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Alcohol & Alcoholism Vol. 35, No. 1, pp. 76–83, 2000
COMBINATION PHARMACOTHERAPY: A MIXTURE OF SMALL DOSES OF NALTREXONE,
FLUOXETINE, AND A THYROTROPIN-RELEASING HORMONE ANALOGUE REDUCES
ALCOHOL INTAKE IN THREE STRAINS OF ALCOHOL-PREFERRING RATS
AMIR H. REZVANI1,2 *, DAVID H. OVERSTREET2, GEORGE A. MASON2, DAVID S. JANOWSKY2,
MANI HAMEDI2, E. CLARK, Jr2 and YING YANG2
1
Duke University Medical Center, Department of Psychiatry, Box 3412, Durham, NC 27710 and 2The 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)
Abstract — It is common to treat some diseases with more than one medication simultaneously. Since more than
one neurotransmitter system is involved in alcohol-seeking behaviour, then a therapeutic approach that targets more
than one system should be more effective in reducing alcohol intake than one addressing a single system. To test
this hypothesis, we compared the efficacy of low doses of individual drugs reported to reduce voluntary alcohol
drinking to the efficacy of a mixture of these agents at the same low doses in reducing alcohol intake in three strains
of alcohol-preferring rats (P, HAD, and Fawn-Hooded). After establishment of a stable baseline for alcohol intake
in a continuous access paradigm, each rat received separate single i.p. injections of relatively low doses of either
naltrexone (2.0 mg/kg), fluoxetine (1.0 mg/kg), the thyrotropin-releasing hormone analogue TA-0910 (0.2 mg/kg),
a mixture of all three drugs, or the vehicle at 09:30. Each rat received all treatments, with an inter-injection washout
period of at least 3 days. Alcohol and water intakes were measured at 6 and 24 h, and food intake was measured at
24 h, after the injection. Our results show that individual drugs did not significantly affect food, water, or alcohol
intake. However, the mixture significantly reduced alcohol intake in all three strains, but had no effect on food
intake. Similar results were obtained when the HAD rats received an oral dose of the individual drugs or the mixture.
When P rats were given an i.p. injection of the mixture for 10 consecutive days, there was a continued suppressing
effect. These findings show that a combination treatment designed to target simultaneously serotonergic, dopaminergic,
and opioidergic systems can reduce alcohol intake, even though the doses of the individual drugs in the mixture are
relatively low and ineffective when given singly.
INTRODUCTION
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 alcoholpreferring rats. For this initial study, we compared the effects
of naltrexone, an opioid receptor antagonist; fluoxetine, a
serotonin reuptake inhibitor; and TA-0910, a thyrotropinreleasing 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 FawnHooded (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
Alcoholism is a major health problem. In spite of large and
intense efforts devoted to the treatment of this devastating
disease, remediation of alcohol dependence remains a great
challenge. In addition to disulfiram (antabuse) which is not an
effective therapy for most alcoholics, several pharmacological
agents including the opioid receptor antagonists naloxone and
naltrexone (Froehlich et al., 1990; O’Malley et al., 1992;
Volpicelli et al., 1992), calcium channel blockers (Rezvani
and Janowsky, 1990; Rezvani et al., 1991a; Pucilowski et al.,
1992), dopaminergic agents (McBride et al., 1990; Hodge
et al., 1993a), serotonin antagonists (Hodge et al., 1993b),
serotonin uptake inhibitors (Rezvani et al., 1986, 1990, 1991b;
McBride et al., 1990), and GABA-altering drugs (McBride
et al., 1990) have been shown to reduce alcohol intake significantly or to diminish relapse in rodent models of alcoholism
and in alcoholics. However, many of these compounds, in
addition to reducing alcohol intake, may suppress appetite or
have other undesirable effects. Thus, the development of suitable medications with greater selectivity toward excessive
alcohol intake remains a major goal of alcohol researchers.
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.,
*Author to whom correspondence should be addressed.
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© 2000 Medical Council on Alcoholism
COMBINATION PHARMACOTHERAPY FOR ALCOHOLISM
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.
MATERIALS AND METHODS
Animals
The three strains of alcohol-preferring rats were housed
individually in stainless-steel wire mesh cages (26 × 34 ×
20 cm) under constant temperature of 21 ± 1°C and reversed
12 h light–12 h dark cycle (10:00–22:00 dark). These rats consume significantly more alcohol than their respective control
strains: the selectively-bred alcohol non-preferring (NP), the
low alcohol-drinking (LAD) rat, and the Wistar rat. The FH
and P rats were derived from the Wistar rat. Water and food
(Agway Prolab Rat/Mouse/Hamster 3000 formula, Agway,
Syracuse, USA) were provided ad lib.
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 1–2 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
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(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 stainlesssteel 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)
× 100 (Rezvani et al., 1990; Rezvani and Grady, 1994). Statistical differences between different groups were determined
using analysis of variance followed by Newman–Keuls protected t-test.
RESULTS
Experiment 1: acute systemic administration
Baseline consumption levels of alcohol were 8.47 ± 0.73,
6.9 ± 0.8, and 6.1 ± 0.56 g/kg/day for P, HAD, and FH rats, respectively (means ± SEM). Compared to the vehicle, a single
injection of the mixture significantly suppressed alcohol
intake (Fig. 1A) and alcohol preference (Fig. 1B) in P rats.
Separately administered naltrexone or TA-0910 did not induce
a significant effect on 6-h alcohol intake and alcohol preference, and the effect of fluoxetine was significantly less than
that of the mixture of drugs (Fig. 1A). The mixture of drugs,
but not the individual drugs, significantly increased water
intake at 6 h (Fig. 1C). Neither the mixture of drugs nor the
individual drugs changed food intake (Fig. 1D).
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A. H. REZVANI et al.
Fig. 1. Effects of a single i.p. administration of naltrexone, fluoxetine, TA-0910, or a mixture of the three drugs on 6-h alcohol intake and
alcohol preference and water and food intake in alcohol-preferring P rats.
Rats had free 24-h access to water, food, and a solution of 10% (v/v) alcohol. Drug doses were as follows: naltrexone (2 mg/kg), fluoxetine
(1 mg/kg), TA-0910 (0.2 mg/kg). *P < 0.05 and **P < 0.001 vs saline.
In both HAD and FH rats, systemic administration of the
mixture, but not its individual constituents, also significantly
reduced alcohol intake (Fig. 2). However, contrary to P rats,
water intake was not significantly affected in these two strains
(Table 1). Food intake was also unaffected by the mixture or
by individual drugs in FH or HAD rats (Table 1).
Experiment 2: acute oral administration
Compared with the vehicle, oral administration of the mixture, and fluoxetine alone, significantly reduced alcohol intake
in HAD rats at 6 h (Fig. 3). However, fluoxetine administration
was significantly (P < 0.01) less effective than the mixture
(Fig. 3) and also significantly (P < 0.01) reduced water intake
in HAD rats (Table 2). Neither the mixture nor its constituents
reduced the 24-h food intake (Table 2). Oral administration
of naltrexone or TA-0910 alone did not exert any significant effects on alcohol, food or water intakes (Fig. 3 and
Table 2).
Experiment 3: chronic systemic administration
Repeated single daily i.p. administration of the mixture for
10 consecutive days, but not the vehicle, significantly reduced
alcohol intake in P rats, both at 6 (P < 0.0001, Fig. 4A) and
24 h (P < 0.004, Fig. 4B) without development of tolerance to
the suppressant effect of the mixture on alcohol intake. Chronic
administration of the mixture to P rats also significantly
(P < 0.03) increased the water intake at 6 h (Fig. 5A) but not
at 24 h. (Fig. 5B), whereas food intake was increased significantly (P < 0.0001) following chronic administration of the
mixture to these rats (Fig. 6).
DISCUSSION
The present study shows that a mixture composed of
relatively low doses of three different kinds of alcohol intakesuppressing drugs can significantly reduce alcohol intake
COMBINATION PHARMACOTHERAPY FOR ALCOHOLISM
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Fig. 3. Effects of a single oral administration of naltrexone, fluoxetine,
TA-0910, or a mixture of the three drugs on 6-h alcohol intake in HAD rats.
Rats had free 24-h access to water, food, and a solution of 10% alcohol.
The doses of the drugs were as follows: naltrexone (6 mg/kg), fluoxetine
(3 mg/kg), TA-0910 (0.6 mg/kg). *P < 0.05 and **P < 0.01 vs saline.
Table 2. Effects of oral administration of the mixture and individual
constituents on water and food intakes in eight HAD rats
Intakes
Water
(g/kg/6 h)
Food
(g/kg/day)
Fig. 2. Effects of a single i.p. administration of naltrexone, fluoxetine,
TA-0910, or a mixture of the three drugs on 6-h alcohol intake in FH and
HAD rats.
Rats had free 24-h access to water, food, and a solution of 10% (v/v)
alcohol. Doses of drugs were as in Fig. 1. *P < 0.02 and **P < 0.01 vs
saline.
Table 1. Effects of a single systemic (i.p.) administration of the
mixture and individual constituents on water and food intake in
FH and HAD rats
Intakes
FH rats
Water
(g/kg/6 h)
Food
(g/kg/day)
HAD rats
Water
(g/kg/6 h)
Food
(g/kg/day)
Saline
Naltx
Fluox
TA-0910 Mixture
14 ± 2.0
9 ± 3.0
10 ± 3.0
11 ± 5.0
12 ± 2.0
47 ± 2.0 44 ± 3.0
49 ± 4.0
45 ± 3.0
46 ± 2.0
6.0 ± 2.0 3.0 ± 1.0 5.0 ± 1.0
8.0 ± 4.0
7 ± 3.0
52 ± 4.0 49 ± 6
47 ± 6.0
51 ± 5.0
48 ± 2.0
Naltx = naltrexone, 2 mg/kg; Fluox = fluoxetine, 1 mg/kg; TA-0910,
0.2 mg/kg.
Values are means ± SEM (n = 10–15 for FH and eight for HAD rats).
Saline
Naltx
Fluox
TA-0910
Mixture
3.0 ± 1.0 3.0 ± 2.0 0.3 ± 0.3* 2.0 ± 1.0
4.0 ± 1.0
47 ± 2.0 43 ± 3.0 42 ± 2.0
41 ± 6.0
42 ± 3.0
Naltx = naltrexone, 6 mg/kg; Fluox = fluoxetine, 3 mg/kg; TA-0910,
0.6 mg/kg.
Values are means ± SEM. *Significantly different from saline
at P < 0.01.
without altering food consumption in three different strains of
alcohol-preferring rats. Two of the component drugs, fluoxetine
and naltrexone, have been shown to reduce food intake and
body weight in rats when administered separately at doses that
individually suppress alcohol intake (Murphy et al., 1988;
Overstreet et al., 1995; Rezvani et al., 1996; Gardell et al.,
1997). The fact that the mixture of drugs was more efficacious
in suppressing alcohol intake than any of the constituents alone,
but did not suppress food intake, suggests that the serotonergic, dopaminergic, and opioidergic systems may interact
synergistically or additively to reduce alcohol consumption
but not food intake. Thus, the combination treatment may
produce fewer or weaker non-specific side-effects, such as
appetite suppression, which might be counter-productive in
treating alcoholism.
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
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A. H. REZVANI et al.
Fig. 4. Effects of repeated i.p. administration of saline or the mixture of
drugs (naltrexone + fluoxetine + TA-0910) on alcohol intake at 6 and 24 h
in P rats.
Rats had free 24-h access to water, food, and a solution of 10% alcohol.
The i.p. doses were the same as those given in the single experiments of
Fig. 1. F(17,1) = 62.8, P < 0.0001 for 6-h data and F(17,1) = 11.5, P < 0.004
for 24-h data. *P < 0.05 and **P < 0.01 vs the corresponding saline values.
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
Fig. 5. Effects of repeated i.p. administration of saline or the mixture of
drugs (naltrexone + fluoxetine + TA-0910) on water intake in P rats.
Rats had free 24-h access to water, food, and a solution of 10% alcohol.
Drug administration details are as in Fig. 4. F(17,1) = 5.5, P < 0.03 for 6-h
data and F(17,1) = 2.4, P = 0.14 for 24-h data. *P < 0.05 and **P < 0.01
vs the corresponding saline values.
Fig. 6. Effects of repeated i.p. administration of saline or the mixture of
drugs (naltrexone + fluoxetine + TA-0910) on food intake in P rats.
Rats had free 24-h access to water, food, and a solution of 10% alcohol.
Other details are as in Fig. 5. F(17,1) = 25.9, P < 0.0001. *P < 0.05 and
**P < 0.01 vs the corresponding saline values.
COMBINATION PHARMACOTHERAPY FOR ALCOHOLISM
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 crosstolerance 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
β-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 alcoholmediated enhancement of DA release, reduces the motivation
to drink.
It is also possible that drug–drug 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
81
(5 mg/kg) on alcohol intake is no different from those of either
drug in Sprague–Dawley 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.
Acknowledgements — We greatly appreciate the generous gifts of fluoxetine
from Eli Lilly and Co. and TA-0910 from Tanabi Inc., Japan. We also thank
Dr T.-K. Li and his colleagues at Indiana University (P50-AA07611) for providing the P and HAD rats. This work was supported in part by a grant from
the NIAAA (AA07809).
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