CNS Drugs

, Volume 18, Issue 15, pp 1105–1118 | Cite as

Role of the Serotonergic System in the Neurobiology of Alcoholism

Implications for Treatment
Review Article


Preclinical studies have contributed greatly to our understanding of the neurochemical pathways associated with the development and maintenance of alcohol-seeking behaviour. These studies have demonstrated the important role of serotonin pathways, particularly as they relate to dopaminergic function, which mediates alcohol-induced reward associated with its abuse liability. Naturally, this has led to the study of serotonergic agents as treatments for alcoholism.

SSRIs do not appear to be effective treatment for a heterogeneous alcoholic group. However, they may be useful as treatment for late-onset alcoholics, or alcoholism complicated by comorbid major depression. Buspirone, a serotonin 5-HT1a partial agonist, does not appear to be an effective treatment for alcoholics without comorbid disease. Buspirone may, however, have some utility for treating alcoholics with comorbid anxiety disorder. The 5-HT2 antagonist ritanserin, at pharmacologically relevant clinical doses, does not appear to be an effective treatment for alcoholism. Ondansetron, a 5-HT3 antagonist, is an efficacious and promising medication for the treatment of early-onset alcoholism. Preliminary evidence suggests that combining the mu antagonist naltrexone with the 5-HT3 antagonist ondansetron promises to be more effective for treating alcoholism than either alone.

The differential treatment effect of SSRIs and ondansetron among various subtypes of alcoholic is intriguing. Future research is needed to understand more clearly the molecular genetic differences and the interactions of such differences with the environment that typify a particular alcoholic subtype. Such an understanding could enable us to make comfortable predictions as to which alcoholic subtype might respond best to a particular serotonergic agent, which could then be provided.


Ondansetron Naltrexone Buspirone Ritanserin Serotonergic Agent 



This work was supported by grants #AA10522-05 and AA10522-0551 from the National Institute on Alcohol Abuse and Alcoholism. I would also like to thank the following colleagues affiliated with my group (alphabetical order) — Drs N. Ait-Daoud, M. Devous, J. Hensler, M. Javors, R. Lamb, and J. Roache — for their comments in developing this hypothesis for the differential effectiveness of specific serotonergic agents in treating alcoholic subtypes. I also am grateful to Mr Robert Cormier BA for his skilled assistance in the preparation of this manuscript. The author has no potential conflicts of interest directly related to the contents of this review.


  1. 1.
    Audet MA, Descarries L, Doucet G. Quantified regional and laminar distribution of the serotonin innervation in the anterior half of adult rat cerebral cortex. J Chem Neuroanat 1989; 2: 29–44PubMedGoogle Scholar
  2. 2.
    Dahlstrom A, Fuxe K. Evidence for the existence of monoamine-containing neurons in the central nervous system: I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand 1964; 62Suppl. 232: 1–55Google Scholar
  3. 3.
    Molliver ME. Serotonergic neuronal systems: what their anatomic organization tells us about function. J Clin Psychopharmacol 1987; 7: 3S–23SPubMedCrossRefGoogle Scholar
  4. 4.
    Herve D, Pickel VM, Joh TH, et al. Serotonin axon terminals in the ventral tegmental area of the rat: fine structure and synaptic input to dopaminergic neurons. Brain Res 1987; 435: 71–83PubMedCrossRefGoogle Scholar
  5. 5.
    Nedergaard S, Hopkins C, Greenfield SA. Do nigro-striatal neurones possess a discrete dendritic modulatory mechanism? Electrophysiological evidence from the actions of amphetamine in brain slices. Exp Brain Res 1988; 69: 444–8PubMedCrossRefGoogle Scholar
  6. 6.
    Hemby SE, Johnson BA, Dworkin SI. Neurobiological basis of drug reinforcement. In: Johnson BA, Roache JD, editors. Drug addiction and its treatment: nexus of neuroscience and behavior. Philadelphia: Lippincott-Raven, 1997: 137–69Google Scholar
  7. 7.
    Bockaert J, Sebben M, Dumuis A. Pharmacological characterization of 5-hydroxytryptamine4 (5-HT4) receptors positively coupled to adenylate cyclase in adult guinea pig hippocampal membranes: effect of substituted benzamide derivatives. Mol Pharmacol 1990; 37: 408–11PubMedGoogle Scholar
  8. 8.
    Ford AP, Baxter GS, Eglen RM, et al. 5-Hydroxytryptamine stimulates cyclic AMP formation in the tunica muscularis mucosae of the rat oesophagus via 5-HT4 receptors. Eur J Pharmacol 1992; 211: 117–20PubMedCrossRefGoogle Scholar
  9. 9.
    Monferini E, Gaetani P, Rodriguez y Baena R, et al. Pharmacological characterization of the 5-hydroxytryptamine receptor coupled to adenylyl cyclase stimulation in human brain. Life Sci 1993; 52: PL61–5PubMedCrossRefGoogle Scholar
  10. 10.
    Grossman CJ, Kilpatrick GJ, Bunce KT. Development of a radioligand binding assay for 5-HT4 receptors in guinea-pig and rat brain. Br J Pharmacol 1993; 109: 618–24PubMedCrossRefGoogle Scholar
  11. 11.
    Roychowdhury S, Haas H, Anderson EG. 5-HT1A and 5-HT4 receptor colocalization on hippocampal pyramidal cells. Neuropharmacology 1994; 33: 551–7PubMedCrossRefGoogle Scholar
  12. 12.
    Waeber C, Sebben M, Grossman C, et al. [3HJ-GR113808 labels 5-HT4 receptors in the human and guinea-pig brain. Neuroreport 1993; 4: 1239–42PubMedCrossRefGoogle Scholar
  13. 13.
    Waeber C, Sebben M, Nieoullon A, et al. Regional distribution and ontogeny of 5-HT4 binding sites in rodent brain. Neuropharmacology 1994; 33: 527–41PubMedCrossRefGoogle Scholar
  14. 14.
    Andrade R, Chaput Y. 5-Hydroxytryptamine4-like receptors mediate the slow excitatory response to serotonin in the rat hippocampus. J Pharmacol Exp Ther 1991; 257: 930–7PubMedGoogle Scholar
  15. 15.
    Chaput Y, Araneda RC, Andrade R. Pharmacological and functional analysis of a novel serotonin receptor in the rat hippocampus. Eur J Pharmacol 1990; 182: 441–56PubMedCrossRefGoogle Scholar
  16. 16.
    Steward LJ, Brown DC, Stokes PR, et al. Antagonism of the (S)-zacopride-induced increase in dopamine release from rat striatal slices by the 5-HT receptor antagonist SDZ 205-557 [abstract]. Third International Union of Pharmacology Satellite Meeting on Serotonin; 1994 Jul 30–Aug 3; Chicago: 84Google Scholar
  17. 17.
    Steward LJ, Barnes NM. The 5-HT4 receptor agonists renzapride and (S)-zacopride stimulate dopamine release from rat striatal slices [abstract]. Br J Pharmacol 1994; 111 Suppl.: 155PGoogle Scholar
  18. 18.
    Myers RD, Veale WL. Alcohol preference in the rat: reduction following depletion of brain serotonin. Science 1968; 160: 1469–71PubMedCrossRefGoogle Scholar
  19. 19.
    Nachman M, Lester D, Le Magnen J. Alcohol aversion in the rat: behavioral assessment of noxious drug effects. Science 1970; 168: 1244–6PubMedCrossRefGoogle Scholar
  20. 20.
    Daoust M, Chretien P, Moore N, et al. Isolation and striatal (3H) serotonin uptake: role in the voluntary intake of ethanol by rats. Pharmacol Biochem Behav 1985; 22: 205–8PubMedCrossRefGoogle Scholar
  21. 21.
    Geller I. Effects of para-chlorophenylalanine and 5-hydroxytryptophan on alcohol intake in the rat. Pharmacol Biochem Behav 1973; 1: 361–5PubMedCrossRefGoogle Scholar
  22. 22.
    Gill K, Amit Z, Koe BK. Treatment with sertraline, a new serotonin uptake inhibitor, reduces voluntary ethanol consumption in rats. Alcohol 1988; 5: 349–54PubMedCrossRefGoogle Scholar
  23. 23.
    Gill K, Filion Y, Amit Z. A further examination of the effects of sertraline on voluntary ethanol consumption. Alcohol 1988; 5: 355–8PubMedCrossRefGoogle Scholar
  24. 24.
    Zabik JE, Binkerd K, Roache JD. Serotonin and ethanol aversion in the rat. In: Naranjo CA, Sellers EM, editors. Research advances in new psychopharmacological treatments for alcoholism: proceedings of the symposium; 1984 Oct 4–5; Toronto. Amsterdam: Excerpta Medica, 1985Google Scholar
  25. 25.
    Blundell JE, Latham CJ. Behavioural pharmacology of feeding. In: Silverstone T, editor. Drugs and appetite. London: Academic Press, 1982Google Scholar
  26. 26.
    Blundell JE. Serotonin and appetite. Neuropharmacology 1984; 23: 1537–51PubMedCrossRefGoogle Scholar
  27. 27.
    Gill K, Amit Z. Serotonin uptake blockers and voluntary alcohol consumption: a review of recent studies. Recent Dev Alcohol 1989; 7: 225–48PubMedGoogle Scholar
  28. 28.
    Gottfries CG. Influence of depression and antidepressants on weight. Acta Psychiatr Scand Suppl 1981; 290: 353–6PubMedCrossRefGoogle Scholar
  29. 29.
    Simpson RJ, Lawton DJ, Watt MH, et al. Effect of zimelidine, a new antidepressant, on appetite and body weight. Br J Clin Pharmacol 1981; 11: 96–8PubMedCrossRefGoogle Scholar
  30. 30.
    Leander JD. Fluoxetine suppresses palatability-induced ingestion. Psychopharmacology 1987; 91: 285–7PubMedCrossRefGoogle Scholar
  31. 31.
    Stellar JR, Stellar E. The neurobiology of motivation and reward. New York: Springer-Verlag, 1985CrossRefGoogle Scholar
  32. 32.
    Barreto Medeiros JM, Cabrai Filho JE, De Souza SL, et al. Early malnourished rats are not affected by anorexia induced by a selective serotonin reuptake inhibitor in adult life. Nutr Neurosci 2002; 5: 211–4PubMedCrossRefGoogle Scholar
  33. 33.
    Wurtman JJ, Wurtman RJ. Fenfluramine and fluoxetine spare protein consumption while suppressing caloric intake by rats. Science 1977; 198: 1178–80PubMedCrossRefGoogle Scholar
  34. 34.
    Wurtman JJ, Wurtman RJ. Drugs that enhance central serotoninergic transmission diminish elective carbohydrate consumption by rats. Life Sci 1979; 24: 895–903PubMedCrossRefGoogle Scholar
  35. 35.
    Li ET, Anderson GH. 5-Hydroxytryptamine control of meal to meal composition chosen by rats. Fed Proc 1983; 42: 542–8Google Scholar
  36. 36.
    Smith GP. The physiology of the meal. In: Silverstone T, editor. Drugs and appetite. London: Academic Press, 1982Google Scholar
  37. 37.
    Fantino M. Role of sensory input in the control of food intake. J Auton Nerv Syst 1984; 10: 347–58PubMedCrossRefGoogle Scholar
  38. 38.
    Wise RA, Raptis L. Effects of pre-feeding on food-approach latency and food consumption speed in food deprived rats. Physiol Behav 1985; 35: 961–3PubMedCrossRefGoogle Scholar
  39. 39.
    Haraguchi M, Samson HH, Tolliver GA. Reduction in oral ethanol self-administration in the rat by the 5-HT uptake blocker fluoxetine. Pharmacol Biochem Behav 1990; 35: 259–62PubMedCrossRefGoogle Scholar
  40. 40.
    Murphy JM, Waller MB, Gatto GJ, et al. Effects of fluoxetine on the intragastric self-administration of ethanol in the alcohol preferring P line of rats. Alcohol 1988; 5: 283–6PubMedCrossRefGoogle Scholar
  41. 41.
    Naranjo CA, Sellers EM, Roach CA, et al. Zimelidine-induced variations in alcohol intake by nondepressed heavy drinkers. Clin Pharmacol Ther 1984; 35: 374–81PubMedCrossRefGoogle Scholar
  42. 42.
    Naranjo CA, Sellers EM, Sullivan JT, et al. The serotonin uptake inhibitor citalopram attenuates ethanol intake. Clin Pharmacol Ther 1987; 41: 266–74PubMedCrossRefGoogle Scholar
  43. 43.
    Naranjo CA, Sellers EM. Serotonin uptake inhibitors attenuate ethanol intake in problem drinkers. Recent Dev Alcohol 1989; 7: 255–66PubMedGoogle Scholar
  44. 44.
    Naranjo CA, Kadlec KE, Sanhueza P, et al. Fluoxetine differentially alters alcohol intake and other consummatory behaviors in problem drinkers. Clin Pharmacol Ther 1990; 47: 490–8PubMedCrossRefGoogle Scholar
  45. 45.
    Naranjo CA, Poulos CX, Bremner KE, et al. Citalopram decreases desirability, liking, and consumption of alcohol in alcohol-dependent drinkers. Clin Pharmacol Ther 1992; 51: 729–39PubMedCrossRefGoogle Scholar
  46. 46.
    Gorelick DA, Paredes A. Effect of fluoxetine on alcohol consumption in male alcoholics. Alcohol Clin Exp Res 1992; 16: 261–5PubMedCrossRefGoogle Scholar
  47. 47.
    Naranjo CA, Bremner KE, Lanctot KL. Effects of citalopram and a brief psycho-social intervention on alcohol intake, dependence and problems. Addiction 1995; 90: 87–99PubMedCrossRefGoogle Scholar
  48. 48.
    Kabel DI, Petty F. A placebo-controlled, double-blind study of fluoxetine in severe alcohol dependence: adjunctive pharmacotherapy during and after inpatient treatment. Alcohol Clin Exp Res 1996; 20: 780–4PubMedCrossRefGoogle Scholar
  49. 49.
    Kranzler HR, Burleson JA, Korner P, et al. Placebo-controlled trial of fluoxetine as an adjunct to relapse prevention in alcoholics. Am J Psychiatry 1995; 152: 391–7PubMedGoogle Scholar
  50. 50.
    Buydens-Branchey L, Branchey MH, Noumair D. Age of alcoholism onset: I. Relationship to psychopathology. Arch Gen Psychiatry 1989; 46: 225–30Google Scholar
  51. 51.
    Linnoila M, Virkkunen M. Biologic correlates of suicidal risk and aggressive behavioral traits. J Clin Psychopharmacol 1992; 12(2 Suppl.): 19S–20SPubMedGoogle Scholar
  52. 52.
    Linnoila M, De Jong J, Virkkunen M. Family history of alcoholism in violent offenders and impulsive fire setters. Arch Gen Psychiatry 1989; 46: 613–6PubMedCrossRefGoogle Scholar
  53. 53.
    Fils-Aime ML, Eckardt MJ, George DT, et al. Early-onset alcoholics have lower cerebrospinal fluid 5-hydroxyindoleacetic acid levels than late-onset alcoholics. Arch Gen Psychiatry 1996; 53: 211–6PubMedCrossRefGoogle Scholar
  54. 54.
    Kranzler HR, Burleson JA, Brown J, et al. Fluoxetine treatment seems to reduce the beneficial effects of cognitive-behavioral therapy in type B alcoholics. Alcohol Clin Exp Res 1996; 20: 1534–41PubMedCrossRefGoogle Scholar
  55. 55.
    Pettinati HM, Volpicelli JR, Kranzler HR, et al. Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype. Alcohol Clin Exp Res 2000; 24: 1041–9PubMedCrossRefGoogle Scholar
  56. 56.
    Johnson BA, Cloninger CR, Roache JD, et al. Age of onset as a discriminator between alcoholic subtypes in a treatment-seeking outpatient population. Am J Addict 2000; 9: 17–27PubMedCrossRefGoogle Scholar
  57. 57.
    Johnson BA, Ait-Daoud N. Neuropharmacological treatments for alcoholism: scientific basis and clinical findings. Psychopharmacology 2000; 149: 327–44PubMedCrossRefGoogle Scholar
  58. 58.
    Cornelius JR, Salloum IM, Ehler JG, et al. Fluoxetine in depressed alcoholics: a double-blind, placebo-controlled trial. Arch Gen Psychiatry 1997; 54: 700–5PubMedCrossRefGoogle Scholar
  59. 59.
    Mason BJ, Kocsis JH, Ritvo EC, et al. A double-blind, placebo-controlled trial of desipramine for primary alcohol dependence stratified on the presence or absence of major depression. JAMA 1996; 275: 761–7PubMedCrossRefGoogle Scholar
  60. 60.
    McGrath PJ, Nunes EV, Stewart JW, et al. Imipramine treatment of alcoholics with primary depression: a placebo-controlled clinical trial. Arch Gen Psychiatry 1996; 53: 232–40PubMedCrossRefGoogle Scholar
  61. 61.
    Pettinati HM, Volpicelli JR, Luck G, et al. Double-blind clinical trial of sertraline treatment for alcohol dependence. J Clin Psychopharmacol 2001; 21: 143–53PubMedCrossRefGoogle Scholar
  62. 62.
    Collins DM, Myers RD. Buspirone attenuates volitional alcohol intake in the chronically drinking monkey. Alcohol 1987; 4: 49–56PubMedCrossRefGoogle Scholar
  63. 63.
    Privette TH, Hornsby RL, Myers RD. Buspirone alters alcohol drinking induced in rats by tetrahydropapaveroline injected into brain monoaminergic pathways. Alcohol 1988; 5: 147–52PubMedCrossRefGoogle Scholar
  64. 64.
    Meert TF. Effects of various serotonergic agents on alcohol intake and alcohol preference in Wistar rats selected at two different levels of alcohol preference. Alcohol Alcohol 1993; 28: 157–70PubMedGoogle Scholar
  65. 65.
    Wilson AW, Costall B, Neill JC. Manipulation of operant responding for an ethanol-paired conditioned stimulus in the rat by pharmacological alteration of the serotonergic system. J Psychopharmacol 2000; 14: 340–6PubMedCrossRefGoogle Scholar
  66. 66.
    Rezvani AH, Overstreet DH, Janowsky DS. Genetic serotonin deficiency and alcohol preference in the fawn hooded rats. Alcohol Alcohol 1990; 25: 573–5PubMedGoogle Scholar
  67. 67.
    Gongwer MA, Murphy JM, McBride WJ, et al. Regional brain contents of serotonin, dopamine and their metabolites in the selectively bred high- and low-alcohol drinking lines of rats. Alcohol 1989; 6: 317–20PubMedCrossRefGoogle Scholar
  68. 68.
    McBride WJ, Bodart B, Lumeng L, et al. Association between low contents of dopamine and serotonin in the nucleus accumbens and high alcohol preference. Alcohol Clin Exp Res 1995; 19: 1420–2PubMedCrossRefGoogle Scholar
  69. 69.
    Korpi ER, Paivarinta P, Abi-Dargham A, et al. Binding of serotonergic ligands to brain membranes of alcohol-preferring AA and alcohol-avoiding ANA rats. Alcohol 1992; 9: 369–74PubMedCrossRefGoogle Scholar
  70. 70.
    Blier P, Ward NM. Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiatry 2003; 53: 193–203PubMedCrossRefGoogle Scholar
  71. 71.
    Malcolm R, Anton RF, Randall CL, et al. A placebo-controlled trial of buspirone in anxious inpatient alcoholics. Alcohol Clin Exp Res 1992; 16: 1007–13PubMedCrossRefGoogle Scholar
  72. 72.
    Kranzler HR, Burleson JA, Del Boca FK, et al. Buspirone treatment of anxious alcoholics: a placebo-controlled trial. Arch Gen Psychiatry 1994; 51: 720–31PubMedCrossRefGoogle Scholar
  73. 73.
    Bruno F. Buspirone in the treatment of alcoholic patients. Psychopathology 1989; 22Suppl. 1: 49–59PubMedCrossRefGoogle Scholar
  74. 74.
    Malec TS, Malec EA, Dongier M. Efficacy of buspirone in alcohol dependence: a review. Alcohol Clin Exp Res 1996; 20: 853–8PubMedCrossRefGoogle Scholar
  75. 75.
    George DT, Rawlings R, Eckardt MJ, et al. Buspirone treatment of alcoholism: age of onset, and cerebrospinal fluid 5-hydroxyindolacetic acid and homovanillic acid concentrations, but not medication treatment, predict return to drinking. Alcohol Clin Exp Res 1999; 23: 272–8PubMedGoogle Scholar
  76. 76.
    Meert TF, Awouters F, Niemegeers CJ, et al. Ritanserin reduces abuse of alcohol, cocaine, and fentanyl in rats. Pharmacopsychiatry 1991; 24: 159–63PubMedCrossRefGoogle Scholar
  77. 77.
    Myers RD, Lankford M, Bjork A. Selective reduction by the 5-HT antagonist amperozide of alcohol preference induced in rats by systemic cyanamide. Pharmacol Biochem Behav 1992; 43: 661–7PubMedCrossRefGoogle Scholar
  78. 78.
    Svensson L, Fahlke C, Hard E, et al. Involvement of the serotonergic system in ethanol intake in the rat. Alcohol 1993; 10: 219–24PubMedCrossRefGoogle Scholar
  79. 79.
    Myers RD, Lankford MF. Suppression of alcohol preference in high alcohol drinking rats: efficacy of amperozide versus naltrexone. Neuropsychopharmacology 1996; 14: 139–49PubMedCrossRefGoogle Scholar
  80. 80.
    Myers RD, Lankford M. Action of the 5-HT2A antagonist amperozide on alcohol-induced poikilothermia in rats. Pharmacol Biochem Behav 1998; 59: 91–5PubMedCrossRefGoogle Scholar
  81. 81.
    Biggs TA, Myers RD. Naltrexone and amperozide modify chocolate and saccharin drinking in high alcohol-preferring P rats. Pharmacol Biochem Behav 1998; 60: 407–13PubMedCrossRefGoogle Scholar
  82. 82.
    Overstreet DH, McArthur RA, Rezvani AH, et al. Selective inhibition of alcohol intake in diverse alcohol-preferring rat strains by the 5-HT2A antagonists amperozide and FG5974. Alcohol Clin Exp Res 1997; 21: 1448–54PubMedCrossRefGoogle Scholar
  83. 83.
    Lankford MF, Bjork AK, Myers RD. Differential efficacy of serotonergic drugs FG5974, FG5893, and amperozide in reducing alcohol drinking in P rats. Alcohol 1996; 13: 399–404PubMedCrossRefGoogle Scholar
  84. 84.
    Ugedo L, Grenhoff J, Svensson TH. Ritanserin, a 5-HT2 receptor antagonist, activates midbrain dopamine neurons by blocking serotonergic inhibition. Psychopharmacology 1989; 98: 45–50PubMedCrossRefGoogle Scholar
  85. 85.
    Awouters F, Niemegeers CJ, Megens AA, et al. The pharmacological profile of ritanserin, a very specific central serotonin-S2 antagonist. Drug Dev Res 1988; 15: 61–73CrossRefGoogle Scholar
  86. 86.
    Johnson BA, Jasinski DR, Galloway GP, et al. Ritanserin in the treatment of alcohol dependence: a multi-center clinical trial. Ritanserin Study Group. Psychopharmacology 1996; 128: 206–15CrossRefGoogle Scholar
  87. 87.
    Wiesbeck GA, Weijers HG, Chick J, et al. Ritanserin in relapse prevention in abstinent alcoholics: results from a placebocontrolled double-blind international multicenter trial. Ritanserin in Alcoholism Work Group. Alcohol Clin Exp Res 1999; 23: 230–5Google Scholar
  88. 88.
    LeMarquand D, Pihl RO, Benkelfat C. Serotonin and alcohol intake, abuse, and dependence: clinical evidence. Biol Psychiatry 1994; 36: 326–37PubMedCrossRefGoogle Scholar
  89. 89.
    Lovinger DM, White G. Ethanol potentiation of 5-hydroxytryptamine3 receptor-mediated ion current in neuroblastoma cells and isolated adult mammalian neurons. Mol Pharmacol 1991; 40: 263–70PubMedGoogle Scholar
  90. 90.
    Zhou Q, Lovinger DM. Pharmacologic characteristics of potentiation of 5-HT3 receptors by alcohols and diethyl ether in NCB-20 neuroblastoma cells. J Pharmacol Exp Ther 1996; 278: 732–40PubMedGoogle Scholar
  91. 91.
    Lovinger DM, Zhou Q. Alcohols potentiate ion current mediated by recombinant 5-HT3RA receptors expressed in a mammalian cell line. Neuropharmacology 1994; 33: 1567–72PubMedCrossRefGoogle Scholar
  92. 92.
    Lovinger DM. Inhibition of 5-HT3 receptor-mediated ion current by divalent metal cations in NCB-20 neuroblastoma cells. J Neurophysiol 1991; 66: 1329–37PubMedGoogle Scholar
  93. 93.
    Lovinger DM. Ethanol potentiates ion current mediated by 5-HT3 receptors on neuroblastoma cells and isolated neurons. Alcohol Alcohol Suppl 1991; 1: 181–5PubMedGoogle Scholar
  94. 94.
    Lovinger DM. 5-HT3 receptors and the neural actions of alcohols: an increasingly exciting topic. Neurochem Int 1999; 35: 125–30PubMedCrossRefGoogle Scholar
  95. 95.
    Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 1988; 85: 5274–8PubMedCrossRefGoogle Scholar
  96. 96.
    Koob GF. Neural mechanisms of drug reinforcement. Ann N Y Acad Sci 1992; 654: 171–91PubMedCrossRefGoogle Scholar
  97. 97.
    Wise RA, Bozarth MA. A psychomotor stimulant theory of addiction. Psychol Rev 1987; 94: 469–92PubMedCrossRefGoogle Scholar
  98. 98.
    Bloom FE, Morales M. The central 5-HT3 receptor in CNS disorders. Neurochem Res 1998; 23: 653–9PubMedCrossRefGoogle Scholar
  99. 99.
    Kilpatrick GJ, Jones BJ, Tyers MB. Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding. Nature 1987; 330: 746–8PubMedCrossRefGoogle Scholar
  100. 100.
    Kilpatrick GJ, Hagan RM, Gale JD. 5-HT3 and 5-HT4 receptors in terminal regions of the mesolimbic system. Behav Brain Res 1996; 73: 11–3PubMedCrossRefGoogle Scholar
  101. 101.
    Oxford AW, Bell JA, Kilpatrick GJ, et al. Ondansetron and related 5-HT3 antagonists: recent advances. Prog Med Chem 1992; 29: 239–70PubMedCrossRefGoogle Scholar
  102. 102.
    Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology 1999; 38: 1083–152PubMedCrossRefGoogle Scholar
  103. 103.
    Johnson BA, Cowen PJ. Alcohol-induced reinforcement: dopamine and 5-HT3 receptor interactions in animals and humans. Drug Dev Res 1993; 30: 153–69CrossRefGoogle Scholar
  104. 104.
    Bradbury AJ, Costall B, Domeney AM, et al. Laterality of dopamine function and neuroleptic action in the amygdala in the rat. Neuropharmacology 1985; 24: 1163–70PubMedCrossRefGoogle Scholar
  105. 105.
    Hagan RM, Jones BJ, Jordan CC, et al. Effect of 5-HT3 receptor antagonists on responses to selective activation of mesolimbic dopaminergic pathways in the rat. Br J Pharmacol 1990; 99: 227–32PubMedCrossRefGoogle Scholar
  106. 106.
    Eison AS, Iversen SD, Sandberg BE, et al. Substance P analog, DiMe-C7: evidence for stability in rat brain and prolonged central actions. Science 1982; 215: 188–90PubMedCrossRefGoogle Scholar
  107. 107.
    Costall B, Domeney AM, Naylor RJ, et al. Effects of the 5-HT3 receptor antagonist, GR38032F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain. Br J Pharmacol 1987; 92: 881–94PubMedCrossRefGoogle Scholar
  108. 108.
    Hodge CW, Samson HH, Lewis RS, et al. Specific decreases in ethanol-but not water-reinforced responding produced by the 5-HT3 antagonist ICS 205-930. Alcohol 1993; 10: 191–6PubMedCrossRefGoogle Scholar
  109. 109.
    Fadda F, Garau B, Marchei F, et al. MDL 72222, a selective 5-HT3 receptor antagonist, suppresses voluntary ethanol consumption in alcohol-preferring rats. Alcohol Alcohol 1991; 26: 107–10PubMedGoogle Scholar
  110. 110.
    Rodd-Henricks ZA, McKinzie DL, Li T-K, et al. Intracranial self-administration of ethanol into the posterior VTA of Wistar rats is mediated by 5-HT3 receptors [abstract]. Alcohol Clin Exp Res 1999; 23Suppl. 5: 49AGoogle Scholar
  111. 111.
    McBride WJ, Li TK. Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in rodents. Crit Rev Neurobiol 1998; 12: 339–69PubMedCrossRefGoogle Scholar
  112. 112.
    Tomkins DM, Le AD, Sellers EM. Effect of the 5-HT3 antagonist ondansetron on voluntary ethanol intake in rats and mice maintained on a limited access procedure. Psychopharmacology 1995; 117: 479–85PubMedCrossRefGoogle Scholar
  113. 113.
    Beardsley PM, Lopez OT, Gullikson G, et al. Serotonin 5-HT3 antagonists fail to affect ethanol self-administration of rats. Alcohol 1994; 11: 389–95PubMedCrossRefGoogle Scholar
  114. 114.
    Johnson BA, Campling GM, Griffiths P, et al. Attenuation of some alcohol-induced mood changes and the desire to drink by 5-HT3 receptor blockade: a preliminary study in healthy male volunteers. Psychopharmacology 1993; 112: 142–4PubMedCrossRefGoogle Scholar
  115. 115.
    Swift RM, Davidson D, Whelihan W, et al. Ondansetron alters human alcohol intoxication. Biol Psychiatry 1996; 40: 514–21PubMedCrossRefGoogle Scholar
  116. 116.
    Doty P, Zacny JP, de Wit H. Effects of ondansetron pretreatment on acute responses to ethanol in social drinkers. Behav Pharmacol 1994; 5: 461–9PubMedCrossRefGoogle Scholar
  117. 117.
    Sellers EM, Toneatto T, Romach MK, et al. Clinical efficacy of the 5-HT3 antagonist ondansetron in alcohol abuse and dependence. Alcohol Clin Exp Res 1994; 18: 879–85PubMedCrossRefGoogle Scholar
  118. 118.
    Johnson BA, Roache JD, Javors MA, et al. Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: a randomized controlled trial. JAMA 2000; 284: 963–71PubMedCrossRefGoogle Scholar
  119. 119.
    Johnson BA, Roache JD, Ait-Daoud N, et al. Ondansetron reduces the craving of biologically predisposed alcoholics. Psychopharmacology 2002; 160: 408–13PubMedCrossRefGoogle Scholar
  120. 120.
    Kranzler HR, Pierucci-Lagha A, Feinn R, et al. Effects of ondansetron in early-versus late-onset alcoholics: a prospective, open-label study. Alcohol Clin Exp Res 2003; 27: 1150–5PubMedCrossRefGoogle Scholar
  121. 121.
    Heils A, Teufel A, Petri S, et al. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996; 66: 2621–4PubMedCrossRefGoogle Scholar
  122. 122.
    Heils A, Mossner R, Lesch KP. The human serotonin transporter gene polymorphism: basic research and clinical implications. J Neural Transm 1997; 104: 1005–14PubMedCrossRefGoogle Scholar
  123. 123.
    Lesch KP, Meyer J, Glatz K, et al. The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective. Alternative biallelic variation in rhesus monkeys: rapid communication. J Neural Transm 1997; 104: 1259–66Google Scholar
  124. 124.
    Greenberg BD, Tolliver TJ, Huang SJ, et al. Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet 1999; 88: 83–7PubMedCrossRefGoogle Scholar
  125. 125.
    Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274: 1527–31PubMedCrossRefGoogle Scholar
  126. 126.
    Johnson BA. Serotonergic agents and alcoholism treatment: rebirth of the subtype concept: an hypothesis. Alcohol Clin Exp Res 2000; 24: 1597–601PubMedGoogle Scholar
  127. 127.
    Heinz A, Jones DW, Mazzanti C, et al. A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol Psychiatry 2000; 47: 643–9PubMedCrossRefGoogle Scholar
  128. 128.
    Enoch M-A, Schuckit MA, Johnson BA, et al. Genetics of alcoholism using intermediate phenotypes. Alcohol Clin Exp Res 2003; 27: 169–76PubMedCrossRefGoogle Scholar
  129. 129.
    Bisaga A, Sikora J, Kostowski W. The effect of drags interacting with serotonergic 5HT3 and 5HT4 receptors on morphine place conditioning. Pol J Pharmacol 1993; 45: 513–9PubMedGoogle Scholar
  130. 130.
    Panocka I, Ciccocioppo R, Polidori C, et al. The 5-HT4 receptor antagonist, GR113808, reduces ethanol intake in alcohol-preferring rats. Pharmacol Biochem Behav 1995; 52: 255–9PubMedCrossRefGoogle Scholar
  131. 131.
    Barnes JM, Barnes NM, Champaneria S, et al. Characterisation and autoradiographic localisation of 5-HT3 receptor recognition sites identified with [3H]-(S)-zacopride in the forebrain of the rat. Neuropharmacology 1990; 29: 1037–45PubMedCrossRefGoogle Scholar
  132. 132.
    Perry DC. Autoradiography of [3H]quipazine in rodent brain. Eur J Pharmacol 1990; 187: 75–85PubMedCrossRefGoogle Scholar
  133. 133.
    Yoshimoto K, McBride WJ. Regulation of nucleus accumbens dopamine release by the dorsal raphe nucleus in the rat. Neurochem Res 1992; 17: 401–7PubMedCrossRefGoogle Scholar
  134. 134.
    Campbell AD, McBride WJ. Serotonin-3 receptor and ethanol-stimulated dopamine release in the nucleus accumbens. Pharmacol Biochem Behav 1995; 51: 835–42PubMedCrossRefGoogle Scholar
  135. 135.
    Gianoulakis C. The effect of ethanol on the biosynthesis and regulation of opioid peptides. Experientia 1989; 45: 428–35PubMedCrossRefGoogle Scholar
  136. 136.
    Reid LD, Hunter GA. Morphine and naloxone modulate intake of ethanol. Alcohol 1984; 1: 33–7PubMedCrossRefGoogle Scholar
  137. 137.
    Hubbell CL, Czirr SA, Reid LD. Persistence and specificity of small doses of morphine on intake of alcoholic beverages. Alcohol 1987; 4: 149–56PubMedCrossRefGoogle Scholar
  138. 138.
    Hubbell CL, Czirr SA, Hunter GA, et al. Consumption of ethanol solution is potentiated by morphine and attenuated by naloxone persistently across repeated daily administrations. Alcohol 1986; 3: 39–54PubMedCrossRefGoogle Scholar
  139. 139.
    Carboni E, Acquas E, Leone P, et al. 5-HT3 receptor antagonists block morphine- and nicotine-induced place-preference conditioning. Eur J Pharmacol 1988; 151: 159–60PubMedCrossRefGoogle Scholar
  140. 140.
    Carboni E, Acquas E, Frau R, et al. Differential inhibitory effects of a 5-HT3 antagonist on drug-induced stimulation of dopamine release. Eur J Pharmacol 1989; 164: 515–9PubMedCrossRefGoogle Scholar
  141. 141.
    Imperato A, Angelucci L. 5-HT3 receptors control dopamine release in the nucleus accumbens of freely moving rats. Neurosci Lett 1989; 101: 214–7PubMedCrossRefGoogle Scholar
  142. 142.
    Pei Q, Zetterstrom T, Leslie RA, et al. 5-HT3 receptor antagonists inhibit morphine-induced stimulation of mesolimbic dopamine release and function in the rat. Eur J Pharmacol 1993; 230: 63–8PubMedCrossRefGoogle Scholar
  143. 143.
    Matsuzawa S, Suzuki T, Misawa M, et al. Roles of 5-HT3 and opioid receptors in the ethanol-induced place preference in rats exposed to conditioned fear stress. Life Sci 1999; 64: PL241–9PubMedCrossRefGoogle Scholar
  144. 144.
    Widdowson PS, Holman RB. Ethanol-induced increase in endogenous dopamine release may involve endogenous opiates. J Neurochem 1992; 59: 157–63PubMedCrossRefGoogle Scholar
  145. 145.
    Le AD, Sellers EM. Interaction between opiate and 5-HT3 receptor antagonists in the regulation of alcohol intake. Alcohol Alcohol Suppl 1994; 2: 545–9PubMedGoogle Scholar
  146. 146.
    Volpicelli JR, Rhines KC, Rhines JS, et al. Naltrexone and alcohol dependence: role of subject compliance. Arch Gen Psychiatry 1997; 54: 737–42PubMedCrossRefGoogle Scholar
  147. 147.
    Gale JD. Serotonergic mediation of vomiting. J Pediatr Gastroenterol Nutr 1995; 21Suppl. 1: S22–8PubMedCrossRefGoogle Scholar
  148. 148.
    Wilde MI, Markham A. Ondansetron: a review of its pharmacology and preliminary clinical findings in novel applications. Drugs 1996; 52: 773–94PubMedCrossRefGoogle Scholar
  149. 149.
    Johnson BA, Ait-Daoud N, Prihoda TJ. Combining ondansetron and naltrexone effectively treats biologically predisposed alcoholics: from hypotheses to preliminary clinical evidence. Alcohol Clin Exp Res 2000; 24: 737–42PubMedCrossRefGoogle Scholar
  150. 150.
    Ait-Daoud N, Johnson BA, Javors M, et al. Combining ondansetron and naltrexone treats biological alcoholics: corroboration of self-reported drinking by serum carbohydrate deficient transferrin, a biomarker. Alcohol Clin Exp Res 2001; 25: 847–9PubMedCrossRefGoogle Scholar
  151. 151.
    Le AD, Poulos CX, Harding S, et al. Effects of naltrexone and fluoxetine on alcohol self-administration and reinstatement of alcohol seeking induced by priming injections of alcohol and exposure to stress. Neuropsychopharmacology 1999; 21: 435–44PubMedCrossRefGoogle Scholar
  152. 152.
    Gardell LR, Whalen CA, Chattophadyay S, et al. Combination of naltrexone and fluoxetine on rats’ propensity to take alcoholic beverage. Alcohol Clin Exp Res 1997; 21: 1435–9PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.University of Virginia Health SystemCharlottesvilleUSA

Personalised recommendations