1 Duke University Medical Center, Department of Psychiatry, Box 3412, Durham, NC 27710 and
2 The University of North Carolina School of Medicine, Chapel Hill, NC 27599-7240, USA
Received 6 April 1999; in revised form 15 June 1999; accepted 2 July 1999
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ABSTRACT |
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INTRODUCTION |
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It is common to treat some medical diseases with more than one medication simultaneously. This strategy is currently employed in the treatment of several major diseases and medical conditions including hypertension (Chalmers, 1993; Menard, 1993
; Bakris and Williams, 1995
; Levine et al., 1995
; Prisant et al., 1995
), depression (Tiller et al., 1992
; Birkenhager et al., 1995
), autoimmune diseases (Schumm-Draeger, 1993
), cancer (Nakagawa et al., 1996
), diabetes (Rosenthal, 1992
), and nicotine addiction (Rose and Levin, 1992
). There is considerable evidence that alcoholism is a multi-factorial disease that may involve impairment of central serotonergic (McBride et al., 1990
; Rezvani et al., 1990
; Rezvani and Grady, 1994
; Grant, 1995
), dopaminergic (McBride et al., 1990
; Koob et al., 1994
), opioidergic (Froehlich et al., 1990
; Reid et al., 1991
), and GABAergic systems (McBride et al., 1990
). If deficits in more than one of these systems additively or synergistically contribute to alcohol-seeking behaviour, theoretically, a therapeutic approach that targets more than one system should be more effective than one addressing a single system.
To test this hypothesis, we examined the effect on alcohol intake of administering simultaneously low doses of three pharmacological agents, which, at higher doses, have been shown to reduce alcohol intake in several strains of alcohol-preferring rats. For this initial study, we compared the effects of naltrexone, an opioid receptor antagonist; fluoxetine, a serotonin reuptake inhibitor; and TA-0910, a thyrotropin-releasing hormone (TRH) analogue with dopaminergic properties (Mason et al., 1994, 1996
) to those of a mixture of these drugs on the intakes of alcohol, water, and food in three different strains of alcohol-preferring rats. The strains of rats used were: alcohol preferring (P, generation 40) rat and the high alcohol-drinking (HAD, generation 25) rat, which were developed at Indiana University by T. K. Li and colleagues (Li and McBride, 1995
), and the inbred alcohol-preferring Fawn-Hooded (FH) strain which was developed by A. H. Rezvani at the University of North Carolina at Chapel Hill (Rezvani et al., 1990
). These rats have been used extensively for studying compounds which reduce alcohol intake (Murphy et al., 1988
; McBride et al., 1990
; Rezvani et al., 1990
, 1991a
, 1992
; Rezvani and Grady, 1994
; Mason et al., 1997
). We hypothesized that the combination treatment would be more potent than the individual compounds in suppressing alcohol intake, because more than one neurotransmitter system in the brain is involved in alcohol-seeking behaviour. Our findings do indeed support the hypothesis.
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MATERIALS AND METHODS |
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Establishment of baseline
Following the standard method (Murphy et al., 1988; Rezvani and Grady, 1994
; Rezvani et al., 1995
), rats were given 1 day access to water in a Richter tube followed by 3 days of free access to a solution of 10% (v/v) ethanol given as the only source of fluid. Thereafter, the rats were given a choice between alcohol and water for the remainder of the study. All experiments involved 24-h free access to food, water, and alcohol in a two-bottle choice paradigm.
Preparation of drugs
Naltrexone HCl (RBI, Natick, MA, USA), fluoxetine HCl (Eli Lilly and Co., Indianapolis, IN, USA), and TA-0910 (Tanabi, Seiyaku, Co. Ltd., Osaka, Japan) were dissolved in saline freshly each day. The concentrations of naltrexone, fluoxetine, and TA-0910 in the mixture or in separate treatments were 2.0, 1.0, and 0.2 mg/ml, respectively. The doses chosen for these experiments are relatively small and although they may reduce alcohol intake in a 12 h scheduled access paradigm (Froehlich et al., 1990; McBride et al., 1990
; Froehlich and Li, 1993
), they exert no significant effect on alcohol intake in alcohol-preferring rats in the 24-h access protocol. The volume of systemic injections was always 1 ml/kg and that for oral administration was 4 ml/kg. Based on our experience comparing the potencies of compounds given systemically and orally, an oral dose three times that given i.p. will exert a similar effect (Overstreet et al., 1996
). Alcohol solutions (10%, v/v) were prepared every 2 days from distilled water and a stock solution of 95% reagent grade ethanol.
Experimental protocols
Experiment 1: acute systemic administration.
After establishment of a stable baseline for alcohol and water intakes, animals were maintained on a continuous access to alcohol and water via a two-bottle choice paradigm for about 2 months. Then, rats (n = 8 for P and HAD rats and n = 15 for FH rats) received a single i.p. injection of the saline vehicle, naltrexone (2.0 mg/kg), fluoxetine (1.0 mg/kg), TA-0910 (0.2 mg/kg), or a mixture of the three drugs at 09:30. Alcohol and water intakes were measured at 6 and 24 h after the injection. Food intake was measured 24 h after the injection. Each rat received all five treatments, separated by washout periods of at least 3 days.
Experiment 2: acute oral administration.
Any compound, which might be used in human subjects, should be orally active. To investigate the effect of the oral administration of the mixture on alcohol intake, the same HAD rats used in experiment 1 received a single oral administration of either the saline vehicle, naltrexone (6.0 mg/kg), fluoxetine (3.0 mg/kg), TA-0910 (0.6 mg/kg), or the mixture of the three drugs at 09:30. All solutions were delivered by gastric intubation into the stomach through a special ball-tipped 16-gauge stainless-steel gavage needle (Beckton Dickinson) (Rezvani et al., 1986). Alcohol and water intakes were measured at 6 and 24 h after drug administration, whereas food intake was measured 24 h after the treatment. Each rat received all five treatments separated by washout periods of at least 3 days.
Experiment 3: chronic systemic administration.
It has been shown that tolerance develops to the suppressing effects of naltrexone, fluoxetine, and TA-0910 and some other drugs on alcohol intake in rats (Rezvani et al., 1993; Mason et al., 1994
; Cowen et al., 1999
). To test this phenomenon with the mixture, a chronic experiment was conducted with nine adult male P rats. After establishment of stable baselines for alcohol and water intakes, and following a cross-over design, the mixture or vehicle was given i.p. once a day for 10 consecutive days. Alcohol and water intakes were measured at 6 and 24 h after the treatment, whereas food intake was measured 24 h after the treatment. Each rat received both treatments, and a washout period of 3 days was imposed between treatments.
Statistical analysis
The results were expressed as means ± standard error of means (SEM). Alcohol intake (g/kg) was calculated by multiplying the volume of alcohol consumed by 10% and 0.7893 (ethanol density)/animal body weight in kg. Alcohol preference, expressed as a percentage, was calculated as follows: (volume of alcohol consumed in ml/total fluid intake in ml) x 100 (Rezvani et al., 1990; Rezvani and Grady, 1994
). Statistical differences between different groups were determined using analysis of variance followed by NewmanKeuls protected t-test.
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RESULTS |
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DISCUSSION |
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The suppressant effects of fluoxetine and naltrexone are not specific to alcohol. Murphy et al. (1988) and Gardell et al. (1997) have shown that fluoxetine, in doses which reduce alcohol intake, prevents growth, and this drug is used to suppress appetite in humans. Naltrexone also has been shown to reduce body weight in rats (Gardell et al., 1997). These effects could be undesirable in chronic alcoholics, who are frequently malnourished. In the present studies, neither food nor water intake was reduced at 24 h by a single injection of the mixture or of its constituent drugs; however, when fluoxetine was given orally to HAD rats, it significantly reduced both alcohol and water intakes, indicating a non-specific effect. We reported previously that the administration of a single large dose (0.75 mg/kg) of TA-0910 into P rats increased food but not total calorie intake (Rezvani et al., 1992
). It is possible that the presence of TA-0910 in the mixture may have counteracted any suppressing effect that fluoxetine and naltrexone together may have had on food intake, resulting in a net outcome of no change in food intake. Our results suggest that this combination treatment is relatively more potent than its individual constituent drugs in reducing alcohol intake, and more selective than larger doses of fluoxetine or naltrexone, which reduce alcohol intake. However, since food intake was not measured at 6 h, it is not clear whether food intake was decreased during this period but was compensated for in the remainder of the 24-h test period.
Although the mechanisms underlying the suppressant effect of the mixture of drugs on alcohol intake were not addressed by the present study, a review of current literature suggests that the mixture might exert its effect by interacting with central dopamine (DA), serotonin (5-HT), and opioids, each of which may be involved in alcohol-seeking behaviour in animals and humans (see Introduction). The mesolimbic DA system has been implicated in the reinforcing properties of abused substances, including alcohol (DiChiara and Imperato, 1988; Koob et al., 1994
). Based on these findings, it is speculated that the mixture may exert its suppressant effect on alcohol intake by modulating, at least in part, the dopaminergic system.
There is evidence that each component of the mixture stimulates the reward system by enhancing DA release in the mesolimbic pathway. Behavioural studies indicate that TA-0910 stimulates DA release in the nucleus accumbens (Yamamura et al., 1991). The development of a partial cross-tolerance between TA-0910 and the DA agonist bromocriptine with respect to the attenuating effect on alcohol intake in P rats (Mason et al., 1994
) and the antagonism of the suppressant effect of TA-0910 on alcohol intake by the DA D2 antagonist eticlopride (Mason et al., 1997
) further support a dopaminergic mechanism in the suppressant effect of TA-0910 on alcohol intake. Fluoxetine has been demonstrated to release DA in the prefrontal cortex of freely moving rats by stimulating local 5-HT3 receptors (Tanada et al., 1995
). There is also evidence of interaction between the opioidergic and dopaminergic systems, including anatomic co-localization of endogenous opioids and DA in the brain which reflects the interplay between these two systems. It has also been shown that microinjection of the selective µ-opioid receptor antagonists D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 and ß-funaltrexamine into the ventral tegmental area produces increases in extracellular DA and DA metabolite concentrations in the ventral striatum (Devine et al., 1993
). However, there are also conflicting reports that peripheral administration of opioid antagonists blocks DA release (Benjamin et al., 1993
). Thus, it is unclear whether administration of naltrexone in the mixture increases mesolimbic DA transmission. Nevertheless, in preliminary experiments, we found that the mixture of the three drugs was more effective in reducing the 6-h alcohol intake than a combination of equivalent doses of TA-0910 and fluoxetine, suggesting that, at the dose we used, naltrexone does not counteract the effects of fluoxetine and TA-0910 and may enhance their suppressive effects on alcohol intake by an as yet unknown mechanism(s). Therefore, the suppressant action of the mixture on alcohol intake may indeed result from enhancement of DA release in the mesolimbic system that, by substituting for alcohol-mediated enhancement of DA release, reduces the motivation to drink.
It is also possible that drugdrug interactions play a role in the effect of the mixture in reducing alcohol intake. For example, one compound in the mixture may influence the pharmacokinetics of another compound, thus affecting its action on alcohol intake. However, this appears unlikely, because we used small doses of each drug in the mixture and the effect of the mixture on alcohol intake was apparent as early as 2 h following intake. Comparing the blood levels of the drugs and their active metabolites when given alone with those obtained when the mixture is given is needed to resolve this issue.
Recently, several groups have examined the effects of different combinations of drugs on alcohol intake with mixed results. Gardell et al. (1997) have shown that the suppressing effect of a combination of naltrexone (5 mg/kg) and fluoxetine (5 mg/kg) on alcohol intake is no different from those of either drug in SpragueDawley rats. However, in a preliminary study, Zink et al. (1997) reported that naltrexone and fluoxetine act synergistically to decrease alcohol intake in P rats. Similar findings have been reported with a combination of naltrexone and ondansetron, a 5-HT3 receptor antagonist, in mice and rats (Le and Sellers, 1994). Since the effects of these combinations on food and water intakes have not been reported, we are unable to compare all of the effects of these combinations with our results. Concurrent administration of amperozide, a 5-HT2a receptor antagonist, and naltrexone has also been shown to suppress volitional drinking of alcohol in HAD rats, without side-effects on food and water intakes. The suppressing effect of this combination on alcohol intake was greater than that of the individual drugs (Lankford and Myers, 1996
).
In a pilot clinical study, Williams and Mason (1997) have shown that a combination of nalmefene and sertraline is more effective than sertraline and placebo in alcohol-dependent patients who failed to respond to nalmefene alone, suggesting the benefit of combination pharmacotherapy for the treatment of alcohol dependence. In another small clinical study, Salloum et al. (1998) combined naltrexone with a selective serotonin reuptake inhibitor (SSRI) for the treatment of patients diagnosed as currently alcohol-dependent and depressed. The naltrexone SSRI combination reduced drinking from 49 drinks per week to six drinks per week. In addition, depressive symptoms improved. Farren et al. (1997) have also examined the effects of the combination of a SSRI (sertraline, 50 and 100 mg/day) and naltrexone (50 mg/day) in the treatment of alcoholism. Using the Obsessive Compulsive Drinking Scale (Anton et al., 1996) the patients on combination therapy tended to report lower levels of craving for alcohol at the end of 10 weeks of treatment, than in the naltrexone only group. It should be mentioned that, although these findings are promising, they should be considered preliminary as the sample size was small in all of these clinical studies.
In summary, the present results demonstrate that combination pharmacotherapy can be more potent and in some cases more specific in reducing alcohol intake than monopharmacotherapy in alcohol-preferring rats. These results show that a mixture of low doses of naltrexone, fluoxetine, and TA-0910, is more potent than any of the individual drugs in suppressing alcohol intake, without producing a significant effect on 24-h food intake. These promising preclinical findings suggest that the strategy of combination pharmacotherapy should be tested in alcoholics.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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REFERENCES |
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---|
Bakris, G. L. and Williams, B. (1995) Angiotensin converting enzyme inhibitors and calcium antagonists alone or combined: does the progression of diabetic renal disease differ? Journal of Hypertension 13, S95S101.[ISI]
Benjamin, D., Grant, E. R. and Pohorecky, L. A. (1993) Naltrexone reverses ethanol-induced dopamine release in the nucleus accumbens in awake, freely moving rats. Brain Research 621, 137140.[ISI][Medline]
Birkenhager, T. K., Moleman, P. and Nolen, W. A. (1995) Benzodiazepines for depression? A review of the literature. International Clinical Psychopharmacology 10, 181195.[ISI][Medline]
Chalmers, J. (1993) The place of combination therapy in the treatment of hypertension. Clinical and Experimental Hypertension 15, 12991313.[ISI][Medline]
Cowen, M. S., Rezvani, A. H., Jarrott, B. and Lawerence, A. J. (1999) Ethanol consumption by Fawn-Hooded rats following abstinence: effects of naltrexone and changes in µ-opioid receptor density. Alcoholism: Clinical and Experimental Research 23, 10081014.[ISI][Medline]
Devine, D. P., Leone, P. and Wise, R. A. (1993) Mesolimbic dopamine neurotransmission by administration of µ-opioid receptor antagonists. European Journal of Pharmacology 24, 5564.
DiChiara, G. and Imperato, A. (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proceeding of the National Academy of Sciences of the USA 85, 52745278.[Abstract]
Farren, C. K., Catapano, D. and O'Malley, S. (1997) Sertraline with naltrexone versus naltrexone alone in the treatment of alcohol dependence. Alcoholism: Clinical and Experimental Research 21 (suppl.), 64 (Abstract no. 366).
Froehlich, J. C. and Li, T.-K. (1993) Recent developments in alcoholism: opioid peptides. Recent Developments in Alcoholism 11, 187205.[Medline]
Froehlich, J. C., Harts, J., Lumeng, L. and Li, T.-K. (1990) Naloxone attenuates voluntary ethanol intake in rats selectively bred for high ethanol preference. Pharmacology, Biochemistry and Behavior 35, 385390.[ISI][Medline]
Gardell, L. R., Whalen, C. A., Chattophadyay, S., Cavallaro, C. A., Hubbell, C. L. and Reid, L. D. (1997) Combination of naltrexone and fluoxetine on rats' propensity to take alcoholic beverage. Alcoholism: Clinical and Experimental Research 21, 14351439.[ISI][Medline]
Grant, K. A. (1995) The role of 5-HT3 receptors in drug dependence. Drug and Alcohol Dependence 38, 155171.[ISI][Medline]
Hodge, C. A., Haraguchi, M., Erickson, H. L. and Samson, H. H. (1993a) Ventral tegmental microinjections of quinpirole decrease ethanol and sucrose-reinforced responding. Alcoholism: Clinical and Experimental Research 17, 370375.[ISI][Medline]
Hodge, C. A., Samson, H. H., Lewis, R. S. and Erickson, H. L. (1993b) Specific decreases in ethanol but not water-reinforced responding produced by the 5-HT3 antagonist ICS 205930. Alcohol 10, 191196.[ISI][Medline]
Koob, G. F., Rassnick, S., Heinrichs, S. and Weiss, F. (1994) Alcohol, the reward system and dependence. EXS 71, 103114.[Medline]
Lankford, M. F. and Myers, R. D. (1996) Opiate and 5-HT2a receptors in alcohol drinking: preference in HAD rats is inhibited by combination treatment with naltrexone and amperozide. Alcohol 13, 5357.[ISI][Medline]
Le, A. D. and Sellers, E. M. (1994) Interaction between opiate and 5-HT3 receptor antagonists in the regulation of alcohol intake. Alcohol and Alcoholism 29 (suppl. 2), 545549.
Levine, J. H., Ferdinand, K. C., Cargo, P., Laine, H. and Lefkowitz, M. (1995) Additive effects of verapamil and enalapril in the treatment of mild to moderate hypertension. American Journal of Hypertension 8, 494499.[ISI][Medline]
Li, T.-K. and McBride, W. J. (1995) Pharmacogenetic models of alcoholism. Clinical Neuroscience 3, 182185.[ISI][Medline]
Mason, G. A., Rezvani, A. H., Grady, D. R. and Garbutt, J. C. (1994) The subchronic effects of the TRH analog TA-0910 and bromocriptine on alcohol preference in alcohol-preferring rats: development of tolerance and cross-tolerance. Alcoholism: Clinical and Experimental Research 18, 11961201.[ISI][Medline]
Mason, G. A., Rezvani, A. H., Overstreet, D. H. and Garbutt, J. C. (1996) The thyrotropin releasing hormone analog TA-0910 reduces voluntary alcohol intake of P rats subchronically in a limited scheduled access paradigm. Alcoholism: Clinical and Experimental Research 20, 10001003.[ISI][Medline]
Mason, G. A., Rezvani, A. H., Overstreet, D. H., Hamedi, M., Walker, C. H., Yang, Y. and Garbutt, J. C. (1997) Involvement of dopamine D2 receptors in the suppressive effect of the thyrotropin releasing hormone analog TA-0910 on alcohol intake in P rats. Alcoholism: Clinical and Experimental Research 21, 16231629.[ISI][Medline]
McBride, W. J., Murphy, J. M., Lumeng, L. and Li, T.-K. (1990) Serotonin, dopamine and GABA involvement in alcohol drinking of selectively bred rats. Alcohol 7, 199205.[ISI][Medline]
Menard, J. (1993) Critical assessment of combination therapy development. Blood Pressure 1, 59.
Murphy, J. M., Waller, M. B., Gatto, G. J., McBride, W. J., Lumeng, L. and Li, T.-K. (1988) Effects of fluoxetine on the intragastric self-administration of ethanol in the alcohol preferring P line of rats. Alcohol 5, 282286.
Nakagawa, H., Kobayashi, K., Tono, T., Fukuda, K., Shinn, E., Mishima, H., YagyKobayashi, T. and Kikkawa N. (1996) Combination of intra-hepatic arterial infusion of low dose cisplatin and oral administration of high-dose doxyfluridine for patients with live metastases of gastric cancer. Japanese Journal of Cancer and Chemotherapy 23, 783785.[Medline]
O'Malley, S. S., Jaffe, A. J., Chang, G., Schottenfeld, R. S., Meyer, R. E. and Rounsaville, B. (1992) Naltrexone and coping skills therapy for alcohol dependence. Archives of General Psychiatry 49, 475481.
Overstreet, D. H., Rezvani, A. H. and Kampov-Polevoy, A. B. (1995) Strain-dependent suppressant effects of dopaminergic, serotonergic and opioidergic agents on alcohol intake. Society for Neuroscience Abstract 666.16.
Overstreet, D. H., Lee, Y. W., Rezvani, A. H., Pei, Y. H., Criswell, H. E. and Janowsky, D. S. (1996) Suppression of alcohol intake after administration of the Chinese herbal medicine, NPI-028, and its derivatives. Alcoholism: Clinical and Experimental Research 20, 221227.[ISI][Medline]
Prisant, L. M., Weir, M. R., Papademetriou, V., Weber, M. A., Adegbile, I. A., Alemayehu, D., Lefkowitz, M. P. and Carr, A. A. (1995) Low-dose drug combination therapy: an alternative first-line approach to hypertension treatment. American Heart Journal 130, 359366.[ISI][Medline]
Pucilowski, O., Rezvani, A. H. and Janowsky, D. S. (1992) Suppression of alcohol and saccharin preference in rats by a novel Ca2+ channel inhibitor, GOE 5438. Psychopharmacology 107, 447452.[ISI][Medline]
Reid, L. D., Delconte, J. D., Nichols, M. L., Bilsky, E. J. and Hubbell, C. L. (1991) Tests of opioid deficiency hypotheses of alcoholism. Alcohol 8, 247257.[ISI][Medline]
Rezvani, A. H. and Janowsky, D. S. (1990) Decrease of alcohol consumption by verapamil in alcohol preferring rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry 14, 623631.[ISI][Medline]
Rezvani, A. H. and Grady, D. R. (1994) Suppression of alcohol consumption by fenfluramine in Fawn-Hooded rats with serotonin dysfunction. Pharmacology, Biochemistry and Behavior 48, 105110.[ISI][Medline]
Rezvani, A. H., Crovi, S. I., Mack, C. M. and Myers, R. D. (1986) Central Ca2+-channel blockade reverses ethanol induced poikilothermia in the rat. Alcohol 3, 273279.[ISI][Medline]
Rezvani, A. H., Overstreet, D. H. and Janowsky D. S. (1990) Genetic serotonin deficiency and alcohol preference in the Fawn-Hooded rats. Alcohol and Alcoholism 25, 573575.[ISI][Medline]
Rezvani, A. H., Grady, D. R. and Janowsky, D. S. (1991a) Effect of Ca2+-channel blockers on alcohol preference in alcohol-drinking monkeys. Alcohol and Alcoholism 26, 161167.[ISI][Medline]
Rezvani, A. H., Overstreet, D. H. and Janowsky, D. S. (1991b) Drug-induced reductions in ethanol intake in alcohol preferring and Fawn-Hooded rats. Alcohol and Alcoholism 26 (suppl. 1), 433437.
Rezvani, A. H., Garbutt, J. C., Shimoda, K., Garges, P. L., Janowsky, D. S. and Mason, G. A. (1992) Attenuation of alcohol preference in alcohol-preferring rats by a novel TRH analogue, TA-0910. Alcoholism: Clinical and Experimental Research 16, 326330.[ISI][Medline]
Rezvani, A. H., Mason, G. A., Garbutt, J. C., Janowsky, D. S. and Overstreet, D. H. (1993) Reductions of tolerance to anti-craving drugs for alcohol. Alcoholism: Clinical and Experimental Research 17, 515.
Rezvani, A. H., Overstreet, D. H. and Lee, Y. W. (1995) Attenuation of alcohol intake by Ibogaine in three strains of alcohol preferring rats. Pharmacology, Biochemistry and Behavior 52, 615620.[ISI][Medline]
Rezvani, A. H., Overstreet, D. H. and McArthur, R. (1996) Amperozide, a 5-HT-2a receptor antagonist, is more effective in reducing alcohol intake than fluoxetine or duloxetine. Society for Neuroscience Abstract 456.13.
Rose, J. E. and Levin, E. D. (1992) Concurrent agonistantagonist administration for the analysis and treatment of drug dependence. Pharmacology, Biochemistry and Behavior 41, 219226.[ISI][Medline]
Rosenthal, T. C. (1992) Combining insulin and oral agents in diabetes: indications and controversies. American Family Physician 46, 17211727.[ISI][Medline]
Salloum, I. M., Cornelius, J. R., Thase, M. E., Daley, D. C., Kirisci, L. and Spotts C. (1998) Naltrexone utility in depressed alcoholics. Psychopharmacology Bulletin 34, 111115.[ISI][Medline]
Schumm-Draeger, P. M. (1993) Drug therapy of goiter. Iodine, thyroid hormones or combined therapy. Zeitschrift fur die Gesamte Innere Medizin und Ihre Grenzgebiete 48, 592598.[Medline]
Tanada, G., Frau, R. and DiChiara, G. (1995) Local 5-HT3 receptors mediate fluoxetine but not desipramine-induced increase of extracellular dopamine in the prefrontal cortex. Psychopharmacology 119, 1519.[ISI][Medline]
Tiller, J. W., Mitchell, P. and Burrows, G. D. (1992) Monoamine oxidase inhibitors (MAOI) or reversible inhibitors of monoamine oxidase (RIMA)/tricyclic antidepressant (TCA) combination therapy. Australian and New Zealand Journal of Psychiatry 26, 327329.[ISI][Medline]
Volpicelli, J. R., Alterman, A. I., Hayashida, M. and O'Brien, C. P. (1992) Naltrexone in the treatment of alcohol dependence. Archives of General Psychiatry 49, 876880.[Abstract]
Williams, L. D. and Mason, B. J. (1997) Combination pharmacotherapy in nalmefene non-responders. Alcoholism: Clinical and Experimental Research, 21 (suppl.), 33, Abstract 179.
Yamamura, M., Kinoshita, K., Nakagawa, H. and Ishida, R. (1991) Pharmacological study of TA-0910, a new thyrotropin-releasing hormone (TRH) analog (II): involvement of the DA system in locomotor stimulating action of TA-0910. Japanese Journal of Pharmacology 55, 5768.[ISI][Medline]
Zink, R. W., Rohrbach, K. and Froehlich, J. C. (1997) Naltrexone and fluoxetine act synergistically to decrease alcohol intake. Alcoholism: Clinical and Experimental Research 21 (suppl.), 105, Abstract no. 606.