10. Serotonergic compounds - clinical data

Editors: Spanagel, Rainer; Mann, Karl F.

Title: Drugs for Relapse Prevention of Alcoholism, 1st Edition

Copyright 2005 Springer

> Table of Contents > Serotonergic compounds: clinical data

Serotonergic compounds: clinical data

Bankole A. Johnson

South Texas Addiction Research & Technology Center, Departments of Psychiatry and Pharmacology, The University of Texas Health Science Center at San Antonio, 3939 Medical Drive, Suite 100, San Antonio, Texas 78229-3900, USA, and Departments of Psychiatric Medicine and Neuroscience, University of Virginia, P.O. Box 800623, Charlottesville, VA 22908-0623, USA


In the last two decades, serotonergic agents have been studied intensely as potential treatments for alcoholism. Basic science studies have implicated the serotonin (5-HT) system, and especially its interaction with midbrain and cortico-mesolimbic dopamine pathways, as being central to the expression and appreciation of alcohol's reinforcing effects associated with its abuse liability. Such studies have increased our understanding of the bio-behavioral basis of alcoholism and provided the foundation for testing medications that interact with specific 5-HT receptor subtypes as treatment for particular types of alcoholic both with and without co-morbid psychiatric disorder.

The sections of this chapter are organized, first, to briefly provide an overview of the scientific rationale for testing a particular class of serotonergic medications for treating alcoholism and, subsequently, to evaluate the reported efficacy of these agents in clinical studies.

Selective serotonin reuptake inhibitors

Ethanol preference can be altered by lesions or pharmacological manipulations that result in 5-HT depletion and reduced 5-HT turnover [1, 2]. Augmentation of serotonergic function by administration of selective serotonin reuptake inhibitors (SSRIs) decreases voluntary ethanol consumption in preference paradigms [3, 4, 5, 6 and 7]. SSRI-associated suppression of ethanol consumption may be due to a decrease in the reinforcing effects of alcohol as well as an effect of SSRIs to reduce consummatory behavior [8, 9 and 10]. Operant studies show that the SSRI, fluoxetine, dose-dependently decreases ethanol responding [11, 12]. Hence, the results of basic science studies suggest that SSRIs would be efficacious in treating alcohol dependence.

Clinical data on the utility of SSRIs as a single agent for the treatment of alcoholics without major depressive disorder have been inconsistent. Early clinical trials of small sample size reported that SSRIs could produce short-term


(1-4 weeks) reductions in alcohol consumption among problem drinkers [13, 14, 15, 16 and 17]. Nevertheless, these studies had three additional limitations. First, the cohort was predominantly male [13, 14 and 15], thereby reducing the generalizability of the results to women. Second, standardized psychosocial treatments, which have a tendency to diminish the effect size of the response to pharmacotherapy, were used infrequently; hence, non-specific factors might be responsible for at least some of the clinical improvement that was observed. Third, the short treatment period did not allow for determination of whether SSRI-related clinical improvement in problem drinkers was sustained. Studies that have employed longer SSRI treatment periods have not demonstrated efficacy. For example, Gorelick and Paredes [18] showed that an initial dramatic decrease in alcohol consumption (approx. 15%) during the first of four weeks in a clinical trial did not result in an overall therapeutic treatment response for fluoxetine compared with placebo over the entire trial period. Naranjo and co-workers [19] also were unable to show differences in alcohol consumption between the SSRI, citalopram (40 mg/day), and placebo after 12 weeks of treatment. Kabel and Petty [20] also did not find 12 weeks of fluoxetine (60 mg/day) treatment to be superior to placebo at reducing drinking among 28 alcohol-dependent men. Furthermore, Kranzler and colleagues [21], in a well-executed 12-week study, did not find fluoxetine 60 mg/day to be superior to placebo in treating alcoholism. Interestingly, predicated on the findings of human laboratory studies that alcoholics with an early onset of disease may have reduced 5-HT levels [22, 23, 24 and 25], Kranzler and colleagues [26] re-analyzed their data. Presumably, their premise was that if type B alcoholics, or those who develop the disease early in life, were deficient in 5-HT, then SSRIs would be expected to be particularly beneficial for this alcoholic subtype. Paradoxically, fluoxetine appeared to actually worsen rather than improve the clinical benefit of the adjunctive cognitive behavioral therapy, and it was certainly no better than placebo. Interestingly, Pettinati and colleagues [27] have shown that sertraline (another SSRI) appears to improve the drinking outcomes of type A alcoholics, or those who develop the disease later in life. Early-onset (i.e., type B-like) alcoholics differ from late-onset (i.e., type A-like) alcoholics by having greater family history and greater propensity toward impulse dyscontrol, serotonergic dysfunction, and antisocial behaviors [28, 29]. It is, therefore, tempting to speculate that the relationship between 5-HT dysfunction and the onset of alcoholism might not be a simple deficiency state but may be due to more fundamental biological differences within the 5-HT system [30, 31].

Although outside the scope of this chapter, SSRIs may be useful in treating alcoholics with severe co-morbid major depression [32]; however, further studies are needed to fully characterize these results, given that tricyclic antidepressants provided to similar populations in other studies have been shown to reduce the dysphoric symptoms with little effect on drinking behavior [33, 34].

In conclusion, SSRIs are not efficacious at improving the drinking outcomes of a heterogeneous alcoholic group. SSRIs may, however, be useful as


treatment for alcoholics who develop the disease later in life, or alcoholics with co-morbid major depression.

5-HT1 partial agonists

The 5-HT1A partial agonist, buspirone, reduces ethanol consumption in a variety of animal paradigms. For instance, buspirone decreases volitional ethanol consumption by up to 60% in macaque monkeys [35]. Also, buspirone suppresses ethanol intake in Sprague-Dawley rats induced to drink by repeated brain-stem injection of tetrahydropapaveroline [36]. Dose-specific effects of buspirone to suppress ethanol intake also have been reported among medium alcohol-preferring rats [37]. Further, buspirone decreases stimulus-conditioned responding for ethanol [38]. Results of studies conducted with relatively 5-HT-deficient Fawn-Hooded rats show that they have a high propensity toward ethanol consumption [39]; correspondingly, alcohol-preferring rats, compared with their non-alcohol-preferring counterparts, have reduced cortical and subcortical gray matter reductions in 5-HT [40, 41 c.f. 42]. Hence, enhancing 5-HT neurotransmission should decrease ethanol consumption. 5-HT1A receptors manifest differential sensitivity, the greater effect being seen at the postsynaptic receptor compared with the autoreceptor. Chronic buspirone administration, therefore, raises 5-HT function and down-regulates autoreceptor function [43]. Despite the paucity of operant dose-response studies examining buspirone's effects on ethanol consumption, there appears to be ample foundation for testing its efficacy as a treatment agent for alcoholism.

Generally, the results of clinical trials do not support a finding of efficacy for buspirone in treating alcoholics without concurrent co-morbid anxiety disorder. Indeed, Malcolm and colleagues [44] did not find that buspirone was superior to placebo at decreasing either the symptoms of anxiety or drinking among anxious alcoholics. In a similarly well-executed trial (N = 61), Kranzler and co-workers [45] did not find buspirone to be an efficacious treatment for alcoholism. An authoritative review of five published studies and a more recent re-evaluation of the data [46] also did not support the utility of buspirone in treating alcoholics; however, in contrast to the study of Kranzler and colleagues [45], alcoholics with co-morbid anxiety disorder appeared to derive therapeutic benefit [47, 48]. Finally, George and colleagues [49] showed that the younger the age of onset, the lower was the cerebrospinal fluid level of 5-HT's major metabolite, 5-hydroxyindole-acetic acid (5-HIAA). Despite the likelihood of 5-HT facilitation by chronic buspirone treatment, buspirone was not superior to placebo at improving the drinking outcomes of early-onset alcoholics. Again, this demonstrates that the apparent 5-HT dysfunction among alcoholics early in life may have complex bio-genetic underpinnings.

In sum, buspirone does not appear to be an effective treatment for alcoholics without co-morbid disease. Buspirone may, however, be useful in treating alcoholics with co-morbid anxiety disorder.


5-HT2 antagonists

Animal studies show that the 5-HT2 receptor antagonist, ritanserin, can reduce ethanol consumption in a variety of paradigms [50, 51 c.f. 52]. Other 5-HT2 antagonists such as amperozide [53, 54 and 55] and FG 5974 [56, 57] also appear to be effective at attenuating ethanol intake [56]. Mechanistically, 5-HT2 receptor antagonist-mediated acute anti-ethanol-drinking behavior may be attributable to substitution for alcohol's pharmaco-behavioral effects through increased levels of burst firing in cortico-mesolimbic dopamine neurons [58] and, later, reciprocal feedback inhibition of dopaminergic activity [59].

In a large (N = 423) multi-center, randomized, double-blind clinical trial by Johnson and colleagues [60], ritanserin (2.5 mg/day or 5 mg/day) was not significantly superior to placebo at improving drinking outcomes. Furthermore, in a later study using a similar methodology, even the higher ritanserin dose of 10 mg/day, compared with placebo, showed no efficacy in treating alcoholism [61]. While it is tempting to speculate that even higher ritanserin doses may show efficacy in treating alcoholism, the potential to test this possibility is limited by ritanserin's ability to produce dose-dependent prolongation of the QTc interval on the electrocardiogram, thereby increasing the potential for serious cardiac arrhythmias and, consequently, sudden death.

In conclusion, ritanserin (2.5 mg/day to 10 mg/day) is not an efficacious treatment for alcoholism. At present, there are no double-blind data from controlled clinical trials on the use of other 5-HT2 antagonists as a treatment for alcoholism.

5-HT3 antagonists

The 5-HT3 antagonist, ondansetron, is a promising medication for treating alcoholism [62]. Basic science studies show that ethanol potentiates 5-HT3 receptor-mediated ion currents in NCB-20 neuroblastoma cells [63, 64] and human embryonic kidney 293 cells transfected with 5-HT3RA cDNA [65]. 5-HT3 receptor antagonists block these effects [66]. Hence, the 5-HT3 receptor is an important site of action for ethanol's effects in the brain [67, 68]. Pharmaco-behavioral studies show that 5-HT3 receptor antagonists attenuate dopamine or ethanol-induced hyperlocomotion in the rat [69], suppress DiMe-C7 (a neurokinin)-induced hyperlocomotion, an effect also diminished by the dopamine antagonist, fluphenazine [70, 71], and reduce alcohol consumption in a variety of animal models and across different species [37, 72, 73, 74, 75, 76, 77 and 78 c.f. 79]. Hence, preclinical studies show that 5-HT3 receptor antagonists are promising medications for treating alcoholism. In humans, ondansetron reduces alcohol's positive subjective effects [80, 81 c.f. 82] and preference for alcohol [83]. Based upon the promising basic science, animal, and human laboratory data, rigorous double-blind clinical studies were needed to test ondansetron's efficacy in treating alcoholism.


In a preliminary 6-week double-blind clinical trial of non-severely alcohol-dependent males (N = 71), Sellers and colleagues [84] showed that ondansetron 0.5 mg/day, but not 4 mg/day, was associated with a non-significant trend (p = 0.06) toward a reduction in alcohol consumption. When those who consumed more than 10 standard drinks/drinking day (N = 11) were excluded from consideration during secondary data analysis, there was a significant treatment effect in favor of ondansetron 0.5 mg/day compared with placebo (p = 0.001). Justification for excluding this group was that such severe drinkers would typically not be enrolled in contemporary clinical trials (and are more likely to have received inpatient treatment), as their persistent level of intoxication may have reduced the validity of their self-reported drinking. Notably, as with other preliminary studies, there are some limitations that should be taken into consideration when evaluating the results, such as the relatively short treatment period (i.e., six weeks), low subject numbers and, therefore, decreased statistical power, and the enrollment of mostly white males, which reduces the generalizability of the findings to the general population. Notwithstanding these limitations, these findings suggested the possibility of efficacy for ondansetron in treating alcoholism in a large-scale clinical trial. Also, the study of Sellers and colleagues [84] suggested the possibility that in humans, as reported in animals, ondansetron might have a non-linear dose-response curve.

In a recent large-scale (N = 321), double-blind, randomized, controlled, 12-week clinical trial, Johnson and colleagues [85] showed that early- but not late-onset alcohol-dependent men and women who received ondansetron (1, 4, and 16 mcg/kg b.i.d.) compared with placebo had fewer drinks/day (1.89, 1.56, and 1.87 versus 3.30; p = 0.03, p = 0.01, and p = 0.02, respectively) and drinks/drinking day (4.75, 4.28, and 5.18 versus 6.90; p = 0.03, p = 0.004, and p = 0.03, respectively). Ondansetron (4 mcg/kg b.i.d.) was more efficacious than placebo at increasing percentage of days abstinent (70.10 versus 50.20; p = 0.02) and total days abstinent per study week (6.74 versus 5.92; p = 0.03). Among early-onset alcoholics, there also was a significant difference in the mean log carbohydrate-deficient transferrin ratio a biochemical marker of heavy alcohol consumption between those who received ondansetron (1 and 4 mcg/kg b.i.d.) and those who got placebo (-0.17 and -0.19 versus 0.12; p = 0.03 and p = 0.01, respectively) [85]. Data from a cohort (N = 253) of this study also showed that ondansetron (4 mcg/kg b.i.d.), compared with placebo, was associated with a significant decrease in craving among early-onset alcoholics [86]. More recently, Kranzler and colleagues [87] showed that ondansetron (4 mcg/kg b.i.d.)-treated early-onset alcoholics had significantly better drinking outcomes and fewer alcohol-related problems compared with their late-onset alcoholic counterparts.

Taken together, these results show that ondansetron is efficacious in treating early- but not late-onset alcoholics, as exemplified by improved drinking outcomes and decreased alcohol craving.


Other 5-HT receptor subtypes

5-HT4 receptor antagonists might play a role in alcohol-induced brain reward mechanisms [88]. Interestingly, Panocka and colleagues [89] have shown that subcutaneous injection of the 5-HT4 antagonist GR113808 (1, 3, or 10 mg/kg) significantly reduces volitional ethanol intake. Supplemental animal studies are, however, needed to establish this result. To date, no human studies have been conducted on the effects of 5-HT4 antagonists on alcohol consumption.


Basic science studies have contributed greatly to our knowledge about the neurochemical pathways associated with the acquisition and maintenance of the drive to drink. Of particular importance have been serotonergic pathways, due to their modulatory effects on dopamine function, the critical substrate by which alcohol mediates its reinforcing effects associated with its abuse liability. Naturally, this has resulted in the study of serotonergic agents as treatments for alcoholism.

Serotonergic agents remain a promising area for the development of efficacious pharmacotherapies to treat alcohol dependence. Various types of serotonergic medication do, however, appear to have differential effects on drinking behavior. SSRIs are not efficacious treatment for a heterogeneous alcoholic group. SSRIs may, however, be efficacious in treating alcoholics who develop the disease later in life, or among alcoholics with co-morbid depression. The 5-HT1A partial agonist, buspirone, is not efficacious for treating alcoholics without co-morbid disease. Buspirone may, however, be useful in treating alcoholics with co-morbid anxiety disorder. Ritanserin, a 5-HT2 antagonist, 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 alcoholics who develop the disease early in life.

The differential response to SSRIs and ondansetron among various subtypes of alcoholic is intriguing. New knowledge on the relationship between molecular genetic and environmental predisposition might aid in better characterizing alcoholics by subtype. Such knowledge would improve our chances of predicting what subtype of alcoholic would respond best to a particular 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 (in 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, B.A., for his skilled assistance with preparing the manuscript.



1 Myers RD, Veale WL (1968) Alcohol preference in the rat: reduction following depletion of brain serotonin. Science 160: 1469-1471

2 Nachman M, Lester D, Le Magnen J (1970) Alcohol aversion in the rat: behavioral assessment of noxious drug effects. Science 168: 1244-1246

3 Daoust M, Chretien P, Moore N, Saligaut C, Lhuintre JP, Boismare F (1985) Isolation and striatal (3H) serotonin uptake: role in the voluntary intake of ethanol by rats. Pharmacol Biochem Behav 22: 205-208

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

5 Gill K, Amit Z, Koe BK (1988) Treatment with sertraline, a new serotonin uptake inhibitor, reduces voluntary ethanol consumption in rats. Alcohol 5: 349-354

6 Gill K, Filion Y, Amit Z (1988) A further examination of the effects of sertraline on voluntary ethanol consumption. Alcohol 5: 355-358

7 Zabik JE, Binkerd K, Roache JD (1985) Serotonin and ethanol aversion in the rat. In: CA Naranjo, EM Sellers (eds): Research advances in new psychopharmacological treatments for alcoholism: proceedings of the symposium, Toronto, 4-5 October 1984. Excerpta Medica, Amsterdam, 87-105

8 Blundell JE, Latham CJ (1982) Behavioural pharmacology of feeding. In: T Silverstone (ed.): Drugs and appetite. Academic Press, London, 41-80

9 Blundell JE (1984) Serotonin and appetite. Neuropharmacology 23: 1537-1551

10 Gill K, Amit Z (1989) Serotonin uptake blockers and voluntary alcohol consumption. A review of recent studies. Recent Dev Alcohol 7: 225-248

11 Haraguchi M, Samson HH, Tolliver GA (1990) Reduction in oral ethanol self-administration in the rat by the 5-HT uptake blocker fluoxetine. Pharmacol Biochem Behav 35: 259-262

12 Murphy JM, Waller MB, Gatto GJ, McBride WJ, Lumeng L, Li TK (1988) Effects of fluoxetine on the intragastric self-administration of ethanol in the alcohol preferring P line of rats. Alcohol 5: 283-286

13 Naranjo CA, Sellers EM, Roach CA, Woodley DV, Sanchez-Craig M, Sykora K (1984) Zimelidine-induced variations in alcohol intake by nondepressed heavy drinkers. Clin Pharmacol Ther 35: 374-381

14 Naranjo CA, Sellers EM, Sullivan JT, Woodley DV, Kadlec K, Sykora K (1987) The serotonin uptake inhibitor citalopram attenuates ethanol intake. Clin Pharmacol Ther 41: 266-274

15 Naranjo CA, Sellers EM (1989) Serotonin uptake inhibitors attenuate ethanol intake in problem drinkers. Recent Dev Alcohol 7: 255-266

16 Naranjo CA, Kadlec KE, Sanhueza P, Woodley-Remus D, Sellers EM (1990) Fluoxetine differentially alters alcohol intake and other consummatory behaviors in problem drinkers. Clin Pharmacol Ther 47: 490-498

17 Naranjo CA, Poulos CX, Bremner KE, Lanctot KL (1992) Citalopram decreases desirability, liking, and consumption of alcohol in alcohol-dependent drinkers. Clin Pharmacol Ther 51: 729-739

18 Gorelick DA, Paredes A (1992) Effect of fluoxetine on alcohol consumption in male alcoholics. Alcohol Clin Exp Res 16: 261-265

19 Naranjo CA, Bremner KE, Lanctot KL (1995) Effects of citalopram and a brief psycho-social intervention on alcohol intake, dependence and problems. Addiction 90: 87-99

20 Kabel DI, Petty F (1996) A placebo-controlled, double-blind study of fluoxetine in severe alcohol dependence: adjunctive pharmacotherapy during and after inpatient treatment. Alcohol Clin Exp Res 20: 780-784

21 Kranzler HR, Burleson JA, Korner P, Del Boca FK, Bohn MJ, Brown J, Liebowitz N (1995) Placebo-controlled trial of fluoxetine as an adjunct to relapse prevention in alcoholics. Am J Psychiatry 152: 391-397

22 Buydens-Branchey L, Branchey MH, Noumair D (1989) Age of alcoholism onset. I. Relationship to psychopathology. Arch Gen Psychiatry 46: 225-230

23 Linnoila M, Virkkunen M (1992) Biologic correlates of suicidal risk and aggressive behavioral traits. J Clin Psychopharmacol 12: 19S-20S

24 Linnoila M, De Jong J, Virkkunen M (1989) Family history of alcoholism in violent offenders and impulsive fire setters. Arch Gen Psychiatry 46: 613-616


25 Fils-Aime ML, Eckardt MJ, George DT, Brown GL, Mefford I, Linnoila M (1996) Early-onset alcoholics have lower cerebrospinal fluid 5-hydroxyindoleacetic acid levels than late-onset alcoholics. Arch Gen Psychiatry 53: 211-216

26 Kranzler HR, Burleson JA, Brown J, Babor TF (1996) Fluoxetine treatment seems to reduce the beneficial effects of cognitive-behavioral therapy in type B alcoholics. Alcohol Clin Exp Res 20: 1534-1541

27 Pettinati HM, Volpicelli JR, Kranzler HR, Luck G, Rukstalis MR, Cnaan A (2000) Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype. Alcohol Clin Exp Res 24: 1041-1049

28 Johnson BA, Cloninger CR, Roache JD, Bordnick PS, Ruiz P (2000) Age of onset as a discriminator between alcoholic subtypes in a treatment-seeking outpatient population. Am J Addict 9: 17-27

29 Johnson BA, Ait-Daoud N (2000) Neuropharmacological treatments for alcoholism: scientific basis and clinical findings. Psychopharmacology 149: 327-344

30 Johnson BA (2000) Serotonergic agents and alcoholism treatment: rebirth of the subtype concept an hypothesis. Alcohol Clin Exp Res 24: 1597-1601

31 Stoltenberg SF (2003) Serotonergic agents and alcoholism treatment: a simulation. Alcohol Clin Exp Res 27: 1853-1859

32 Cornelius JR, Salloum IM, Ehler JG, Jarrett PJ, Cornelius MD, Perel JM, Thase ME, Black A (1997) Fluoxetine in depressed alcoholics: a double-blind, placebo-controlled trial. Arch Gen Psychiatry 54: 700-705

33 Mason BJ, Kocsis JH, Ritvo EC, Cutler RB (1996) A double-blind, placebo-controlled trial of desipramine for primary alcohol dependence stratified on the presence or absence of major depression. JAMA 275: 761-767

34 McGrath PJ, Nunes EV, Stewart JW, Goldman D, Agosti V, Ocepek-Welikson K, Quitkin FM (1996) Imipramine treatment of alcoholics with primary depression: a placebo-controlled clinical trial. Arch Gen Psychiatry 53: 232-240

35 Collins DM, Myers RD (1987) Buspirone attenuates volitional alcohol intake in the chronically drinking monkey. Alcohol 4: 49-56

36 Privette TH, Hornsby RL, Myers RD (1988) Buspirone alters alcohol drinking induced in rats by tetrahydropapaveroline injected into brain monoaminergic pathways. Alcohol 5: 147-152

37 Meert TF (1993) Effects of various serotonergic agents on alcohol intake and alcohol preference in Wistar rats selected at two different levels of alcohol preference. Alcohol Alcoholism 28: 157-170

38 Wilson AW, Costall B, Neill JC (2000) Manipulation of operant responding for an ethanol-paired conditioned stimulus in the rat by pharmacological alteration of the serotonergic system. J Psychopharmacol 14: 340-346

39 Rezvani AH, Overstreet DH, Janowsky DS (1990) Genetic serotonin deficiency and alcohol preference in the fawn hooded rats. Alcohol Alcoholism 25: 573-575

40 Gongwer MA, Murphy JM, McBride WJ, Lumeng L, Li TK (1989) Regional brain contents of serotonin, dopamine and their metabolites in the selectively bred high- and low-alcohol drinking lines of rats. Alcohol 6: 317-320

41 McBride WJ, Bodart B, Lumeng L, Li TK (1995) Association between low contents of dopamine and serotonin in the nucleus accumbens and high alcohol preference. Alcohol Clin Exp Res 19: 1420-1422

42 Korpi ER, Paivarinta P, Abi-Dargham A, Honkanen A, Laruelle M, Tuominen K, Hilakivi LA (1992) Binding of serotonergic ligands to brain membranes of alcohol-preferring AA and alcohol-avoiding ANA rats. Alcohol 9: 369-374

43 Blier P, Ward NM (2003) Is there a role for 5-HT1A agonists in the treatment of depression? Biol Psychiatry 53: 193-203

44 Malcolm R, Anton RF, Randall CL, Johnston A, Brady K, Thevos A (1992) A placebo-controlled trial of buspirone in anxious inpatient alcoholics. Alcohol Clin Exp Res 16: 1007-1013

45 Kranzler HR, Burleson JA, Del Boca FK, Babor TF, Korner P, Brown J, Bohn MJ (1994) Buspirone treatment of anxious alcoholics: a placebo-controlled trial. Arch Gen Psychiatry 51: 720-731

46 Fawcett J, Kravitz HM, McGuire M, Easton M, Ross J, Pisani V, Fogg LF, Clark D, Whitney M, Kravitz G et al. (2000) Pharmacological treatments for alcoholism: revisiting lithium and considering buspirone. Alcohol Clin Exp Res 24: 666-674


47 Bruno F (1989) Buspirone in the treatment of alcoholic patients. Psychopathology 22: 49-59

48 Malec TS, Malec EA, Dongier M (1996) Efficacy of buspirone in alcohol dependence: a review. Alcohol Clin Exp Res 20: 853-858

49 George DT, Rawlings R, Eckardt MJ, Phillips MJ, Shoaf SE, Linnoila M (1999) 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 23: 272-278

50 Meert TF, Awouters F, Niemegeers CJ, Schellekens KH, Janssen PA (1991) Ritanserin reduces abuse of alcohol, cocaine, and fentanyl in rats. Pharmacopsychiatry 24: 159-163

51 Myers RD, Lankford M, Bjork A (1992) Selective reduction by the 5-HT antagonist amperozide of alcohol preference induced in rats by systemic cyanamide. Pharmacol Biochem Behav 43: 661-667

52 Svensson L, Fahlke C, Hard E, Engel JA (1993) Involvement of the serotonergic system in ethanol intake in the rat. Alcohol 10: 219-224

53 Myers RD, Lankford MF (1996) Suppression of alcohol preference in high alcohol drinking rats: efficacy of amperozide versus naltrexone. Neuropsychopharmacology 14: 139-149

54 Myers RD, Lankford M (1998) Action of the 5-HT2A antagonist amperozide on alcohol-induced poikilothermia in rats. Pharmacol Biochem Behav 59: 91-95

55 Biggs TA, Myers RD (1998) Naltrexone and amperozide modify chocolate and saccharin drinking in high alcohol-preferring P rats. Pharmacol Biochem Behav 60: 407-413

56 Overstreet DH, McArthur RA, Rezvani AH, Post C (1997) Selective inhibition of alcohol intake in diverse alcohol-preferring rat strains by the 5-HT2A antagonists amperozide and FG 5974. Alcohol Clin Exp Res 21: 1448-1454

57 Lankford MF, Bjork AK, Myers RD (1996) Differential efficacy of serotonergic drugs FG5974, FG5893, and amperozide in reducing alcohol drinking in P rats. Alcohol 13: 399-404

58 Ugedo L, Grenhoff J, Svensson TH (1989) Ritanserin, a 5-HT2 receptor antagonist, activates midbrain dopamine neurons by blocking serotonergic inhibition. Psychopharmacology 98: 45-50

59 Awouters F, Niemegeers CJ, Megens AA, Meert TF, Janssen PA (1988) The pharmacological profile of ritanserin, a very specific central serotonin-S2 antagonist. Drug Dev Res 15: 61-73

60 Johnson BA, Jasinski DR, Galloway GP, Kranzler H, Weinreib R, Anton RF, Mason BJ, Bohn MJ, Pettinati HM, Rawson R et al. (1996) Ritanserin in the treatment of alcohol dependence a multi-center clinical trial. Ritanserin Study Group. Psychopharmacology 128: 206-215

61 Wiesbeck GA, Weijers HG, Chick J, Naranjo CA, Boening J (1999) Ritanserin in relapse prevention in abstinent alcoholics: results from a placebo-controlled double-blind international multi-center trial. Ritanserin in Alcoholism Work Group. Alcohol Clin Exp Res 23: 230-235

62 LeMarquand D, Pihl RO, Benkelfat C (1994) Serotonin and alcohol intake, abuse, and dependence: clinical evidence. Biol Psychiatry 36: 326-337

63 Lovinger DM, White G (1991) Ethanol potentiation of 5-hydroxytryptamine3 receptor-mediated ion current in neuroblastoma cells and isolated adult mammalian neurons. Mol Pharmacol 40: 263-270

64 Zhou Q, Lovinger DM (1996) Pharmacologic characteristics of potentiation of 5-HT3 receptors by alcohols and diethyl ether in NCB-20 neuroblastoma cells. J Pharmacol Exp Ther 278: 732-740

65 Lovinger DM, Zhou Q (1994) Alcohols potentiate ion current mediated by recombinant 5-HT3RA receptors expressed in a mammalian cell line. Neuropharmacology 33: 1567-1572

66 Lovinger DM (1991) Inhibition of 5-HT3 receptor-mediated ion current by divalent metal cations in NCB-20 neuroblastoma cells. J Neurophysiol 66: 1329-1337

67 Lovinger DM (1991) Ethanol potentiates ion current mediated by 5-HT3 receptors on neuroblastoma cells and isolated neurons. Alcohol Alcoholism Suppl 1: 181-185

68 Lovinger DM (1999) 5-HT3 receptors and the neural actions of alcohols: an increasingly exciting topic. Neurochem Int 35: 125-130

69 Bradbury AJ, Costall B, Domeney AM, Naylor RJ (1985) Laterality of dopamine function and neuroleptic action in the amygdala in the rat. Neuropharmacology 24: 1163-1170

70 Hagan RM, Jones BJ, Jordan CC, Tyers MB (1990) Effect of 5-HT3 receptor antagonists on responses to selective activation of mesolimbic dopaminergic pathways in the rat. Br J Pharmacol 99: 227-232

71 Eison AS, Iversen SD, Sandberg BE, Watson SP, Hanley MR, Iversen LL (1982) Substance P analog, DiMe-C7: evidence for stability in rat brain and prolonged central actions. Science 215: 188-190


72 Costall B, Domeney AM, Naylor RJ, Tyers MB (1987) 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 92: 881-894

73 Hodge CW, Samson HH, Lewis RS, Erickson HL (1993) Specific decreases in ethanol- but not water-reinforced responding produced by the 5-HT3 antagonist ICS 205-930. Alcohol 10: 191-196

74 Fadda F, Garau B, Marchei F, Colombo G, Gessa GL (1991) MDL 72222, a selective 5-HT3 receptor antagonist, suppresses voluntary ethanol consumption in alcohol-preferring rats. Alcohol Alcoholism 26: 107-110

75 Rodd-Henricks ZA, McKinzie DL, Li T-K, Crile RS, Murphy JM, McBride WJ (1999) Intracranial self-administration of ethanol into the posterior VTA of Wistar rats is mediated by 5-HT3 receptors [abstract]. Alcohol Clin Exp Res 23(suppl 5): 49A

76 McBride WJ, Li TK (1998) Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in rodents. Crit Rev Neurobiol 12: 339-369

77 Tomkins DM, Le AD, Sellers EM (1995) Effect of the 5-HT3 antagonist ondansetron on voluntary ethanol intake in rats and mice maintained on a limited access procedure. Psychopharmacology 117: 479-485

78 Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38: 1083-1152

79 Beardsley PM, Lopez OT, Gullikson G, Flynn D (1994) Serotonin 5-HT3 antagonists fail to affect ethanol self-administration of rats. Alcohol 11: 389-395

80 Johnson BA, Campling GM, Griffiths P, Cowen PJ (1993) 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 112: 142-144

81 Johnson BA, Cowen PJ (1993) Alcohol-induced reinforcement: dopamine and 5-HT3 receptor interactions in animals and humans. Drug Dev Res 30: 153-169

82 Doty P, Zacny JP, de Wit H (1994) Effects of ondansetron pretreatment on acute responses to ethanol in social drinkers. Behav Pharmacol 5: 461-469

83 Swift RM, Davidson D, Whelihan W, Kuznetsov O (1996) Ondansetron alters human alcohol intoxication. Biol Psychiatry 40: 514-521

84 Sellers EM, Toneatto T, Romach MK, Somer GR, Sobell LC, Sobell MB (1994) Clinical efficacy of the 5-HT3 antagonist ondansetron in alcohol abuse and dependence. Alcohol Clin Exp Res 18: 879-885

85 Johnson BA, Roache JD, Javors MA, DiClemente CC, Cloninger CR, Prihoda TJ, Bordnick PS, Ait-Daoud N, Hensler J (2000) Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: a randomized controlled trial. JAMA 284: 963-971

86 Johnson BA, Roache JD, Ait-Daoud N, Zanca NA, Velazquez M (2002) Ondansetron reduces the craving of biologically predisposed alcoholics. Psychopharmacology 160: 408-413

87 Kranzler HR, Pierucci-Lagha A, Feinn R, Hernandez-Avila C (2003) Effects of ondansetron in early- versus late-onset alcoholics: a prospective, open-label study. Alcohol Clin Exp Res 27: 1150-1155

88 Bisaga A, Sikora J, Kostowski W (1993) The effect of drugs interacting with serotonergic 5HT3 and 5HT4 receptors on morphine place conditioning. Pol J Pharmacol 45: 513-519

89 Panocka I, Ciccocioppo R, Polidori C, Pompei P, Massi M (1995) The 5-HT4 receptor antagonist, GR113808, reduces ethanol intake in alcohol-preferring rats. Pharmacol Biochem Behav 52: 255-259

Drugs for Relapse Prevention of Alcoholism
Drugs for Relapse Prevention of Alcoholism (Milestones in Drug Therapy)
ISBN: 3764302143
EAN: 2147483647
Year: 2005
Pages: 26
Flylib.com © 2008-2017.
If you may any questions please contact us: flylib@qtcs.net