ATTENUATION OF ETHANOL WITHDRAWAL SIGNS BY HIGH DOSES OF L-ARGININE IN RATS

I. Tayfun Uzbay* and B. Faruk Erden1

Gülhane Military Medical Academy, Faculty of Medicine, Department of Medical Pharmacology, Psychopharmacology Research Unit, Etlik 06018 Ankara and
1 University of Kocaeli, Faculty of Medicine, Department of Pharmacology, Derince 41900 Kocaeli, Turkey

Received 15 May 2002; in revised form 13 September 2002; accepted 16 January 2003


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Aims: Effects of l-arginine, a nitric oxide (NO) precursor, on ethanol withdrawal syndrome were investigated in rats. Methods: Ethanol (7.2% v/v) was given to rats by a liquid diet for 16 days. l-Arginine (250, 500 and 1000 mg/kg) or saline were injected into rats intraperitoneally 20 min before ethanol withdrawal. All injections were repeated 30 min before the 6th h of the observation period. The effects of l-arginine on ethanol withdrawal syndrome were evaluated during the first 6 h of ethanol withdrawal. Results: l-Arginine (250 mg/kg) potentiated significantly vertical and ambulatory locomotor activities at only the 30th minute of the observation period. l-Arginine (500 and 1000 mg/kg) inhibited behavioural signs of ethanol withdrawal significantly. l-Arginine (1000 mg/kg) also prolonged the latency and attenuated the intensity of audiogenic seizures. This dose of l-arginine also reduced both vertical and ambulatory locomotor hyperactivity of the rats from the 2nd hour of ethanol withdrawal. l-Arginine (1000 mg/kg) did not produce any significant change in the locomotor activities of the naive (non-ethanol-dependent) rats. Conclusions: Our results indicate that l-arginine at high doses alleviates the signs of ethanol withdrawal syndrome in rats.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
l-Arginine is the physiological precursor for the formation of nitric oxide (NO) in peripheral (Palmer et al., 1988Go) and central (Knowles et al., 1989Go) tissues. NO is formed by conversion of l-arginine and molecular oxygen in the presence of NO synthase (NOS). The process is inhibited by several NOS inhibitors, such as NG-nitro-l-arginine methyl ester (l-NAME) and 7-nitro indazole (7-NI) (Rees et al., 1990Go; Moncada et al., 1997Go).

NO has been implicated in several brain functions, including modulation of nociception (Moore et al., 1991Go, 1993Go), learning and memory (Yamada et al., 1995Go), anxiety (Quock and Nguyen, 1992Go), seizure activity (Kaputlu and Uzbay, 1997Go), feeding (Morley and Flood, 1991Go) and drinking (Calapai et al., 1992Go) behaviours, regulation of release and uptake of neurotransmitters such as dopamine (Yamada et al., 1995Go), and development of dependence on various substances, such as ethanol and opioids (Uzbay and Oglesby, 2001Go). An l-arginine-NO pathway also exists in the central nervous system (Garthwaite, 1991; Snyder and Bredt, 1991Go; Bredt and Snyder, 1992Go; Moncada and Higgs, 1993Go), with NOS activity found in various amounts in all major brain regions (Forstermann et al., 1990Go).

Some studies have indicated a possible relationship between ethanol withdrawal syndrome and NO. Adams et al.(1995)Go observed that some behavioural signs of ethanol withdrawal, such as hyperactivity, tremors and rigidity, were inhibited by l-NAME, a NOS inhibitor, and these signs were enhanced by isosorbide dinitrate, an NO donor. They hypothesized that NO mediates the behavioural aspects of ethanol withdrawal. This hypothesis was further confirmed by the results of studies investigating the effects of various NOS inhibitors on the ethanol withdrawal syndrome in rats (Lallemand and De Witte, 1997Go; Uzbay et al., 1997Go). If the hypothesis that NO mediates the ethanol withdrawal syndrome is true, it would be expected that like NO donors, l-arginine which is a precursor of NO, should also augment the severity of ethanol withdrawal. However, in our preliminary study (Uzbay et al., 1995Go), we observed interestingly that l-arginine treatment at high doses produced some inhibitory effects on the incidence of audiogenic seizures in ethanol-dependent rats.

The main objective of the present study was to investigate the effects of various doses of l-arginine, a NO precursor, on various behavioural symptoms of the ethanol withdrawal syndrome, including audiogenic seizures, in rats.


    MATERIALS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
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 (Bethesda, MD, USA). Adult male Wistar rats (225–275 g at the beginning of the experiments) were used. They were placed in a quiet, temperature- and humidity-controlled room (22 ± 3°C and 62 ± 7% relative humidity) in which 12–12 h light–dark cycle was maintained (lights on 08:00–20:00).

Drugs
l-Arginine (Sigma Chemical, St Louis, MO, USA) was dissolved in saline and injected intraperitoneally at a volume of 1 ml/100 g. Ethanol (96.5 % ethyl alcohol) was purchased from Turkish State Monopoly.

Chronic ethanol consumption
The rats were individually housed in metal cages and assigned to separate groups. Ethanol (7.2% v/v) was given to rats in a modified liquid diet as previously described (Uzbay and Kayaalp, 1995Go). At the beginning of the study, the modified liquid diet without ethanol was given to rats for 7 days. Then liquid diet with 2.4% (v/v) ethanol was administered for 3 days. The ethanol concentration was increased to 4.8% (v/v) for the following 4 days and finally to 7.2% (v/v) for 16 days. The liquid diet was prepared daily and presented at the same time of day (10:00). The weight of the rats was recorded every day and daily ethanol intake was measured and expressed as g/kg per day. Naive rats were pair-fed with an isocaloric liquid diet containing sucrose as a caloric substitute for ethanol.

Drug treatment and evaluation of drug effects on ethanol withdrawal
At the end of the exposure to the 7.2% ethanol-containing liquid diet, ethanol was withdrawn from the diet by replacing the diet with that without ethanol at 10:00 and the ethanol-dependent rats were assigned to separate groups (n = 10 each). l-Arginine (250, 500 and 1000 mg/kg), and saline were injected intraperitoneally to separately grouped rats 20 min before ethanol withdrawal.

Then, the rats were observed for 5 min at the 30th minute, 2nd, 4th and 6th hours of the withdrawal period. At each observation session, rats were assessed simultaneously for the following comprehensive behavioural conditions: vertical and ambulatory locomotor activities (Opto Varimex Minor, Columbus, OH, USA), body posture, gait, agitation, tail stiffness, tremor, stereotyped behaviour and wet dog shakes (Uzbay et al., 1994Go; Uzbay and Kayaalp, 1995Go).

Tremors and wet dog shakes were expressed as incidence. Wet dog shake behaviour was considered significant if it occurred at least three times during the observation period. Tremor was determined after lifting rats vertically by the tail: a positive score was assigned to rats clearly showing distinct forelimb tremor when rotated 180° around the axis of the tail. Grooming, sniffing, head weaving, gnawing and chewing were observed as stereotyped behaviours during ethanol withdrawal in the study. Stereotyped behaviours, abnormal posture and gait, tail stiffness and agitation were scored using a rating scale as previously described (Uzbay et al., 1997Go) (Table 1Go). The intensity of these parameters was expressed as a median value. The ratings were done by naive observers.


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Table 1. Rating scale for the behavioural signs of ethanol withdrawal in rats
 
All injections were repeated 30 min before the 6th hour of ethanol withdrawn. At the 6th hour of the withdrawal, an audiogenic stimulus (100 dB) was given to rats with a cut-off time of 1 min (Morriset et al., 1990Go). Then the incidence, intensity and latency of the seizures were recorded. The intensity of the seizures was scored as previously described (Uzbay and Kayaalp, 1995Go; Uzbay et al., 1997Go).

Naive control experiment
l-Arginine (1000 mg/kg) and saline were also administered to two groups of naive rats (pair-fed with control liquid diet) (n = 10 each). Vertical and ambulatory locomotor activities were recorded by the same method during the first 6 h after injections. Naive control animals were also evaluated for the behavioural symptoms of ethanol withdrawal including audiogenic seizures.

Statistical analysis
Changes in vertical and ambulatory locomotor activities of ethanol-dependent rats, as compared with ethanol non-dependent control rats, were analysed by unpaired (between groups) Student’s t-test. Latency of the audiogenic seizures was evaluated by Student’s t-test. Analysis of variance (one-way ANOVA) followed by Dunnett’s test was used in evaluation of the effects of l-arginine on the locomotor activities of ethanol-dependent rats for each observation interval. The intensities of the signs appearing in ethanol withdrawal in different groups were compared by Mann–Whitney U-test. Comparison of incidences of the audiogenic seizures, tremors and wet dog shake behaviours were made by the {chi}2 test. The level of significance was set at a P < 0.05 level.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Ethanol consumption and body weight changes
Daily ethanol consumption of the rats was in a range of 13.2–16.1 g/kg during exposure to ethanol (7.2%). No significant differences between the ethanol-ingesting groups were observed.

Body weights of the ethanol-treated rats were 248.53 ± 2.83 and 256.83 ± 3.88 g (means ± SEM) just before ethanol consumption and ethanol withdrawal, respectively.

Behavioural changes during the first 6 h of ethanol withdrawal
Locomotor hyperactivity was observed in the ethanol-dependent, in comparison with the naive group (ethanol non-dependent) from the 2nd h of the withdrawal (Fig. 1A and BGo). The other behavioural signs of ethanol withdrawal syndrome, such as abnormal posture and gait, agitation, tail-stiffness, stereotyped behaviour, tremor and wet dog shakes, were also established during the first 6 h of ethanol withdrawal (Fig. 2Go A–G, black bars).



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Fig. 1. Effects of l-arginine on locomotor activity in rats. Vertical (A) and ambulatory (B) locomotor activities (mean ± SEM) of the ethanol-dependent rats were measured during the first 6 h of ethanol withdrawal [n = 10 for each group; 1/2, 30th min of ethanol withdrawal; h, hour; L-Arg, l-arginine; #P < 0.05 significantly different from saline (-) (ethanol non-dependent) group (Student’s t-test); *P < 0.05, significantly different from saline (+) (ethanol-dependent) treatment (Dunnett’s test)].

 


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Fig. 2. Effects of l-arginine on behavioural symptoms during the first 6 h of the ethanol withdrawal syndrome in rats. Data for abnormal posture, abnormal gait, agitation, tail stiffness and stereotypy represent the median score; n = 10 for each group; 1/2, 30th min of ethanol withdrawal; l-Arg, l-arginine; *P < 0.05, significantly different from saline.

 
Effects of l-arginine on locomotor activity of ethanol-dependent rats
Effects of l-arginine on vertical and ambulatory locomotor activities of the ethanol-dependent rats are shown in Fig. 1Go A and B. l-Arginine produced some significant changes on both vertical [Fs(3.36) > 2.50; Ps< 0.05] and ambulatory [Fs(3.36) > 2.99; Ps< 0.05] locomotor activities of the ethanol-dependent rats during the observation periods. While l-arginine (250 mg/kg) caused significant increases on vertical and ambulatory activities at the beginning of the ethanol withdrawal, it did not produce any significant change of the locomotor activities in ethanol-dependent rats at the 2nd, 4th and 6th hours of ethanol withdrawal. In contrast to this effect, the highest dose of l-arginine (1000 mg/kg) reduced significantly the vertical and ambulatory locomotor hyperactivities appearing in ethanol withdrawal from the 2nd hour onwards. l-Arginine (500 mg/kg) also inhibited the ambulatory hyperactivity at the 4th and 6th h of ethanol withdrawal (Fig. 1A and BGo).

Effects of drugs on behavioural symptoms of ethanol withdrawal
Effects of l-arginine on the behavioural symptoms which were precipitated during the first 6 h of ethanol withdrawal are shown in Fig. 2Go. l-Arginine (500 and 1000 mg/kg) produced some significant reductions in the intensity of abnormal posture, abnormal gait, agitation, tail-stiffness, tremor and stereotypic behaviour (Fig. 2A–EGo) and the incidence of tremor and wet dog shakes (Fig. 2F and GGo) during the observation period. l-Arginine (250 mg/kg) did not produce any significant effects on the signs of the ethanol withdrawal syndrome during the observation period (Fig. 2A–GGo).

Effects of l-arginine on audiogenic seizures
Exposure to audiogenic stimulus at the 6th hour of the withdrawal precipitated seizures with an incidence rate of 60% and a latency of 17.0 ± 4.7 s (Table 2Go). No mortality was recorded during seizures. l-Arginine (1000 mg/kg) decreased significantly the intensity and increased the latency of the audiogenic seizures, but their incidence remained unchanged. The two lower doses of l-arginine were ineffective in these respects (Table 2Go).


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Table 2. Effects of l-arginine on the incidence, intensity and latency of audiogenic seizures in rats
 
Effects of l-arginine in naive animals
The effects of l-arginine (1000 mg/kg) on vertical and ambulatory locomotor activities of ethanol non-dependent (naive) rats were evaluated. l-Arginine did not cause any significant changes in both vertical and ambulatory activities of the non-dependent (naive) rats (data not shown). Any symptom reminiscent of those of ethanol withdrawal syndrome was also not observed in these control (naive) groups.


    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The results of the present study indicate that l-arginine, a NO precursor (500 and 1000 mg/kg) has some beneficial effects on the signs of ethanol withdrawal in rats. At the highest dose, l-arginine blocked both vertical and ambulatory hyperactivity from the 2nd hour of ethanol withdrawal. In addition, it attenuated the intensity of abnormal posture and gait, agitation, tail stiffness and stereotyped behaviour, and also the incidence of tremor and wet dog shakes in ethanol-dependent rats during the ethanol withdrawal period. It produced a significant attenuation of the intensity of the audiogenic seizures appearing in the 6th hour of ethanol withdrawal. Latency of the audiogenic seizures was also prolonged significantly by l-arginine (1000 mg/kg) treatment. These results imply that the high doses of l-arginine may be useful in the treatment of ethanol withdrawal syndrome in rats.

The findings from the present study are not consistent with the hypothesis that NO mediates some aspects of the expression of ethanol dependence (Uzbay and Oglesby, 2001Go). Previous studies indicated that NOS inhibitors, such as l-NAME and 7-NI, had beneficial effects on the ethanol withdrawal syndrome in rats (Adams et al., 1995Go; Uzbay et al., 1997Go). Uzbay et al.(1997)Go showed that the beneficial effects of 7-NI, a central selective inhibitor of NOS, on the signs of ethanol withdrawal were prevented by l-arginine (100 mg/kg) pre-treatment. Because l-arginine is a precursor of NO, we expected an aggravation of the behavioural signs of ethanol withdrawal by l-arginine treatment. For example, Adams et al.(1995)Go found that the NO donor, isosorbide dinitrate, increased the severity of most of the ethanol withdrawal signs. However, in the present study, l-arginine did not enhance the behavioural signs of ethanol withdrawal, in contrast to isosorbide dinitrate. Although, l-arginine (250 mg/kg) produced significant increases in vertical and ambulatory activities at the 30th minute of ethanol withdrawal, these increases were not observed during the observation periods. In addition, behavioural signs of ethanol withdrawal and audiogenic seizures were not affected significantly by this dose of l-arginine. One possibility that may account for the discrepancy of expected results is the role played by arginine in NO production. If the endogenous supply of l-arginine was adequate to keep NOS at maximal levels of activity, then additional arginine would not be expected to enhance ethanol withdrawal signs, because administered l-arginine would not lead to greater concentrations of NO.

It might be argued that higher doses of l-arginine would have enhanced the withdrawal syndrome. However, l-arginine at higher doses produced inhibitory effects on the signs of ethanol withdrawal, as do NOS inhibitors. Moreover, it prolonged the latency and attenuated the severity of audiogenic seizures, which is one of the most reliable and unambiguous signs indicating the development of physical dependence on ethanol in rats (Trzaskowska et al., 1989Go; Morriset et al., 1990Go). Because l-arginine did not produce any significant change in locomotor activities of the naive (non-ethanol-dependent) rats, the beneficial effects of l-arginine on the ethanol withdrawal signs could not be related to its sedative or muscle relaxative effects.

The hypothesis that NO serves as an endogenous antiepileptic compound has been tested in several systems, with conflicting results. l-Arginine and NOS inhibitors were both shown to worsen behavioural and electrographic seizures (East and Gartwaite, 1991Go; Mollace et al., 1991Go; DeSarro et al., 1993Go; Rondouin et al., 1993Go; Przegalinski et al., 1994Go). NOS inhibition accelerates the progression of seizures induced by stimulation of amygdala (Rondouin et al., 1992Go), facilitates initiation of bursts in vitro (Grooms and Jones, 1994Go), and prolongs seizures induced by bicuculline (Wang et al., 1994Go). The nitric oxide donor sodium nitroprusside has been reported to reduce the amount of epileptiform activity induced by penicillin (Marangoz et al., 1994Go) and endogenous NO produced in response to NMDA receptor activation leads to an increase in cGMP, which terminates the seizure activity (Buisson et al., 1993Go), suggesting an anticonvulsant role for NO. In contrast to these suggestions, NO appears to contribute to the genesis of seizure activity when injected into the the deep prepriform cortex (DeSarro et al., 1993Go), and inhibition of NOS suppresses tonic–clonic seizures induced by pentylenetetrazole (Osonoe et al., 1994Go; Kaputlu and Uzbay, 1997Go) and kainic acid (Mulsch et al., 1994Go). Convulsions induced by kainic acid and the resulting formation of NO are also attenuated by pretreatment with NOS inhibitor 7-NI (Mulsch et al., 1994Go). We also observed that l-NAME and 7-NI, NOS inhibitors, blocked audiogenic seizures in ethanol-dependent rats (Uzbay et al., 1997Go). On the other hand, it was suggested that NO did not appear to function as an endogenous antiepileptic agent in the rat hippocampus (Stringer and Erden, 1995Go). The discrepancies in these results may be related to the mode of seizure induction, or it may be that seizure termination mechanisms vary in different brain regions. In addition, the pathophysiology of epilepsy is not fully understood for any of the seizure types previously described. However, it is known that multiple mechanisms are involved. Some mechanisms operate in one seizure type, but not in others, but no seizure type is explained by a single mechanism (Stringer, 1991Go). Our results on l-arginine (1000 mg/kg) decreasing the intensity and prolonging the latency of audiogenic seizures are also in line with our previous findings indicating that high doses of l-arginine have some inhibitory effects on audiogenic seizures in ethanol-dependent rats (Uzbay et al., 1995Go). Since l-arginine action appeared after its second injection, it may be possible that the inhibitory effect of l-arginine on audiogenic seizure may be related to a negative feedback inhibition by its excessive dose. It was shown that endogenous NO can act as a negative feedback inhibitor in neurons to modulate their own or neighbouring cell NMDA receptor activities (Wang et al., 1995).

Another explanation of the beneficial effects of l-arginine on ethanol withdrawal may be metabolites. Metabolites of arginine can also exert important biological effects. Recently, agmatine (decarboxylated arginine) has been demonstrated to be an important biological compound in several tissues (Lortie et al., 1996Go; Blantz et al., 2000Go). Agmatine binds with high affinity to both imidazoline and {alpha}2-adrenergic receptors of all subclasses (Raasch et al., 2001Go). It has also been suggested that agmatine blocks NOS in rat brain (Abe et al., 2000Go). It is well known that both imidazoline/{alpha}2-adrenergic receptor agonists (Parale and Kulkarni, 1986Go) and NOS inhibitors (Adams et al., 1995Go; Uzbay et al., 1997Go) have beneficial effects on the ethanol withdrawal syndrome in rats. Furthermore, in a recent study, we also showed that agmatine produces some inhibitory effects on some signs of ethanol withdrawal in rats (Uzbay et al., 2000Go). Agmatine, a metabolite of l-arginine, may be responsible for the beneficial effects of l-arginine at high doses. Ineffectiveness of l-arginine on ethanol withdrawal syndrome at lower doses could be explained on this basis, although this suggestion needs confirmation by further studies.

In the present study, effective doses of l-arginine on ethanol withdrawal signs were too high. Thus, the beneficial effects of l-arginine may be non-specific. On the other hand, it is known that NO modulates the activity of some central neurotransmitters (i.e. dopamine, serotonine and glutamate) that have an important role in development of dependence on ethanol (Hanbauer et al., 1992Go; Yamada et al., 1995Go; Trabace and Kendrick, 2000Go). l-Arginine at high doses might affect these neurotransmitters. This suggestion also needs confirmation by additional experiments.

In conclusion, our results suggest that l-arginine at high doses has some beneficial effects on ethanol withdrawal syndrome in rats.


    ACKNOWLEDGEMENTS
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 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The authors would like to thank Dr Bora Sever for his technical assistance during the study. This study was supported by The Scientific and Technical Research Council of Turkey (Project No. TÜBITAK, SBAG-AYD-73).


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* Author to whom correspondence should be addressed. Back


    REFERENCES
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 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
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