JOURNALOF

PSYCHIATRIC

ARTICLE IN PRESS

Journal of Psychiatric Research xxx (2004) xxx–xxx

www.elsevier.com/locate/jpsychires

RESEARCH

Effects of fluoxetine on ethanol withdrawal syndrome in rats

I. Tayfun Uzbay a,*, Esra Sa�glam b, Hakan Kayir a, Turgay C�elik a, Mansur Beyazy€urek c

a Department of Medical Pharmacology, Faculty of Medicine, Psychopharmacology Research Unit, G€ulhane Military Medical Academy,

Etlik, 06018 Ankara, Turkeyb Department of Pharmacology, Faculty of Medicine, Maltepe University, Istanbul, Turkey

c Department of Psychiatry, Faculty of Medicine, Maltepe University, Istanbul, Turkey

Received 15 August 2003; received in revised form 17 November 2003; accepted 26 November 2003

Abstract

The present study was designed to investigate the effects of fluoxetine, a selective serotonin reuptake inhibitor, on ethanol

withdrawal syndrome in rats. Adult male Wistar rats (218–255 g) were subjects. Ethanol (7.2%, v/v) was given to rats by a liquid diet

for 21 days. Control rats were pair fed an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. Fluoxetine (2.5,

5 and 10 mg/kg) and saline were injected to rats intraperitoneally just before ethanol withdrawal. After 2nd, 4th and 6th hour of

ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, agitation, stereo-

typed behavior, wet dog shakes and tremor were recorded or rated. A second series of injections was given at 6 h after the first one,

and subjects were then tested for audiogenic seizures. Fluoxetine produced some dose-dependent and significant inhibitory effects on

all the signs of ethanol withdrawal during ethanol withdrawal period. Our results suggest that acute fluoxetine treatment has some

beneficial effects on ethanol withdrawal in rats. Thus, this drug may be useful for treatment of ethanol withdrawal syndrome.

� 2003 Elsevier Ltd. All rights reserved.

Keywords: Ethanol withdrawal syndrome; Ethanol dependence; Fluoxetine; Rat(s)

1. Introduction

Alcoholism and depression are often associated in

psychiatric patients. Many alcoholic patients have

symptoms of depression (Weissman and Myers, 1980;

Miguel-Hidalgo and Rajkowska, 2003). Some antide-

pressant drugs are of general use in patients with ethanoldependence. They are mainly indicated in the ethanol

withdrawal and the treatment of combined psychiatric

disorders (Miller, 1995; Favre et al., 1997; Myrick et al.,

2001).

Serotonergic drugs are of particular interest in that

point, especially because of the hypothesized links be-

tween mood disorders and ethanol consumption. Neu-

rochemical findings from clinical (Roy et al., 1987; LeMarquand et al., 1994) and experimental (Murphy et al.,

* Corresponding author. Tel.: +90-312-304-4764; fax: +90-312-304-

2010.

E-mail address: tuzbay@gata.edu.tr (I.T. Uzbay).

0022-3956/$ - see front matter � 2003 Elsevier Ltd. All rights reserved.

doi:10.1016/j.jpsychires.2003.11.007

1987) studies suggested some significant chances in

central serotonergic neurotransmission during ethanol

consumption and/or withdrawal. A couple of previous

study from our laboratory indicated some marked re-

ductions in striatal serotonin (5-hydroxytriptamine, 5-

HT) levels of rats during early ethanol withdrawal

(Uzbay et al., 1998) and chronic ethanol consumption(Uzbay et al., 2000a). These observations imply that

there might be a correlation between decreasing sero-

tonergic activity and ethanol withdrawal syndrome.

Fluoxetine is a selective 5-HT reuptake inhibitor

(SSRI) drug that exhibits antidepressant activity in ex-

perimental models (Detke et al., 1995; Contreras et al.,

2001) and clinical trials (Stokes and Holtz, 1997;

Vaswani et al., 2003). Fluoxetine increases serotonergictransmission in synaptic cleft (Stahl, 1996). Studies

suggest that SSRIs such as zimelidine, citalopram and

fluoxetine may reduce ethanol consumption and that

is not an antidepressant effect (Miller, 1995). In a pre-

vious study, we observed some significant reductions in

2 I.T. Uzbay et al. / Journal of Psychiatric Research xxx (2003) xxx–xxx

ARTICLE IN PRESS

striatal 5-HT levels in rats during early ethanol with-

drawal (Uzbay et al., 1998). If that is true, some bene-

ficial effects of 5-HT enhancers such as fluoxetine on

ethanol withdrawal syndrome could be expected and

agents that can increase central serotonergic neuro-transmission might be useful for treatment of ethanol

abuse and/or dependence. Thus, limited clinical studies

have indicated that fluoxetine reduced the extent of

anxiety and depression during ethanol withdrawal

(Romeo et al., 2000) and at antidepressant doses; it was

able to prevent relapses in alcoholics (Janiri et al., 1996).

However, detailed studies have not been reported that

investigate the effects of fluoxetine on several signs ofethanol withdrawal.

The main objective of the present study was to in-

vestigate the effects of fluoxetine on the signs of ethanol

withdrawal syndrome in rats.

2. Material and methods

2.1. Animals and laboratory

All procedures in this study are in accordance with

the Guide for the Care and Use of Laboratory Animals

as adopted by the National Institutes of Health (USA).

Adult male Wistar rats (214–339 g weight at the begin-

ning of the experiments) were subjects. They were

housed in a quiet and temperature and humidity-con-trolled room (22� 3 �C and 65� 5%, respectively) in

which a 12-h light/dark cycle was maintained (07:00–

19:00 h light). Exposure to ethanol and all behavioral

experiments involved in ethanol withdrawal syndrome

were carried out in the separate and isolated laborato-

ries, which have the same environmental conditions with

the colony room.

2.2. Chronic exposure to ethanol

For chronic ethanol exposure, the rats were housed

individually and ethanol was given in the modified liquid

diet as previously described (Uzbay and Kayaalp, 1995).

The rats received a modified liquid diet with or without

ethanol ad libitum. No extra chow or water was sup-

plied. The composition of the modified liquid diet withethanol is: cow milk 925 ml (Mis S€ut, Turkey), 25–75 ml

ethanol (96.5% ethyl alcohol; Tekel, Turkish State

Monopoly), vitamin A 5000 IU (Akpa _Ilac� Sanayi,

Turkey) and sucrose 17 g (Uzbay and Kayaalp, 1995).

This mixture supplies 1000.7 kcal/L.

At the beginning of the study, rats were given the

modified liquid diet without ethanol for 7 days. Then

liquid diet with 2.4% ethanol was administered for3 days. The ethanol concentration was increased to

4.8% for the following 4 days and finally to 7.2% for

21 days. Liquid diet was freshly prepared daily and

presented at the same time of the day (10:00 h). The

weight of the rats was recorded every day, and daily

ethanol intake was measured and expressed as g per kg

per day. Control rats (n ¼ 8) were pair fed an isocaloric

liquid diet containing sucrose as a caloric substitute toethanol.

2.3. Drug used in the study

Fluoxetine hydrochloride was purchased from Sigma

Chemical (USA). The drugs were dissolved in saline.

Fluoxetine or saline were injected to rats intraperitone-

ally at a volume of 1 ml/200 g body weight. Drug so-lutions were prepared freshly in the morning of each

experiment.

2.4. Evaluation of ethanol withdrawal syndrome

At the end of the exposure to 7.2% ethanol-contain-

ing liquid diet, ethanol was withdrawn from the diet by

replacing the diet with one that did not contain ethanolat 10:00 h. Ethanol-dependent rats were then assigned

into four groups randomly (n ¼ 8 for each group).

Fluoxetine (2.5, 5 and 10 mg/kg) and saline were injected

to the rats 30 min before ethanol withdrawal testing.

The rats were then observed for 5 min at the 2nd, 4th

and 6th hour of the withdrawal period. At each obser-

vation time, rats were assessed simultaneously for the

following behavioral conditions: agitation, tremor, ste-reotyped behavior and wet dog shakes. Locomotor ac-

tivities of the rats were also recorded (Opto Varimex

Minor, Columbus, OH, USA) as a total of horizontal,

vertical and ambulatory activities of the rats and ex-

pressed as mean� SEM. The subjects were returned

to their home cages between the observation periods.

Wet dog shakes, tremors and audiogenic seizures were

assessed as incidence. Wet dog shakes behavior wasconsidered positive if they occurred at least three times

during the observation period. Tremor was determined

after lifting rats vertically by the tail; positive was

assigned to rats showing clearly distinct forelimb tremor

(Frye et al., 1983). Grooming, sniffing, head weaving,

gnawing and chewing were observed as major stereo-

typed behaviors during the ethanol withdrawal in the

study. Stereotypic behaviors and agitation were scoredusing a rating scale as previously described (Uzbay

et al., 1997; Uzbay et al., 2000b) (Table 2).

Each group received a second injection of its original

drug given at 6 h after the first injection. After 6 h of

withdrawal testing, rats were exposed to an audiogenic

stimulus (100 dB) for 60 s in a separate and soundproof

place in the laboratory. The incidence and latency of the

audiogenic seizures were recorded.Control rats receiving no ethanol contained liquid

diet were also evaluated for ethanol withdrawal signs as

parallel to ethanol dependent groups.

Table 2

Rating scale for agitation and stereotyped behavior signs induced by

ethanol withdrawal in rats

Signs Scoring

Agitation 0: no irritability or aggressive behavior

1: rats showing mild or moderate irritability

2: very irritable

3: handling vocalization and moderately aggressive

4: handling vocalization and very aggressive

5: spontaneous vocalization and very aggressive

Stereotyped

behavior

0: no stereotyped behavior

1: rats showing only one stereotyped behavior

during observation (5 min)

2: two different stereotyped behaviors

3: three different stereotyped behaviors

4: four different stereotyped behaviors

5: five or six different stereotyped behaviors

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All experiments were carried out during the light

period. All ratings were done by a naive observer who

was unaware of which treatment the rats received.

2.5. Measurements of locomotor activity in naive control

rats

Fluoxetine (2.5, 5 and 10 mg/kg) and saline were

administered in four groups of naive (not ethanol-

dependent) Wistar rats. Thirty minutes after the injec-

tions, rats were put into the locomotor activity test

apparatus and locomotor activities of the rats were

measured for 30 min. The results of the locomotor ac-tivity tests were expressed as mean� SEM.

2.6. Statistical analysis

Changes in locomotor activities and body weights of

ethanol-dependent rats as compared with ethanol non-

dependent control rats were analyzed by unpaired (be-

tween groups) Student�s t-test. Analysis of variance(one-way ANOVA) followed by Dunnett�s test was usedin evaluation of the effects of fluoxetine on the loco-

motor activities. The intensities of the agitation and

stereotyped behaviors in different groups were compared

by Mann–Whitney-U test. Comparison of the incidences

of the audiogenic seizures, wet dog shakes behavior and

tremors were done by v2-square test. The level of sig-

nificance was set at p < 0:05 levels.

3. Results

3.1. Ethanol consumption of the rats

Daily ethanol consumption of the rats in control and

fluoxetine treated groups ranged from 11.39� 0.47 to17.24� 0.6 g/kg during the exposure to ethanol (7.2%).

No significant difference between the groups was ob-

served.

Body weight changes of the ethanol-fed and control

rats are presented in Table 1. Body weights of the rats

increased progressively during the study. An increase in

body weight of approximately 8% (ethanol-fed) and 12%

Table 1

Changes in weight gains of the rats fed by liquid diet with or without

ethanol

Groups Body weight (g) Changes

Beginning of

the study

End of the

Study

Control 236.71� 4.87 265.54� 5.80 +12%

Ethanol-fed 226.04� 5.38 244.54� 5.55 +8%

Values are means� SEM; g, gram; Control, liquid-diet fed without

ethanol.

(control) over the initial weights was observed at the end

of the study.

3.2. Behavioral changes during ethanol withdrawal

A significant locomotor hyperactivity was observed

in the ethanol-dependent groups at the 2nd and 6th hour

of the withdrawal-testing period as compared with theethanol non-dependent saline groups (Student�s t-test;ps < 0:05 (Fig. 1). Other behavioral signs of ethanol

withdrawal syndrome such as agitation, stereotyped

behaviors, tremor and wet dog shakes appeared at the

2nd hour and lasted during the whole observation pe-

riod (Fig. 2(A)–(D) dark bars). Audiogenic seizures

occurred at 6th hour of ethanol withdrawal with an

incidence of 50% and latency of 21.75� 4.56 s in etha-nol-dependent control group (Table 3). No ethanol

withdrawal signs were observed in the ethanol non-

dependent rats.

Fig. 1. Effects of fluoxetine on the locomotor activities of the rats [n ¼ 8

for each group; Flu., Fluoxetine; h, hour; # p < 0:05 significantly dif-

ferent from Control ()), Student�s t-test; �p < 0:05 significantly differ-

ent from Control (+), Dunnett�s test; ): ethanol non–dependent; +:ethanol-dependent].

Fig. 2. Effects of fluoxetine treatment on the signs of ethanol withdrawal syndrome [n ¼ 8 for each group; Flu., Fluoxetine; h, hour; �p < 0:05

significantly different from Control, Mann–Whitney-U test for score and v2-square test for %].

4 I.T. Uzbay et al. / Journal of Psychiatric Research xxx (2003) xxx–xxx

ARTICLE IN PRESS

3.3. Effects of fluoxetine on ethanol withdrawal syndrome

Fluoxetine produced some dose-dependent and sig-

nificant inhibitory effects on locomotor hyperactivity at

2nd and 6th hour of ethanol withdrawal [F ð3; 28Þ ¼4:073; p ¼ 0:016 and F ð3; 28Þ ¼ 3:362; p ¼ 0:03, re-

spectively] (Fig. 1). Post-hoc analysis of data indicated

that fluoxetine (5 mg/kg) significantly reduced ethanol

withdrawal-induced locomotor hyperactivity (p < 0:05,Dunnett�s test). It produced some significant reductions

in the intensity of agitation, stereotyped behaviors and

in the incidence of tremor, wet dog shakes and audio-

genic seizures (Fig. 2(A)–(D) and Table 3).

Table 3

Effects of fluoxetine on incidence of the audiogenic seizures in ethanol-

dependent rats

Treatment Incidence (%)

Saline (ethanol non-dependent) 0.0 (0/8)

Saline (ethanol-dependent) 50 (4/8)

Fluoxetine (2.5 mg/kg) 12.5 (1/8)�

Fluoxetine (5 mg/kg) 0.0 (0/8)�

Fluoxetine (10 mg/kg) 12.5 (1/8)�

n ¼ 8 for each group. Figures in the parenthesis represent the

number of animals that have seizure activity after audiogenic stimulus.* p < 0:05 significantly different from control (chi-square test).

3.4. Effects of fluoxetine on locomotor activity in ethanol

non-dependent (naive) rats

Fluoxetine treatment (2.5, 5 and 10 mg/kg) did not

cause any significant change on locomotor activity ofthe naive (no ethanol-dependent) rats (data not shown).

4. Discussion

The main finding of the present study is that fluoxe-

tine, an SSRI, has some inhibitory effects on the with-

drawal syndrome in ethanol-dependent rats. Consistentwith our previous findings (Uzbay et al., 1994; Uzbay et

al., 1997; Uzbay et al., 1998; Uzbay et al., 2000a,b) the

present data demonstrated that daily ethanol con-

sumption ranged from 11 to 17 g/kg for 21 consecutive

days produced physical dependence in rats. Maj-

chrowicz (1975) also showed that dependence and signs

of ethanol withdrawal could be produced in rats with 4-

day intragastric administration of 9–15 g/kg of ethanolper day. Thus, we observed several signs of ethanol

withdrawal such as locomotor hyperactivity, agitation,

stereotyped behavior, tremor, wet dog shakes and au-

diogenic seizures. Because we did not observe any sig-

nificant change on the locomotor activity in naive

group, the beneficial effects of fluoxetine on ethanol

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ARTICLE IN PRESS

withdrawal syndrome are not related to other non-spe-

cific effects such as sedation or muscle relaxation.

A main body of several studies indicated that there

was a marked relationship between ethanol intake,

ethanol dependence and central serotonergic system(Tollefson, 1989; McBride et al., 1993; Wallis et al.,

1993; De Witte et al., 2003). It could be expected to

influence the occurrence of mood symptoms in ethanol

dependents, especially during withdrawal. This hypoth-

esis was tested in ethanol dependent rats, suggesting that

deficits in accumbal 5-HT release may contribute to the

negative affective consequences of ethanol withdrawal

(Weiss et al., 1996). In human, a significant reduction inthe availability of 5-HT transporters was found in the

raphe nuclei area of recently detoxified alcoholics, which

was strongly correlated with increased levels of anxiety

and depression during early abstinence. Furthermore,

reduced transcriptional efficiency of 5-HT transporter

may underlie another set of symptoms during ethanol

withdrawal (Heinz et al., 1998; De Witte et al., 2003). In

a study from our laboratory (Uzbay et al., 1998), weshowed some significant reductions in striatal 5-HT

levels of ethanol-dependent Wistar rats during the first 6

h of ethanol withdrawal. We also observed that signs of

ethanol withdrawal such as increased locomotor activity

and stereotyped behaviors, tremors, wet dog shakes,

agitation and audiogenic seizures appeared in a parallel

group of the ethanol-dependent rats. Taking together,

these findings indicate a relationship between reducedbrain 5-HT levels and some behavioral signs of ethanol

withdrawal. Thus, fluoxetine may exhibit its inhibitory

effects on the behavioral signs of ethanol withdrawal by

increasing serotonergic activity in the synaptic cleft.

However, fluoxetine could also affect other neuro-

transmitter systems that involved in ethanol dependence

and withdrawal. Dopaminergic neurotransmission is

also responsible for various symptoms of ethanol with-drawal as well as serotonergic neurotransmission (De

Witte et al., 2003). It has been shown that repeated

fluoxetine administration induces adaptive changes in

the dopaminergic system and especially enhances the

functional responsiveness of dopamine D2/D3 receptors

(Dziedzicka-Wasylewska et al., 2002). Ainsworth et al.

(1998) also suggested that repeated administration of

fluoxetine increased dopamine D2-like receptor functionin rats. On the other hand, bromocriptine, dopamine D2

receptor agonist, has been used to treat ethanol with-

drawal to a limited extent (Borg and Weinholdt, 1982;

Sitland-Marken et al., 1990) and it had some beneficial

effects of the signs of ethanol withdrawal in Wistar rats

(Uzbay et al., 1994). The effects of fluoxetine on dopa-

mine D2 receptors may be responsible for its inhibitory

effects of some signs of ethanol withdrawal. Moreover,Mirovsky et al. (1995) showed that dopaminergic and

serotonergic agonists given jointly, but not separately,

prevented ethanol withdrawal seizures as effectively as

benzodiazepines. Thus, fluoxetine as a drug that have

both serotonergic and dopaminergic properties may be a

good choice for acute treatment of ethanol withdrawal.

Another explanation may be a central inhibition of

nitric oxide synthase (NOS), an enzyme that producesnitric oxide (NO) from precursor LL-arginine. Several

studies have been shown that NOS inhibitors cause a

prominent attenuation signs of ethanol withdrawal

syndrome in rats (Adams et al., 1995; Lallemand and De

Witte, 1997; Uzbay et al., 1997). Recently, Wegener et

al. (2003) suggested that local administration of sero-

tonergic antidepressants significantly decreased hippo-

campal NOS activity in rat brain. In addition, somestudies indicated that fluoxetine had some NOS inhibi-

tory effects in human (Yaron et al., 1999) and rats (Luo

and Tan, 2001). On the other hand, activation of ex-

citatory amino acid receptors, particularly the NMDA

subtype, causes an influx of calcium into neurons lead-

ing to calmodulin-dependent activation of NOS (Gart-

hwaite et al., 1989). Thus, activation of NMDA

receptors may be accompanied by formation of NO(Garthwaite, 1991). The role of NMDA receptors in the

development of ethanol dependence is well known

(Krystal et al., 2003). NMDA receptor activation relies

upon NO as a significant neuronal messenger, then NOS

inhibition in the glutamate system may also be respon-

sible for the beneficial effects of fluoxetine on ethanol

withdrawal syndrome.

In conclusion, fluoxetine seems to be a pharmaco-logically active agent on mechanisms involved in de-

velopment of physical dependence to ethanol in rats,

and it may have therapeutic potential in the treatment of

ethanol-type dependence.

Acknowledgements

Authors would like to thank to Dr. Burak K€uc�€uk and

Mr. Selami Alan for their valuable technical assistance

to the study.

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