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Recent Developments in Alcoholism pp 267–281Cite as

Serotonin Uptake Blockers and the Treatment of Alcoholism

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Part of the book series: Recent Developments in Alcoholism ((RDIA,volume 7))

Abstract

There is growing research and clinical interest in the role of brain serotonin in regulating alcohol consumption, based on two lines of evidence: negative correlations between brain serotonin levels and spontaneous alcohol consumption in rodents, and decreased alcohol intake produced by drug-induced increases in brain serotonin activity in rodents and humans. Specific blockers of neuronal serotonin uptake, such as Citalopram, fluoxetine, and zimelidine, are the major drugs used in such studies. More than a dozen studies have consistently found that such specific serotonin uptake blockers reduce alcohol preference and intake in rodents, whereas nonspecific monoamine uptake blockers (e. g., amitriptyline, doxepin) do not. The effect begins within 1 hr of administration, wears off within several days of stopping drug, and often shows tolerance after 4–10 days of daily administration (the opposite time course from antidepressant action in humans). In four human, double-blind, placebo-controlled studies, Citalopram (40 mg but not 20 mg daily), fluoxetine (80 mg daily), and zimelidine (200 mg more than 300 mg daily) significantly reduced alcohol intake 10–26% in social drinkers, early problem drinkers, and chronic alcoholics. The effect occurred within a few days, wore off within several days of stopping drug, and lasted throughout the 2–4 weeks of drug administration, except that in the fluoxetine study with chronic alcoholics the effect was significant only during the first week. The reduced alcohol intake was not due to sedation, antidepression, or antianxiety effects, or an aversive drug-alcohol interaction, but could be explained in part by decreased appetitive behavior (two studies found that subjects lost weight) or a conditioned (taste) aversion to alcohol promoted by serotonin (as occurs in animals). Further research is also needed to clarify the neuropharmacological mechanism of action, since the alcohol intake-reducing effects in rodents are not blocked by serotonin receptor antagonists or brain serotonin depletion. Regardless of mechanism, serotonin uptake blockers offer a potentially promising new treatment for alcoholism.

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References

  1. McBride WJ, Murphy JM, Lumeng L, et al: The role of serotonin in ethanol preference, in Galanter M (ed): Recent Developments in Alcoholism, Vol 7. New York, Plenum Press, 1988.

    Google Scholar 

  2. Amit Z, Sutherland EA, Gill K, et al: Zimelidine: A review of its effects on ethanol consumption. Neurosci Biobehav Rev 8: 35–54, 1984.

    Article  PubMed  CAS  Google Scholar 

  3. Naranjo CA, Sellers EM, Lawrin MO: Modulation of ethanol intake by serotonin uptake inhibitors. J Clin Psychiatry 47(4 suppl): 16–22, 1986.

    PubMed  CAS  Google Scholar 

  4. Fuller RW, Wong DT: Serotonin reuptake in vitro and in vivo. J Clin Psychopharmacol 7(6 suppl): 36–43, 1987.

    Article  Google Scholar 

  5. Hill SY: Intraventricular injection of 5-hydroxytryptamine and alcohol consumption in rats. Biol Psychiatry 8: 151–158, 1974.

    PubMed  CAS  Google Scholar 

  6. Myers RD, Veale WL: The determinants of alcohol preference in animals, in Begleiter H, Kissin B (eds): Biology of Alcoholism, Vol. 2. New York, Plenum Press, 1972, pp 131–168.

    Chapter  Google Scholar 

  7. Zabik JE, Binkerd K, Roache JD: Serotonin and ethanol aversion in the rat, in Naranjo CA, Sellers EM (eds): Research Advances in New Psychopharmacological Treatments for Alcoholism. Amsterdam, Excerpta Medica, 1985, pp 87–105.

    Google Scholar 

  8. Geller I: Effects of para-chlorophenylalanine and 5-hydroxytryptophan on alcohol intake in the rat. Pharmacol Biochem Behav 1: 361–365, 1973.

    Article  PubMed  CAS  Google Scholar 

  9. Myers RD, Martin GE: The role of cerebral serotonin in the ethanol preference of animals. Ann NY Acad Sci 215: 135–144, 1975.

    Article  Google Scholar 

  10. Zabik, JE, Liao SS, Jeffreys M, et al: The effects of DL-5-hydroxytryptophan on ethanol consumption by rats. Res Commun Chem Pathol Pharmacol 20: 69–78, 1978.

    PubMed  CAS  Google Scholar 

  11. Miksic SL, Barry H, Krimmer EC: Increased serotonin activity reduces alcohol preference in rats. Alcohol Clin Exp Res 6: 149, 1982.

    Google Scholar 

  12. Walters JK: Effects of PCPA on the consumption of alcohol, water and other solutions. Pharmcol Biochem Behav 6: 377–383, 1977.

    Article  CAS  Google Scholar 

  13. Lawrin MO, Naranjo CA, Sellers EM: Enhanced serotonergic neurotransmission decreases ethanol consumption: Consistent results with a serotonin agonist. Proc Can Fed Biol Soc 28: 81, 1985.

    Google Scholar 

  14. Myers RD, Melchior CL: Alcohol drinking in the rat after destruction of serotonergic and catecholaminergic neurons in the brain. Res Commun Chem Pathol Pharmacol 10: 363–378, 1975.

    PubMed  CAS  Google Scholar 

  15. Sprince H, Parker CM, Smith GG, et al: Alcoholism: Biochemical and nutritional aspects of brain amines, aldehydes, and amino acids. Nutr Rep Int 5: 185–200, 1972.

    CAS  Google Scholar 

  16. Rockman GE, Amit Z, Brown ZW, et al: An investigation of action of 5-hydroxytryptamine in the suppression of ethanol intake. Neuropharmacology 21: 341–347, 1982.

    Article  PubMed  CAS  Google Scholar 

  17. Murphy JM, Waller MB, Gatto GJ, et al: Monoamine uptake inhibitors attenuate ethanol intake in alcohol-preferring (P) rats. Alcohol 2: 349–352, 1985.

    Article  PubMed  CAS  Google Scholar 

  18. Geller I, Hartmann RJ, Messiha FS: Effects of cinanserin, a serotonin antagonist, on ethanol preference in the rat. Proc West Pharmacol Soc 18: 141–145, 1975.

    PubMed  CAS  Google Scholar 

  19. Kiianmaa K: Alcohol intake in the rat after lowering brain 5-hydroxytryptamine content by electrolytic midbrain raphe lesions, 5,6-dihydroxytryptamine or p-chlorophenylalanine. Med Biol 54: 203–209, 1976.

    PubMed  CAS  Google Scholar 

  20. Lorens SA: Some behavioral effects of serotonin depletion depend on method. A comparison of 5,7-dihydroxytryptamine, p-chlorophenylalanine and electrolytic raphe lesions. Ann NY Acad Sci 305: 532–555, 1978.

    Article  PubMed  CAS  Google Scholar 

  21. Yoshimoto K, Komura S: Reexamination of the relationship betwen alcohol preference and brain monoamines in inbred strains of mice including senescence-accelerated mice. Pharmacol Biochem Behav 27: 317–322, 1987.

    Article  PubMed  CAS  Google Scholar 

  22. Murphy JM, McBride WJ, Lumeng L, et al: Alcohol preference and regional brain monoamine contents of N/NIH heterogeneous stock rats. Alc Drug Res 7: 33–39, 1986.

    Google Scholar 

  23. Murphy JM, McBride WJ, Lumeng L, et al: Regional brain levels of monoamines in alcoholpreferring and nonpreferring lines of rats. Pharmacol Biochem Behav 16: 245–249, 1982.

    Article  Google Scholar 

  24. Murphy JM, McBride WJ, Lumeng L, et al: Contents of monoamines in forebrain regions of alcohol-preferring (P) and-nonpreferring (NP) lines of rats. Pharmacol Biochem Behav 26: 389–392, 1987.

    Article  PubMed  CAS  Google Scholar 

  25. Wong DT, Lumeng L, Threlkeld PG, Reid LR, Li T-K: Serotonergic and adrenergic receptors in alcohol-preferring and non-preferring rats. J Neural Trans 71: 207–218, 1988.

    Article  CAS  Google Scholar 

  26. Ho AKS, Tasi CS, Kissin B: Neurochemical correlates of alcohol preference in inbred strains of mice. Pharmacol Biochem Behav 3: 1073–1076, 1975.

    Article  PubMed  CAS  Google Scholar 

  27. Pickett RA, II, Collins AC: Use of genetic analysis to test the potential role of serotonin in alcohol preference. Life Sci 17: 1291–1296, 1975.

    Article  PubMed  CAS  Google Scholar 

  28. Ahtee L, Eriksson K: 5-Hydroxytryptamine and 5-hydroxyindolacetic acid content in brain of rat strains selected for their alcohol intake. Physiol Behav 8: 123–126, 1972.

    Article  PubMed  CAS  Google Scholar 

  29. Ahtee L, Eriksson K: Regional distribution of brain 5-hydroxytyptamine in rat strains selected for their alcohol intake. Ann NY Acad Sci 215: 126–134, 1973.

    Article  PubMed  CAS  Google Scholar 

  30. Orenberg EK, Zarcone VP, Renson JF, et al: The effects of ethanol ingestion on cyclic AMP, homovanillic acid and 5-hydroxyindoleacetic acid in human cerebrospinal fluid. Life Sci 19: 1669–1672, 1976.

    Article  PubMed  CAS  Google Scholar 

  31. Zarcone V, Barchas J, Hoddes E, Montplaisir J, Sack R, Wilson R: Experimental ethanol ingestions: Sleep variables and metabolites of dopamine and serotonin in the cerebrospinal fluid. Adv Exp Med Biol 59: 431–451, 1975.

    PubMed  CAS  Google Scholar 

  32. Ballenger JC, Goodwin FK, Major LF, et al: Alcohol and central serotonin metabolism in man. Arch Gen Psychiatry 36: 224–227, 1979.

    Article  PubMed  CAS  Google Scholar 

  33. Banki C: Factors influencing monoamine metabolites and tryptophan in patients with alcohol dependence. J Neural Trans 50: 98–101, 1981.

    Article  Google Scholar 

  34. Borg S, Kvande H, Liljeberg P, et al: 5-Hydroxyindoleacetic acid in cerebrospinal fluid in alcoholic patients under different clinical conditions. Alcohol 2: 415–418, 1985.

    Article  PubMed  CAS  Google Scholar 

  35. Baccino E, Caroff J, Menez JF, Mottier D, Floch HH: Changes in metabolites of neuroamines in CSF during withdrawal in alcoholics with hepatopaty. Alc Alcohol 22: A21, 1987.

    Google Scholar 

  36. Takhashi S, Yamane H, Kondo H, et al: CSF monoamine metabolites in alcoholism: A comparative study with depression. Folia Psychiatrica Neurologica Jap 28: 347–354, 1974.

    Google Scholar 

  37. Carlsson A, Adolfsson R, Aquilonius SM, Gottfries CG, Oreland L, Svennerholm L, Winblad B: Biogenic amines in human brain in normal aging, senile dementia and chronic alcoholism. In Goldstein, M, et al. (eds): Ergot Compounds and Brain Function: Neuroendocrine and Neuropsychiatrie Aspects. New York, Raven Press, 1980, pp 295–304.

    Google Scholar 

  38. Baccino E, Menez JF, Caroff J, Henry A, Mottier D, Floch H: Changes in serotonin uptake and storage in platelets during withdrawal of alcoholics with hepatopaty. Alc Alcohol 22: A21, 1987.

    Google Scholar 

  39. Olson RE, Gursey D, Vester JW: Evidence for defect in tryptophan metabolism in chronic alcoholism. N Engl J Med 263: 1169–1174, 1960.

    Article  PubMed  CAS  Google Scholar 

  40. Murphy GE, Guze SB, King LJ: Urinary excretion of 5-HIAA in chronic alcoholism. J Am Med Assoc 182: 167, 1962.

    Article  Google Scholar 

  41. Lawrin M, Naranjo CA, Sellers EM: Studies on the mechanism of zimelidine-induced decrease in alcohol consumption in rats. Proc Can Fed Biol Soc 26: 116, 1983.

    Google Scholar 

  42. Le Bourhis B, Uzan A, Aufrere G, et al.: Effects de l’indalpine, inhibiteur specifique de la recapture de la Serotonine sur la dependance comportementale a l’ethanol et sur la prise volontaire d’alcohol chez le rat. Ann Pharm Fr 39: 11–20, 1981.

    PubMed  Google Scholar 

  43. Zabik, JE, Roache JD, Sidor R, Nash JF, Jr.: effects of fluoxetine on ethanol preference in the rat. Pharmacologist 24: 204, 1982.

    Google Scholar 

  44. Rockman GE, Amit Z, Carr G, et al: Attenuation of ethanol intake by 5-hydroxtryptamine uptake blockade in laboratory rats. I. Involvement of brain 5-hydroxytryptamine in the mediation of the positive reinforcing properties of ethanol. Arch Int Pharmacodyn 241: 145–159, 1979.

    Google Scholar 

  45. Hyttel J, Larsen J: Neuropharmacological mechanisms of serotonin reuptake inhibitors, in Naranjo CA, Sellers EM (eds): Research Advances in New Psychopharmacological Treatments for Alcoholism. Amsterdam, Excerpta Medica, 1985, pp 107–121.

    Google Scholar 

  46. Mendels J: Clinical experience with serotonin reuptake inhibiting antidepressants. J Clin Psychiatry 48(3 suppl): 26–30, 1987.

    PubMed  Google Scholar 

  47. Gill K, Amit Z, Ogren SO: The effects of zimelidine on voluntary ethanol consumption: Studies on the mechanism of action. Alcohol 2: 343–347, 1985.

    Article  PubMed  CAS  Google Scholar 

  48. Amit Z, Brown Z, Sutherland Z, et al: Reduction in alcohol intake in humans as a function of treatment with zimelidine: Implications for treatment, in Naranjo CA, Sellers EM (eds): Research Advances in New Psychopharmacological Treatments for Alcoholism. Amsterdam, Excerpta Medica, 1985, pp 189–198.

    Google Scholar 

  49. Naranjo CA, Sellers EM, Roach CA, Woodley DV, Sanchez-Craig M, Sykora K: Zimelidineinduced variations in alcohol intake by nondepressed heavy drinkers. Clin Pharmacol Ther 35: 374–381, 1984.

    Article  PubMed  CAS  Google Scholar 

  50. Naranjo CA, Sellers EM, Jullivan JT, Woodley DV, Kadlec K, Sykora K: The serotonin uptake inhibitor Citalopram attenuates ethanol intake. Clin Pharmacol Ther 41: 266–274, 1987.

    Article  PubMed  CAS  Google Scholar 

  51. Gorelick DA: Effect of fluoxetine on alcohol consumption in male alcoholics. Alcohol Clin Exp Res 10: 13, 1986.

    Article  Google Scholar 

  52. American Psychiatric Association: Diagnostic and Statistic Manual, Third Edition, Washington, DC, 1980, pp 169-170.

    Google Scholar 

  53. Gottheil E, Corbett LO, et al: Fixed interval drinking decisions. I. A research and treatment model. Q J Stud Alcohol 33: 311–324, 1972.

    PubMed  CAS  Google Scholar 

  54. Hwang EC, Magnussen I, Van Woert MH: Effects of chronic fluoxetine administration on serotonin metabolism. Res Commun Chem Pathol Pharmacol 29: 79–98, 1980.

    PubMed  CAS  Google Scholar 

  55. Lemberger L, Rowe H, Carmichael R, et al: Fluoxetine, a selective serotonin uptake inhibitor. Clin Pharmacol Ther 23: 421–429, 1978.

    PubMed  CAS  Google Scholar 

  56. Ogren SO, Ross B, Hall H, et al: The pharmacology of zimelidine: A 5-HT selective reuptake inhibitor. Acta Psychiatr Scand 63 (Suppl 290): 127–151, 1981.

    Article  Google Scholar 

  57. Wamsley JK, Byerley WF, McCabe RT, et al: Receptor alterations associated with serotonergic agents: An autoradiographic analysis. J Clin Psychiatry 48(3 suppl): 19–25, 1987.

    PubMed  CAS  Google Scholar 

  58. Wong DT, Reid LR, Bymaster FP, et al: Chronic effects of fluoxetine, a selective inhibitor of serotonin uptake, on neurotransmitter receptors. J Neural Transm 64: 251–269, 1985.

    Article  PubMed  CAS  Google Scholar 

  59. Blier P, DeMontigny C, Chaput Y: Modifications of the serotonin system by antidepressant treatments: Implications for the therapeutic response in major depression. J Clin Psychopharmacol 7(6 suppl): 24–35, 1987.

    Article  Google Scholar 

  60. Brown ZW, Amit Z, Sutherland A, et al: An examination of possible interactions betwen zimelidine, a serotonin uptake inhibitor, and ethanol ingested conjointly in human subjects. Neurosci Lett 27: 351–355, 1981.

    Article  PubMed  CAS  Google Scholar 

  61. Naranjo CA, Sellers E, Kaplan HL, et al: Acute kinetic and dynamic interactions of zimelidine with ethanol. Clin Pharmacol Ther 36: 654–660, 1984.

    Article  PubMed  CAS  Google Scholar 

  62. Scott DB, Fagan D, Tiplady B: Effects of amitriptyline and zimelidine in combination with ethanol. Psychopharmacology 76: 209–211, 1982.

    Article  PubMed  CAS  Google Scholar 

  63. Lemberger L, Rowe H, Bergstrom RF, et al: Effect of fluoxetine on psychomotor performance, physiologic response, and kinetics of ethanol. Clin Pharmacol Ther 37: 658–664, 1985.

    Article  PubMed  CAS  Google Scholar 

  64. Deitrich RA, Melchior CL: A critical assessment of animal models for testing new drugs for altering ethanol intake, in Naranjo CA, Sellers EM (eds): Research Advances in New Psychoparmacological Treatments for Alcoholism. Amsterdam, Excerpta Medica, 1985, pp 23–43.

    Google Scholar 

  65. Gill K, Amit Z: Effects of serotonin uptake blockade on food, water, and ethanol consumption in rats. Alcohol Clin Exp Res 11: 444–449, 1987.

    Article  PubMed  CAS  Google Scholar 

  66. Gill K, Shatz, K, Amit Z, et al: Conditioned taste aversion to ethanol induced by zimelidine. Pharmacol Biochem Behav 24: 463–468, 1986.

    Article  PubMed  CAS  Google Scholar 

  67. Zabik JE, Roache JD: 5-Hydroxytryptophan-induced conditioned taste aversion to ethanol in the rat. Pharmacol Biochem Behav 18: 785–790, 1983.

    Article  PubMed  CAS  Google Scholar 

  68. Lorden JF, Nunn WB: Effects of central and peripheral pretreatment with fluoxetine in gustatory conditioning. Pharmacol Biochem Behav 17: 435–443, 1982.

    Article  PubMed  CAS  Google Scholar 

  69. Molliver ME: Serotonergic neuronal systems: What their anatomic organization tells us about function. J Clin Psychopharmacol 7(6 suppl): 3–23, 1987.

    Google Scholar 

  70. Peroutka SJ: Serotonin receptors, in Meltzer HY (ed): Psychopharmacology, The Third Generation of Progress. New York, Raven Press, 1987, pp 303–311.

    Google Scholar 

  71. Kilpatrick GJ, Jones BJ, Tyers MB: Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding. Nature 330: 746–748, 1987.

    Article  PubMed  CAS  Google Scholar 

  72. Schinitsky MR: The Effect of Modification of Serotonergic System on Alcohol and Food Consumption. Indianapolis, Eli Lilly & Co, 1977.

    Google Scholar 

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Author information

Authors and Affiliations

  1. Alcohol and Drug Treatment Program and Behavioral Pharmacology Laboratory, Brentwood Division, VA Medical Center, Los Angeles, California, 90073, USA

    David A. Gorelick

  2. Department of Psychiatry, School of Medicine, University of California-Los Angeles, California, 90024, USA

    David A. Gorelick

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  1. David A. Gorelick
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Editors and Affiliations

  1. New York University School of Medicine, New York, New York, USA

    Marc Galanter

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Gorelick, D.A. (1989). Serotonin Uptake Blockers and the Treatment of Alcoholism. In: Galanter, M. (eds) Recent Developments in Alcoholism. Recent Developments in Alcoholism, vol 7. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-1678-5_14

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  • DOI: https://doi.org/10.1007/978-1-4899-1678-5_14

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4899-1680-8

  • Online ISBN: 978-1-4899-1678-5

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