li, T.-K. (1990) Serotonin, dopamine and GABA involvement in alcohol drinking of selectively bred rats. Alcohol 7, 199205.[ISI][Medline]
McBride, W. J., Chernet, E., Rabold, J. A., Lumeng, L. and Li, T.-K. (1993) Serotonin-2 receptors in the CNS of alcohol-preferring and -nonpreferring rats. Pharmacology, Biochemistry and Behavior 30, 170177.
Melchart, D. (1996) St John's wort for depression an overview and meta-analysis of randomized clinical trials. British Medical Journal 313, 241242.
Meltzer, H. Y. (1990) Role of serotonin in depression. Annals of the New York Academy of Science 600, 486500.[ISI][Medline]
Muller, W. E., Rolli, M., Schafer, C. and Hafner, U. (1997) Effects of Hypericum extract (LI-160) in biochemical models of antidepressant activity. Pharmacopsychiatry 30 (Suppl.), 102107.[ISI][Medline]
Murphy, J. M., McBride, W. J., Lumeng, L. and Li, T.-K. (1988) Effects of serotonin and dopamine agents on ethanol intake of alcohol-preferring P rats. Alcoholism: Clinical and Experimental Research 12, 306.
Nahrstedt, A. and Butterweck, V. (1997) Biologically active and other chemical constituents of the herb Hypericum perforatum L. Pharmacopsychiatry 30 (Suppl.), 129134.[ISI][Medline]
Naranjo, C. A., Kadlec, K. E., Sanhueza, P., Woodley-Remus, D. and Sellers, E. M. (1990) Fluoxetine differentially alters alcohol intake and other consummatory behaviors in problem drinkers. Clinical Pharmacology and Therapeutics 47, 490498.[ISI][Medline]
Nordfors, M. and Hartvig, P. (1997) St John's wort against depression in favor again. Lakartidningen 94, 23652367.[Medline]
Overstreet, D. H., Rezvani, A. H., Pucilowski, O. and Janowsky, D. S. (1994) 5-HT receptors: implications for the neuropharmacology of alcohol and alcoholism. Alcohol and Alcoholism 29 (Suppl. 2), 207212.
Overstreet, D. H., McArthur, R. A., Rezvani, A. H. and Post, C. (1997) Selective inhibition of alcohol intake in diverse alcohol preferring rat strains by 5-HT2A antagonists amperozide and FG 5974. Alcoholism: Clinical and Experimental Research 21, 14481457.[ISI][Medline]
Perfumi, M., Ciccocioppo, R., Angeletti, S., Cucculelli, M. and Massi, M. (1999) Effects of Hypericum perforatum extract on alcohol intake in Marchigian Sardinian alcohol-preferring rats. Alcohol and Alcoholism 34, 690698.
Rezvani, A. H. and Grady, D. R. (1994) Suppression of alcohol consumption by fenfluramine in fawn-hooded rats with serotonin dysfunction. Pharmacology, Biochemistry and Behavior 48, 105110.[ISI][Medline]
Rezvani, A. H., Crovi, S. I., Mack, C. M. and Meyers, R. D. (1986) Central Ca2+-channel blockade reverses ethanol induced poikilothermia in the rat. Alcohol 3, 273279.[ISI][Medline]
Rezvani, A. H., Overstreet, D. H. and Janowsky, D. S. (1990) Genetic serotonin deficiency and alcohol preference in the fawn-hooded rats. Alcohol and Alcoholism 25, 573575.[ISI][Medline]
Rezvani, A. H., Overstreet, D. H. and Janowsky, D. S. (1991) Drug-induced reductions in ethanol intake in alcohol preferring and fawn-hooded rats. Alcohol and Alcoholism 26 (Suppl. 1), 433437.
Rezvani, A. H., Mason, G. A., Garbutt, J. C., Overstreet, D. H. and Janowsky, D. S. (1992) Reduction of tolerance to anti-craving drugs for alcohol. Paper presented at the 31st Annual Meeting of the American College of Neuropsychopharmacology, Puerto Rico, December 1992, pp. 1418.
Rezvani, A. H., Overstreet, D. H., Ying, Y., Maisonneuve, I. M., Bandarage, U. K., Kuehne, M. E. and Glick, S. D. (1997) Attenuation of alcohol consumption by a novel non-toxic ibogaine analog (18-methoxycoronaridine) in alcohol-preferring rats. Pharmacology, Biochemistry and Behavior 58, 615619.[ISI][Medline]
Rezvani, A. H., Yang, Y., Overstreet, D. H. and Clark, E. Jr (1998) Hypericum perforatum (St John's Wort) reduces alcohol intake in alcohol-preferring rats. Alcoholism: Clinical and Experimental Research 22, 121A.
Rosenthal, N. E., Davenport, Y., Cowdery, R. W., Webster, M. H. and Goodwin, F. K. (1980) Monoamine metabolites in cerebral spinal fluid of depressive subgroups. Psychiatry Research 2, 113119.[ISI][Medline]
Samson, H. H., Hodge, C. W., Tolliver, G. A. and Haraguchi, M. (1993) Effect of dopamine agonists and antagonists on ethanol-reinforced behavior: the involvement of the nucleus accumbens. Brain Research Bulletin 30, 133141.[ISI][Medline]
Sellers, E. M., Higgins, G. A. and Sobell, M. B. (1992) 5-HT and alcohol abuse. Trends in Pharmacological Sciences 13, 6975.[ISI][Medline]
Suzuki, O., Katsumata, Y., Oya, M., Bladt, S. and Wagner, H. (1984) Inhibition of monoamine oxidase by hypericin. Planta Medica 50, 272274.[ISI][Medline]
Teufel-Mayer, R. and Gleitz, J. (1997) Effects of long-term administration of Hypericum extracts on the affinity and density of the central serotonergic 5-HT1A and 5-HT2A receptors. Pharmacopsychiatry 30 (Suppl.), 113116.
Tomkins, D. M., Le, A. D. and Sellers, E. M. (1995) Effects of the 5-HT3 antagonist ondansetron on voluntary ethanol intake in rats and mice maintained on a limited access procedure. Psychopharmacology 117, 479485.[ISI][Medline]
Volz, H. P. (1997) Controlled trials of Hypericum extracts in depressed patients: an overview. Pharmacopsychiatry 30 (Suppl.), 7276.[ISI][Medline]
Wagner, H. and Bladt, S. (1994) Pharmaceutical quality of Hypericum extracts. Journal of Geriatric Psychiatry and Neurology 7 (Suppl. 1), S65S68.
Waller, M. B., McBride, W. J., Lumeng, L. and Li, T. K. (1982) Induction of dependence on ethanol by free-choice drinking in alcohol preferring rats. Pharmacology, Biochemistry and Behaviour 16, 501507.[ISI][Medline]
Weiss, F., Lorang, M. T., Bloom, F. E. and Koob, G. F. (1993) Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and motivational determinants. Journal of Pharmacology and Experimental Therapeutics 267, 250258.[Abstract]