THE EFFECTS OF CHRONIC ETHANOL CONSUMPTION AND ETHANOL WITHDRAWAL ON SERUM CHOLINESTERASE ACTIVITY IN RATS

Cumhur Bilgi, Serhat Tokgöz, Ahmet Aydin1, Turgay Çelik2 and I. Tayfun Uzbay2,*

Department of Emergency Medicine, Laboratory of Biochemistry,
1 Pharmaceutical Sciences Center, Department of Pharmaceutical Toxicology and
2 Department of Medical Pharmacology, Psychopharmacology Research Unit, Gülhane Military Medical Academy, Etlik, 06018 Ankara, Turkey

Received 5 July 2002; in revised form 12 February 2003; accepted 6 March 2003


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Aims: The effect of chronic ethanol consumption and ethanol withdrawal on serum cholinesterase (ChE) activity was investigated in female Wistar rats. Methods: Ethanol was administered by a modified liquid diet with 4.8% (v/v) ethanol for 3 days followed by 25 days on a liquid diet in which the ethanol concentration was increased to 7.2%. Control rats were pair-fed with an isocaloric liquid diet not containing ethanol. The blood ethanol concentration and serum ChE activity were measured at the end of the 4.8% ethanol consumption period; after 7, 14 and 35 days of ethanol (7.2%) consumption, and at 24 and 72 h after ethanol withdrawal following ethanol consumption of 35 days. Results: Daily ethanol consumption of the rats ranged from 11.5 to 14.9 g/kg. Serum ChE activity was found significantly increased from the 3rd day of ethanol (4.8%) consumption. Serum ChE activities of the rats receiving 7.2% ethanol also increased significantly compared with rats ingesting 4.8% ethanol. Blood ethanol levels were measured as 121 and 0.88 mg/dl on the 35th day of ethanol (7.2%) consumption (just before ethanol withdrawal) and after 24 h of ethanol withdrawal, respectively. Increased serum ChE activity (1968 U/l) was still observed (1942 U/l) after 24 h of ethanol withdrawal. ChE activity returned to control levels (501 U/l) after 72 h of ethanol withdrawal. Audiogenic seizures indicating development of physical dependence on ethanol were also observed after 8 h of ethanol withdrawal in another individual group of ethanol-fed rats. Conclusions: Our results show that serum ChE activity is increased by chronic ethanol consumption in rats and that this increase is affected by ethanol concentration and duration of ethanol ingestion.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Acetylcholine (ACh) is a neurotransmitter that has a crucial role in the central nervous system and its implication in behavioural (including learning and memory) and neurodegenerative disorders has long been known (Vanderwolf, 1988Go; Blockland, 1996Go). ACh is also a neurotransmitter of the peripheral parasympathetic or cholinergic system (Ruffolo, 1991Go). There are a number of enzymes that can hydrolyse ACh in central or peripheral tissues. The two major types are ACh esterase (AChE) and butyryl-cholinesterase or cholinesterase (ChE) (Mclsaac, 1992Go). AChE degrades ACh in all effector organs or surrounding fluids and is of importance for cognitive functions and anaesthetic medication in both humans and experimental animals (Hodges et al., 1991Go). AChE activity in the cerebrospinal fluid is assumed to be a biochemical marker for clinical diagnosis and prognosis of several central and peripheral nervous system dysfunctions, such as Alzheimer’s disease, Parkinson’s disease, dementia, schizophrenia and chronic alcoholism (Kluge et al., 1999Go).

Data on the effects of ethanol on the central cholinergic system reveal some conflicting aspects. While some studies showed a decrease in concentrations of ACh in various areas of the brain (Erickson and Graham, 1973Go; Carmichael and Israel, 1975Go), others showed increases (Reisberg, 1974Go; Parker et al., 1978Go). Other laboratories measured AChE activity in the brain following exposure to ethanol and obtained conflicting results. Some authors found it unaltered (Rawat, 1974Go; Pereira et al., 1998Go) or decreased (Owasoyo and Iramain, 1981Go; Miller and Rieck, 1993Go). In contrast to these findings, Imperato et al.(1998)Go observed some prominent increases in AChE activity in rat brain. These conflicting results may be related mainly to the variety of techniques and experimental models employed in the studies.

Haboubi and Thurnham (1986)Go suggested that erythrocyte AChE activity might be an early indicator of potential ethanol-induced disturbances of the autonomic nervous system. Ethanol-dependent patients are known to be affected by disturbances of the autonomic nervous system, such as sweating, fever, dilated pupils, vomiting and diarrhoea, and high blood pressure. Therefore, measurement of serum AChE or ChE activity may be useful in determining the effect of ethanol on the cholinergic system. However, studies performed to investigate changes to the blood ChE activity under chronic ethanol consumption and ethanol withdrawal are very limited. The main objective of the present study was to investigate the possible effects of chronic ethanol consumption and ethanol withdrawal on serum ChE activity in rats.


    MATERIALS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Animals and laboratory conditions
The experiments performed in this study have been carried out according to the rules in the Guide for the Care and Use of Laboratory Animals adopted by the National Institutes of Health (USA) and the Declaration of Helsinki. Adult female Wistar rats (182–244 g) were used. They were placed in a quiet, temperature- and humidity-controlled room (22 ± 2°C and 60 ± 5 %, respectively) in which a 12 h/12 h light/dark cycle was maintained (lights on: 08:00 h).

Exposure to ethanol and behavioural experiments assessing the ethanol withdrawal syndrome were carried out in separate, isolated laboratories under the same environmental conditions as the colony room.

Chronic exposure to ethanol
For chronic exposure to ethanol, the rats were housed individually and ethanol was given in the form of a modified liquid diet as previously described (Uzbay and Kayaalp, 1995Go). The rats received a modified liquid diet with or without ethanol ad libitum. No extra chow or water was supplied. The composition of the modified liquid diet with ethanol was: cows’ milk 925 ml (Mis Süt, Istanbul, Turkey), ethanol 25–75 ml (96.5% ethyl alcohol; Tekel, Turkish State Monopoly), vitamin A 5000 IU (Akpa Ilaç Sanayi, Istanbul, Turkey) and sucrose 17 g (Uzbay and Kayaalp, 1995Go). This mixture supplies 1000.7 kcal/l.

At the beginning of the study, rats received the liquid diet without ethanol for 7 days. Then a liquid diet with 4.8% (v/v) ethanol was administered for 3 days. The ethanol concentration was increased to 7.2% (v/v) for the following 35 days. Control rats were pair-fed with an isocaloric liquid diet containing sucrose as a caloric substitute for ethanol for 35 days. The liquid diet was freshly prepared daily and presented at the same time (10:00 h). The weight of the rats was recorded every day, and daily ethanol intake was measured and expressed as grams per kilogram body weight per day.

Experimental procedure
At the beginning of the 7.2% ethanol consumption period, ethanol-consuming and control rats were assigned into nine groups according to the protocols in Table 1Go. Blood samples were taken by intracardiac puncture under light ether anaesthesia on the 3rd day of 4.8% ethanol consumption and after 7, 14 and 35 days of 7.2% ethanol consumption. In these groups, the samples were taken 6 h after the daily renewal of the diet (i.e. at 16:00 h). In groups 6 and 7, on the 35th day of the 7.2% ethanol-containing diet, ethanol was withdrawn from the diet. Blood samples were also taken from these groups by the same method after 8, 24 and 72 h of ethanol withdrawal. Blood samples for measurements of ChE activity were taken from the control rats by the same procedure on the 35th day of ethanol-free isocaloric liquid diet administration. The samples were collected into test tubes and centrifuged (4500 r.p.m. — 2268 g for 5 min) at room temperature. The supernatants were separated and divided into two portions for measuring ChE activity and blood ethanol levels. Samples were stored at –20°C until analysed.


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Table 1. Groups and experimental protocols
 
ChE activity in the supernatant was measured using 1 mmol/l butyrylthiocholine iodide (Roche Diagnostic, Germany) as substrate, as previously described (Kluge et al., 1999Go). The progress of the enzymatic reaction was monitored spectrophotometrically at 415 nm using an autoanalyser (Hitachi-902, Hitachinaka, Japan). The assay for each sample was run in duplicate and each measurement was performed in triplicate. ChE activities were expressed as units per litre (U/l).

Blood ethanol levels were also measured spectrophotometrically at 340 nm (Shimadzu UV Model 2100S, Kyoto, Japan) using a commercial ethanol assay kit which employs alcohol dehydrogenase (EC 1.1.1.1) (Sigma Chemical, St. Louis, MO, USA). Levels were expressed as milligrams per decilitre (mg/dl).

Observation of audiogenic seizures
Audiogenic seizures were precipitated in group 8 of the ethanol-fed rats. After 8 h of ethanol withdrawal, an audiogenic stimulus (100 dB) was given to the rats with a 60 s cut-off time, as previously described (Morriset et al., 1990Go; Uzbay and Kayaalp, 1995Go). The incidence of seizures was recorded. No other experiments were performed on these rats.

Statistical analysis
The results relating to ethanol consumption, ChE activity and blood ethanol levels were expressed as means ± standard error of the mean (SEM). The data were evaluated by one-way analysis of variance (ANOVA) followed by Tukey’s test for post-hoc comparison.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Ethanol consumption and body weight changes
Daily ethanol consumption of the rats ranged from 11.5 to 14.9 g/kg during the 7.2% ethanol exposure period. No significant difference between the ethanol-ingesting groups was observed [F (4, 27) = 2.270; P > 0.05, one-way ANOVA test]. The daily mean ethanol consumption of the rats in the test periods is shown in Fig. 1Go.



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Fig. 1. Daily ethanol (EtOH) consumption of the study groups.

 
Body weight changes of the ethanol-fed rats are presented in Table 2Go. Body weights of the ethanol-fed rats increased progressively during the study. An increase in body weight of approximately 13% over the initial weight was observed at the end of the study.


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Table 2. Changes in weight gains of rats fed ethanol-containing liquid diets
 
Body weights of the control rats were 215 ± 6 and 260 ± 5 on the 1st and 35th days of the experiment, respectively.

Serum ChE activity
Serum ChE activities of the control, ethanol-feeding and ethanol-withdrawn rats are shown in Fig. 2Go. Chronic ethanol administration and ethanol withdrawal produced some significant increases in serum ChE activity in rats [F (6, 49) = 18.065; P < 0.0001, one-way ANOVA test]. ChE activities of the ethanol-fed rats were significantly increased compared with controls on the 3rd (4.8% ethanol), 7th, 14th and 35th days of chronic ethanol (7.2%) consumption and at 24 h after ethanol withdrawal (P < 0.05; Tukey’s test). The increases of the ChE levels in the groups feeding on 7.2% ethanol were also found to be significantly higher than the group taking ethanol at lower concentration (4.8%) (P < 0.05; Tukey’s test). The significant increases in ChE level persisted at 24 h after ethanol withdrawal compared with both control and 4.8% ethanol administered rats (P < 0.05, Tukey’s test). However, ChE levels returned to control values at 72 h after withdrawal (Fig. 2Go).



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Fig. 2. Serum choline esterase activity of the rats during chronic ethanol consumption and subsequent withdrawal. n = 8 for each group; C = control group fed the isocaloric control diet for 35 days. *P < 0.05, significantly different from control (Tukey’s test); #P < 0.05, significantly different from the 4.8% ethanol-fed group (Tukey’s test).

 
Blood ethanol levels
Blood ethanol levels of rats during the test periods are shown in Fig. 3Go. Large concentrations of ethanol were observed in the blood of ethanol-fed and ethanol-withdrawn rats. Blood ethanol levels were found to be significantly higher in the 7.2% ethanol-fed groups than in the group fed 4.8% ethanol (P < 0.05, Tukey’s test). Blood ethanol levels significantly decreased at 8, 24 and 72 h after withdrawal (P < 0.05, Tukey’s test). No significant difference between the 14th and 35th days was observed in the groups ingesting ethanol (7.2%) (Fig. 3Go).



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Fig. 3. Blood ethanol levels of the ethanol-fed rats. #P < 0.05 significantly different from the 4.8% ethanol-fed group (Tukey’s test); *P < 0.05 significantly different from the 14th and 35th days values (Tukey’s test).

 
Ethanol withdrawal-induced audiogenic seizures
After 8 h of ethanol withdrawal, audiogenic seizures were precipitated in six of eight animals (75%) with a latency of 15–28 s (data not shown).


    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The present study has demonstrated that chronic ethanol administration to rats produces a concentration-dependent increase in serum ChE activity and the increase persists after 24 h of ethanol withdrawal. This is the first study to investigate effects of ethanol withdrawal on serum ChE activity in rats.

The enzymes that metabolize ACh may be important therapeutic targets. For example, reversible inhibitors of AChE have been used in several types of dementia such as Alzheimer’s disease (Enz et al., 1993Go). Some researchers have also shown a decreased level of AChE in patients with Alzheimer’s disease (Kuhl et al., 1999Go). In addition, there is a differential involvement of the molecular isoforms of AChE in stress and cognitive functions in mice (Das et al., 2000Go).

ChE is also known as plasma cholinesterase or pseudocholinesterase. The enzyme is relatively non-specific in its subtrate requirements and can catalyse the hydrolysis of ACh in the subsynaptic area. Butyrylcholine (BCh) is used experimentally to identify this enzyme, because the butyryl ester is a substrate for ChE but not for AChE, the enzyme that is specific for the hydrolysis of ACh. ChE is widely distributed throughout the body, including the plasma, liver, kidney and gastrointestinal tract. There is no known physiological function for this enzyme, but it may be important for the hydrolysis of ingested esters (Mclsaac, 1992Go). AChE only hydrolyses ACh, but ChE breaks down ACh as well as BCh. ChE does not only derive from neural tissues but to a much larger extent from the blood (Kluge et al., 1999Go). Thus, measurement of ChE activity in serum may be important for estimating ethanol effects or ethanol-related damage in both central and peripheral cholinergic systems. On the other hand, investigation of changes in ChE activity during ethanol withdrawal could give an idea about the role of this enzyme in the development of physical dependence on ethanol. Thus, we studied the effects of chronic ethanol administration and ethanol withdrawal on serum ChE activity.

Many of the previous studies addressing the effects of ethanol on the cholinergic system have been focused on AChE. These studies generally indicated an inhibition of AChE activity in the brain (Reisberg, 1974Go; Owasoyo and Iramain, 1981Go) and erythrocyte (Haboubi and Thurnham, 1986Go). In a more recent study, Husain and Somani (1998)Go studied the effects of chronic ethanol ingestion (2 g/kg per day for 6.5 weeks) on ChE activity in plasma and AChE activity in several regions of the brain. They found increased ChE activity in plasma and decreased AChE activity in the hypothalamus. Our results indicating significantly increased serum ChE activities from the 3rd day of ethanol consumption are in line with these results. We confirmed Husain and Somani’s findings by higher ethanol consumption (above 10 g/kg per day) and, additionally to this study, we showed that the increased serum ChE activity persisted at the end of the 24 h ethanol-withdrawal period. At this time, the blood ethanol level was very close to zero (0.88 mg/dl). These findings imply that the effects of ethanol on serum ChE activity are due to earlier consumption and that the persistently high level of ChE activity after 24 h of withdrawal is not related to blood ethanol level. In addition, because no significant differences were observed between the groups ingesting the higher concentrations of ethanol for various periods of time, the increases of ChE activities may not be related to the duration of ethanol consumption. Overall, the data indicate that serum ChE activity seems to be an indicator that can provide some information about the effects of chronic ethanol consumption and ethanol withdrawal on the cholinergic system.

Consistent with our previous findings in the same model of rats (Uzbay and Kayaalp, 1995Go; Uzbay et al., 1997Go, 1998Go, 2000Go; Uzbay, 2001Go), the present data demonstrated that daily ethanol consumption above 11.5 mg/kg for 35 consecutive days produced physical dependence in Wistar rats. Majchrowicz (1975)Go 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 ethanol per day. In the present study, the rats were exposed to high doses of ethanol for a longer period. Thus, we observed audiogenic seizures that are an easily quantifiable and objective element of intense ethanol withdrawal in rats (Majchrowicz, 1975Go; Uzbay et al., 1997Go) after 8 h of ethanol withdrawal. The audiogenic seizure rate (75%) was close to those of our previous studies performed in the same model (Uzbay et al. 1997Go, 1998Go, 2000Go; Ergün et al., 2001Go; Uzbay, 2001Go). On the other hand, Miller and Rieck (1993)Go suggested that six weeks (42 days) of ethanol (6.7% v/v) administration to rats by the liquid diet technique is sufficient to alter the cholinergic innervations of the cerebral cortex. Accordingly, we gave ethanol to rats for 6 weeks. Thus, the results of the present study clearly indicate that there might be a relationship between serum ChE activity and development of physical dependence to ethanol. However, data provided by the present study are not adequate to explain which mechanism could be responsible for the increases of serum ChE activity during chronic ethanol consumption. Further studies are needed in order to clarify these points.


    ACKNOWLEDGEMENTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
This study has been partially supported by the State Planning Institution and Ministry of Defense of the Turkish Government (Grant no: DPT-MSB-3; 99K120150). The authors would like to thank Professor Nazmi Özer and Mr Selami Alan for their valuable scientific contributions and technical assistance to the study, respectively.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
* Author to whom correspondence should be addressed. Back


    REFERENCES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
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