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Pharmacological action ofPanax Ginseng on the behavioral toxicities induced by psychotropic agents

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Abstract

Morphine-induced analgesia has been shown to be antagonized by ginseng total saponins (GTS), which also inhibit the development of analgesic tolerance to and physical dependence on morphine. GTS is involved in both of these processes by inhibiting morphine-6-dehydrogenase, which catalyzes the synthesis of morphinone from morphine, and by increasing the level of hepatic glutathione, which participates in the toxicity response. Thus, the dual actions of ginseng are associated with the detoxification of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contractions in guinea pig ileum (μ-receptors) and mouse vas deferens (δ-receptors) are not mediated through opioid receptors, suggesting the involvement of non-opioid mechanisms. GTS also attenuates hyperactivity, reverse tolerance (behavioral sensitization), and conditioned place preference induced by psychotropic agents, such as methamphetamine, cocaine, and morphine. These effects of GTS may be attributed to complex pharmacological actions between dopamine receptors and a serotonergic/adenosine A2A/δ-opioid receptor complex. Ginsenosides also attenuate the morphine-induced cAMP signaling pathway. Together, the results suggest that GTS may be useful in the prevention and therapy of the behavioral side effects induced by psychotropic agents.

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References

  • Bhargava, H. N. and Ramarao, P., The effects of Panax ginseng on the development of tolerance to the pharmacological actions of morphine in the rats.Gen. Pharmac., 2, 521–525 (1991).

    Google Scholar 

  • Butcher, S. P., Fairbrother, I. S., Kelly, J. S., and Arbuthnott, G. W., Amphetamine-induced dopamine release in rat striatum: Anin vivo microdialysis study.J. Neurochem., 50, 346–355 (1988).

    Article  PubMed  CAS  Google Scholar 

  • Choi, S., Jung, S. Y., Rhim, H., Jeong, S. W., Lee, S. M., and Nah, S. Y., Evidence that ginsenosides prevent the development of opioid tolerance at the central nervous system.Life Sci., 67, 969–975 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Collier, H. O. J. and Francis, D. L., Morphine abstinence is associated with increased cyclic AMP.Nature, 225, 159–162 (1975).

    Article  Google Scholar 

  • Di Chiara, G. and Imperato, A., Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesilimbic system of freely moving rats.Proc. Natl. Acad. Sci. U.S.A., 85, 5274–5278 (1988a).

    Article  PubMed  Google Scholar 

  • Di Chiara, G. and Imperato, A., Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats.J. Pharmacol. Exp. Ther., 185, 1067–1080 (1988b).

    Google Scholar 

  • Hadfield, M. G., Mott, D. E. W., and Ismay, J. A., Cocaine: Effects ofin vivo administration on synaptosomal uptake of norepinephrine.Biochem. Pharmacol., 29, 1861–1863 (1980).

    Article  PubMed  CAS  Google Scholar 

  • Heikkila, R. E., Orlansky, H., Mytilineou, C., and Cohen, G., Amphetmaine: Evaluation ofd- andl-isomers as releasing agents and uptake inhibitors for3H-dopamine and3H-norepinephrine in slices of rat neostriatum and cerebral cortx.J. Pharmacol. Exp. Ther., 193, 47–56 (1975).

    Google Scholar 

  • Heikkila, R. E., Cobbat, F. S., Mazino, L., and Duvoisin, R. C., Rotational behavior induced by cocaine analogue in rats with unilateral 6-OHDA lesions for the substantia nigra: Dependence upon dopaminergic uptake inhibition.J. Pharmacol. Exp. Ther., 211, 198–194 (1979).

    Google Scholar 

  • Hunt, P., Kannengiesser, M. H., and Raynauld, J. P., Nomifensine: A new potent inhibitor of dopamine uptake into synaptosomes from rat brain corpus stiatum.J. Pharm. Pharmacol., 26, 370–371 (1974).

    PubMed  CAS  Google Scholar 

  • Huong, N. T. T., Matsumoto, K., Yamasaki, K., Duc, N. M., Nham, N. T., and Watanabe, H., Majonosides-R2, a major constituent of Vietnamese ginseng attenuates opioid-induced antinociception.Pharmacol. Biochem. Behav., 57, 285–291 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Iwamoto, E. T., Ho, I. K., and Way, E. L., Elevation of brain dopamine during naloxone precipitated withdrawal in morphine dependent mice and rats.J. Pharmacol. Exp. Ther., 187, 558–567 (1973).

    CAS  Google Scholar 

  • Joo, C. N., Biochemical studies ofPanax ginseng.Kor. Biochem. News, 4 5 (1984).

    Google Scholar 

  • Justinova, Z., Ferre, S., Segal, P. N., Antoniou, K., Soinas, M., Pappas, L. A., Highkin, J. L., Hockemeyer, J., Munzar, P., and Goldberg, S. R., Involvement of adenosine A1 and A2A receptors in the adenosinergic modulation of the discriminative-stimulus effects of cocaine and methamphetamine in rats.J. Pharmacol. Exp. Ther., 307, 977–986 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Kim, H. S., Oh, K. W., and Oh, S., Antagonism of analgesic effects of morphine in mice by ginseng saponins.J. Kor. Pharm. Sci., 16, 135–138 (1986).

    Google Scholar 

  • Kim, H. S., Oh, K. W., Park, W. K., Choi, J. W., and Bae, D. S., Effects ofPanax ginseng on the development of morphine induced tolerance and dependence (VI).Arch. Pharm. Res., 10, 188–192 (1987a).

    Article  Google Scholar 

  • Kim, H. S., Oh, K. W., Park, W. K., Yanmano, S., and Toki, S., Effects ofPanax ginseng on the development of morphine tolerance and dependence.Kor. J. Ginseng Sci., 11, 182–190 (1987b).

    Google Scholar 

  • Kim, H. S., Oh, K. W., Lee, M. K., Choi, K. J., and Kim, S. C., Effects of ginseng total saponin on the development of acute and delayed typed tolerance to morphine.Kor. J. Ginseng Sci., 13, 239–241 (1989).

    CAS  Google Scholar 

  • Kim, H. S., Oh, K. W., Lee, M. K., Back, D. Y., Rheu, H. M., and Seong, Y. H., Antinarcotic effects ofPanax ginseng.Kor. J. Ginseng Sci., 14, 178–186 (1990a).

    CAS  Google Scholar 

  • Kim, H. S., Jang, C. G., and Lee, M. K., Antinarcotic effects of the standardized ginseng extract G115 on morphine.Planta Med., 56, 158–163 (1990b).

    Article  PubMed  CAS  Google Scholar 

  • Kim, H. S., Oh, K. W., Rheu, H. M., and Kim, S. H., Antagonism of U-50,488H-induced antinociception by ginseng total saponins is dependent on serotonergic mechanisms.Pharmacol. Biochem. Behav., 42, 587–593 (1992a).

    Article  PubMed  CAS  Google Scholar 

  • Kim, H. S., Ann, S. H., Seong, Y. H., Kim, S. H., and Oh, K. W., Effects of ginseng total saponins on the analgesia and tolerance development of pentazocine.Kor. J. Ginseng Sci., 16, 93–98 (1992b).

    Google Scholar 

  • Kim, H. S., Oh, K. W., Park, W. K., and Ho, I. K., Effects of ginseng saponin on morphine physical dependence.Kor. J. Ginseng Sci., 16, 13–17 (1992c).

    Google Scholar 

  • Kim, H. S., Kim, S. H., Seong, Y. H., and Oh, K. W., Effects of ginseng total saponins on the antinociception and the development of U-50,488H.Arch. Pharm. Res., 16, 237–243 (1993a).

    Article  CAS  Google Scholar 

  • Kim, H. S., Seong, Y. H., Kim, S. H., Kim, S. C., Choi, K. J., and Oh, K. W., Effects of ginseng saponins and U-50,488H on electrically induced twitch response of mouse vas deferens.Kor. J. Ginseng Sci., 17, 109–113 (1993c).

    CAS  Google Scholar 

  • Kim, H. S., Seong, Y. H., Lim, H. J., Jang, C. G., and Oh, K. W., Effects of ginseng saponins and morphine on electrically induced twitch response of mouse vas deferens.Experimental Neurobiology, 2, 43–47 (1993d).

    Google Scholar 

  • Kim, H. S. and Oh, K. W., Effects of ginseng total saponin on the development of psychic and physical dependence on nalbuphine.J. Appl. Pharmacol., 2, 316–321 (1994).

    Google Scholar 

  • Kim, H. S., Kang, J. G., Seong, Y. H., Nam, K. Y., and Oh, K. W., Blockade by ginseng total saponin of the development of cocaine induced reverse tolerance and dopamine receptor supersensitivity in mice.Pharmacol. Biochem. Behav., 50, 23–27 (1995a).

    Article  PubMed  CAS  Google Scholar 

  • Kim, H. S., Kang, J. G., Rheu, H. M., Cho, D. H., and Oh, K. W., Blockade by ginseng total saponin of the development of methamphetamine reverse tolerance and dopamine receptor supersensitivity in mice.Planta Med., 61, 22–25 (1995b).

    Article  PubMed  CAS  Google Scholar 

  • Kim, H. S., Kang, J. G., and Oh, K. W., Inhibition by ginseng total saponin of the development of morphine reverse tolerance and dopamine receptor supersensitivity in mice.Gen. Pharmac., 26, 1071–1076 (1995c).

    Article  CAS  Google Scholar 

  • Kim, H. S., Jang, C. G., Oh, K. W., Seong, Y. H., Rheu, H. M., Cho, D. H., and Kang, S. Y., Effects of ginseng total saponin on cocaine-induced hyperactivity and conditioned place preference in mice.Pharmacol. Biochem. Behav., 53, 185–190 (1996a).

    Article  CAS  Google Scholar 

  • Kim, H. S., Jang, C. G., Park, W. K., Oh, K. W., Rheu, H. M., Cho, D. H., and Oh, S., Blockade by ginseng total saponin of the development of methamphetamine-induce hyperactivity and conditioned place preference in mice.Gen. Pharmac., 27, 199–204 (1996b).

    CAS  Google Scholar 

  • Kim, H. S., Hong, Y. T., Oh, K. W., Seong, Y. H., Rheu, H. M., Cho, D. H., Oh, S., Park, W. K., and Jang, C. G., Inhibition by ginsenosides Rb1 and Rg1 of methamphetamine-induce hyperactivity, conditioned place preference and dopamine receptor supersensitivity in mice.Gen. Pharmac., 30, 783–789 (1998a).

    Article  CAS  Google Scholar 

  • Kim, H. S., Jang, C. G., Oh, K. W., Oh, S., Rheu, H. M., Lee, G. S., Seong, Y. H., and Park, W. K., Effects of ginseng total saponin on the morphine-induce hyperactivity and conditioned place preference in mice.J. Ethnopharmacol., 60, 33–42 (1998b).

    Article  PubMed  CAS  Google Scholar 

  • Kim, H. S., Hong, Y. T., and Jang, C. G., Effects of ginsenosides Rg1 and Rb1 on morphine-induced hyperactivity and reinforcement in mice.J. Pharm. Pharmacol., 50, 555–560 (1998c).

    PubMed  CAS  Google Scholar 

  • Kim, H. S., Kim, K. S., and Oh, K. W., Inhibition by ginsenosides Rb1 and Rg1 of cocaine-induced hyperactivity, conditioned place preference and postsynaptic dopamine receptor supersensitivity in mice.Pharmcol. Biochem. Behav., 63, 407–412 (1999a).

    Article  CAS  Google Scholar 

  • Kim, H. S., Zhang, Y. H., Fang, L. H., and Lee, M. K., Effects of ginsenosides on bovine adrenal tyrosine hydroxylase.J. Ethanopharmacol., 66, 107–111 (1999b).

    Article  CAS  Google Scholar 

  • Kim, Y. C., Lee, J. H., Kim, M. S., and Lee, N. C., Effects of the saponin fraction of Panax ginseng on catecholamines in mouse brain.Arch. Pharm. Res., 8, 45–48 (1985).

    Article  CAS  Google Scholar 

  • Kimura, T., Saunders, P. A., Kim, H. S., Rheu, H. M., Oh, K. W., and Ho, I. K., Interactions of ginsenosides with ligand-bindings of GABAA and GABAB receptors.Gen. Pharmac., 25, 193–199 (1994).

    CAS  Google Scholar 

  • Kosten, T. R. and Hollister, L. E., Drugs of abuse, In Katzung, B. G. 8th (Eds.), Basic and Clinical Pharmacology, McGraw Hill, Medical Publishing Division, New York, pp. 532–548, (2001).

    Google Scholar 

  • Nabata, H., Saito, H., and Takagi, K., Pharmacological studies on neutral saponins (GNS) ofPanax ginseng root.Jpn. J. Pharmacol., 23, 29–41 (1973).

    PubMed  CAS  Google Scholar 

  • Nagamatsu, K., Kido, Y., Terao, T., Ishida, T., and Toki, S., Protective effects of sulfhydryl compounds on acute toxicity of morphine.Life Sci., 30, 1121–1127 (1982).

    Article  PubMed  CAS  Google Scholar 

  • Nagamatsu, K., Kido, Y., Terao, T., Ishida, T., and Toki, S., Studies on the antagonism of covalent binding of morphine metabolites to proteins in mouse.Drug Met. Disps., 11, 190 (1983).

    CAS  Google Scholar 

  • Nicola, S. M., Surmeier, D. J., and Malenka, R. C., Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens.Annu. Rev. Neurosci., 23, 185–215 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Oh, K. W., Kim, H. S., and Wagner, G. C., Ginseng total saponin inhibits the dopaminergic depletions induced by methamphetamine.Planta Medica, 63, 80–81 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Oh, K. W., Lim H. K., Park, C. B., Shin, I. C., and Hong, J. T., Effects of ginseng saponin on [3]DAGO bindings of opioid m-receptors.J. Ginseng Res., 26, 187–190 (2002).

    Article  Google Scholar 

  • Park, C. W., Pharmacological studies ofPanax ginseng.Kor. Biochem. News, 4, 37 (1984).

    Google Scholar 

  • Robinson, T. E. and Becker, J. B., Enduring changes in brain and behavior produced by chronic amphetamine administration: A review and evaluation of animal models of amphetamine psychosis.Brain Res. Rev., 11, 157–198 (1986).

    Article  CAS  Google Scholar 

  • Roy, S. N., Bhattachacharyya, S., and Pradhan, S. N., Behavioral and neurochemical effects of repeated administration of cocaine in rats.Neuropharmacol., 17, 559–564 (1978).

    Article  CAS  Google Scholar 

  • Saito, H., Morita, M., and Takagi, K., Pharmacological studies ofPanax ginseng leaves.Jpn. J. Pharmacol., 23, 43–56 (1973).

    PubMed  CAS  Google Scholar 

  • Scheel-Kruger, J., Greastrup, C., Nielson, M., Golembiowski, K., and Mogilmicka, E., Cocaine: Discussion on the role of dopamine in the biochemical mechanism of action. In Kilby, E. E. (Eds.). Cocaine and other stimulants, Plenum Press, New york, pp. 373–407 (1977).

    Google Scholar 

  • Schole, J., Influence of Panax ginseng on the glutathione system of rats liver,Belastung, Emahrung und Resistenz-Forschritte in der Tierphysiologie und Tieremahrung, 9, 35 (1978).

    Google Scholar 

  • Schultz, W., Dopamine neurons and their role in reward mechamism.Curr. Opin. Neurobiol., 7, 191–197 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Segal, D. S., Geyer, M. A., and Schuckit, M. A., Stimulant-induced psychosis: An evaluation of animals models, In Youdim, M. B. H., Lovenberg, W., Sharman, D. F., and Lagnado, J. R. (Eds). Essays in neurochemistry and neuropharmacology, John Wiley & Sons, Sussex, England, pp. 95–129 (1981).

    Google Scholar 

  • Segal, D. S. and Geyer, M. A., Animal models of psychophathology, in Carvenar, J. O. Jr. (Eds.). Psychiatry, Lippincortt, Philadelphia, pp. 1–18, (1985).

    Google Scholar 

  • Shin, E. J., Nabeshima, T., Suh, H. W., Jhoo, W. K., Oh, K. W., Lim, Y. K., Kim, D. S., Choi, K. W., and Kim, H. C., Ginsenosides attenuate methamphetamine-induced behavioural side effects in micevia activation of adenosine A2A receptors: Possible involvements of the striatal reduction in AP-1 DNA binding activity and proenkephalin gene expression.Behav. Brain Res., 158, 143–157 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Suh, H. W., Song, D. K., and Kim, Y. H., Effects of ginsenosides injected intrayhecally or intracerebroventricularly on antinociception induced by morphine administered intracerebroventricaularly in the mouse.Gen. Pharmac., 29, 873–977 (1997).

    CAS  Google Scholar 

  • Takagi, H., Takahashi, T., and Kimura, K., Antagonism of the analgesic effect of morphine in mice by tetrabenazine and reserpine.Archsint. Pharmacodyn. Ther., 149, 484–490 (1964).

    CAS  Google Scholar 

  • Takahashi, E., Kudo, K., Akasaka, Y., Miyate, Y., and Tachikawa, E., Actions of saponins of red ginseng on the sympathetic nerve and effects of combination of red ginseng with other herb medicines on cardiac functions.Ginseng Rev., 16, 88–92 (1993).

    CAS  Google Scholar 

  • Tokuyama, S., Oh, K. W., Kim, H. S., Takahashi, M., and Kaneto, H., Blockade by ginseng extract of the development of reverse tolerance to the ambulation-accelerating effects of methamphetamine in mice.Jpn. J. Pharmacol., 59, 423–423 (1992).

    Article  PubMed  CAS  Google Scholar 

  • Tokuyama, S., Takahashi, M., and Kaneto, H., The effect of ginseng extract on locomotor sensitization and conditioned place preference induced by methamphetamine and cocaine in mice.Pharmacol. Biochem. Behav., 54, 671–676 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Verri, R. A., Graeff, F. G., and Corrado, A. P., Antagonism of morphine analgesia by reserpine and alpha-methyltyrosine, and the role of played by catecholamines in the morphine analgesic action.J. Pharm. Pharmacol., 19, 709–714 (1967).

    Google Scholar 

  • Wagner, G. C., Ricaurte, G. A., Johnson, C. E., Schuster, C. R., and Seiden, L. S., Amphetmaine induced depletion of dopamine and loss of dopamine uptake sites in caudate.Neurology, 30, 547–550 (1980a).

    PubMed  CAS  Google Scholar 

  • Wagner, G. C., Ricaurte, G. A., Seiden, L. S., Schuster, C. R., Miller, R. G., and Westley, J., Long lasting depletions of striatal dopamine and uptake sites following repeated administration of methamphetamine.Brain Res., 181, 151–160 (1980b).

    Article  PubMed  CAS  Google Scholar 

  • Watanabe, J., Oh, K. W., Kim, H. S., Takahashi, M., and Kaneto, H., A non-opioid mechanism in the inhibitory effect of ginseng saponins on electrically evoked contractions of guinea pig ileum and mouse vas deferens.J. Pharmacobiodyn., 11, 453–458 (1988a).

    PubMed  CAS  Google Scholar 

  • Watanabe, J., Takahashi, M., and Kaneto, H., Distinctive effect of ginseng saponins on the development of morphine tolerance in guinea pig ileum and mouse vas deferens.J. Pharmacobiodyn., 11, 744–748 (1988b).

    PubMed  CAS  Google Scholar 

  • Wu, C. F., Liu, Y. L., Song, M., Liu, W., Wang, J. H., Li, X., and Yang, J. Y., Protective effects of pseudoginsenosides-F11 on methamphetamine-induced neurotoxicity in mice.Pharmacol. Biochem. Behav., 76, 103–109 (2003).

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto, S., Kageura, E., Ishida, T., and Toki, S., Purification and characterization of guinea pig liver morphine 6-dehydrogenase.J. Biol. Chem., 260, 5259–5264 (1985).

    Google Scholar 

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Kim, HC., Shin, EJ., Jang, CG. et al. Pharmacological action ofPanax Ginseng on the behavioral toxicities induced by psychotropic agents. Arch Pharm Res 28, 995–1001 (2005). https://doi.org/10.1007/BF02977391

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