Erciyes University School of Medicine, Departments of Psychiatry and
1 Biochemistry, Talas Road, 38039-Kayseri, Turkey
Received 19 July 2001; in revised form 9 November 2001; accepted 21 November 2001
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ABSTRACT |
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INTRODUCTION |
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Although platelet MAO-B activity has been extensively investigated in alcoholism, there is a considerable inconsistency in terms of the association between alcoholism and alterations in MAO activity. A significant number of studies reported a decrease in MAO-B activity in platelets during the alcohol consumption period (Alexopoulos et al., 1983; Faraj et al., 1987
; Lykouras et al., 1987
, 1989
; Rommelspacher et al., 1994
), during an active withdrawal syndrome (Pandey et al., 1988
; Rommelspacher et al., 1994
) or after an abstinence period (Major and Murphy, 1978
; Alexopoulos et al., 1983
; Faraj et al., 1987
, 1994
; Pandey et al., 1988
; Sullivan et al., 1990
; Rommelspacher et al., 1994
). Therefore, it has been suggested by some authors that low platelet MAO-B activity represents a biochemical marker for alcohol dependence (Sullivan et al., 1990
; Faraj et al., 1994
; Rommelspacher et al., 1994
). However, the finding of low platelet MAO activity in alcohol-dependent patients has not been consistently replicated (Giller and Hall, 1983
; Sherif et al., 1992
; Farren et al., 1998
). Furthermore, some recent papers have suggested that decreased MAO activity is not a marker for alcoholism, but rather, is due to cigarette smoking, which is claimed to inhibit MAO activity and is seen far more prevalently in alcoholic patients than in the normal population (Anthenelli et al., 1995
, 1998
; Whitfield et al., 2000
). Nevertheless, in Farren et al.'s study (1998), no correlation was found between platelet MAO activity and smoking status.
The alcohol withdrawal syndrome is the result of a complex mal adaptation of the main neurotransmitter systems. It generally reflects altered neurotransmitter function of the brain involved in the development of tolerance to alcohol. Withdrawal is a combination of reduced central inhibition (e.g. by -aminobutyric acid) and increased excitation (e.g. by N-methyl-d-aspartate, dopamine, noradrenaline) (Nutt, 1999
). As in alcoholism in general, previous studies have yielded equivocal results with regard to MAO-B activity changes during the withdrawal period. Thus, whereas some authors reported a transitory increase in platelet MAO activity during withdrawal (Alexopoulos et al., 1981
; Alling et al., 1982
), others showed a decrease (Major and Murphy, 1978
; Pandey et al., 1988
; Rommelspacher et al., 1994
; Berggren et al., 2000
).
Besides alcoholism, low MAO-B activity has been suggested to be linked to some personality traits, such as aggressiveness, impulsiveness and sensation-seeking behaviour (Fowler et al., 1980; Zuckerman, 1984
; Schalling et al., 1987
; Stalenheim et al., 1997
) and type II alcoholism, a proposed subgroup associated with early onset alcoholism, male predominance, and a history of sociopathic activity (Cloninger et al., 1981
; von Knorring et al., 1985
; Sullivan et al., 1990
).
The objectives of the present study were to test the hypothesis that MAO-B activity, even if it is abnormal, may not be stable during the period of alcohol withdrawal, and to investigate whether MAO-B activity changes during the withdrawal period are related to the level of aggressiveness of alcoholic patients.
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SUBJECTS AND METHODS |
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Demographic and clinical procedures
Demographic and clinical data were collected after the patients had returned to sobriety. Severity of anxiety and depressive symptoms were assessed with the Clinical Anxiety Scale (CAS) (Snaith et al., 1982) and the 21-item Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960
), respectively. Patients obtaining a HRSD depression score of
10 in evaluations performed at either the first or fourth week were excluded from the study. All patients also completed the BrownGoodwin Assessment for Life History of Aggression (BGARS), which assesses several elements of lifetime aggression history (Brown et al., 1981
). The patient group was divided into two subgroups: a low-aggression group and a high-aggression group, according to their BGARS scores. Those who had scores of
8 on this scale were considered the low-aggression group (n = 13, mean age ± SD: 43.8 ± 8.6 years, mean BGARS score ± SD: 2.0 ± 1.41), and those with scores
8 formed the high-aggression group (n = 9, mean age ± SD: 43.0 ± 10.1, mean BGARS score ± SD: 9.0 ± 1.2).
This study was carried out in accordance with the Helsinki Declaration of the World Medical Association and was approved by the local Ethics Committee. All subjects gave their written informed consent after full understanding of the study.
Biochemical procedures
A single blood specimen was obtained after fasting from all subjects, at 07.0008.00. The blood sampling procedure was carried out during the first week (7 days after alcohol cessation) and fourth week (28 days after alcohol cessation) of alcohol withdrawal for patients, but only once for controls. The patients remained in hospital throughout the study. Venous blood was divided into three portions. One part was placed into the EDTA-containing tube for platelet counts, whilst the second was allowed to clot at room temperature and serum was collected for total protein measurement. Platelet number was measured by a Coulter® Max M autoanalyser (USA), and total serum protein level was assayed using a Konelab 60i analyser (Thermoclinical lab systems OY, Ruukintie 18, FIN-02330 Espoo, Finland).
The third portion of the blood sample was drawn into an ice-cold heparinized tube and centrifuged at 4°C. Platelet-rich plasma (PRP) (2.0 ml aliquots) was removed from the top of the plasma samples. The separated PRP sample was kept at 70°C until analysis. MAO-B activity in PRP was measured by the method described by McEwen (1971), a spectrophotometric assay based on the measurement of the conversion of benzylamine into benzaldehyde by the catalytic activity of MAO-B. One unit of MAO activity was defined as the amount of enzyme catalysing the production of 1 nmol of benzaldehyde per hour at 37°C. The protein content of PRP was also measured by the biuret reaction using bovine albumin as the standard. MAO-B activity in PRP was expressed in units per mg of protein as specific activity (nmol/mg protein/h).
Statistical analysis
The numbers of cigarettes consumed per day by both patients and controls in the first and fourth weeks were compared using independent samples and paired t-tests, respectively. Statistical comparison of the MAO values obtained in the first and fourth weeks was performed by using paired t-test. Two-tailed independent samples t-test was used to compare the MAO-B values of both patients and controls. Comparison of MAO-B values obtained in the low- and high-aggression groups and in patients with and without family history of alcoholism, during both the first and fourth weeks of the withdrawal period were carried out by using the MannWhitney U-test due to the small sizes of the groups. Platelet numbers and total serum protein levels of the patients in the first and fourth weeks and those of controls were compared using one-way analysis of variance (ANOVA). Statistical correlations between MAO values and clinical variables were tested by means of Pearson's correlation test.
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RESULTS |
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MAO-B values obtained for patients during the first week of withdrawal were significantly reduced, compared with both those of controls and those obtained during the fourth week (P < 0.001 in both cases) (Table 2). However, no difference was observed between the MAO-B values obtained from patients during the fourth week of the withdrawal and controls (P > 0.05).
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No significant correlations were found between MAO-B values and other clinical variables (age, age at onset of alcohol dependence, duration of alcohol dependence, amount of alcohol consumed daily, number of cigarettes smoked daily, benzodiazepine doses, CAS and HRSD scores) (data not shown).
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DISCUSSION |
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Since smoking status has recently been reported to be an important factor that can alter MAO activity (Anthenelli et al., 1995, 1998
; Whitfield et al., 2000
), and seems to be the biggest confounding factor in the results of MAO studies (Farren and Tipton, 1999
), we selected all patients and control subjects from among cigarette smokers and thus equated this variable. In contrast to these studies reporting that there is no link between alcoholism and MAO activity, and that decreased platelet MAO activity is associated with cigarette smoking, we found a relation between alcohol dependence and reduced MAO activity, but only during the first week of withdrawal.
It is generally reported that low platelet MAO activity may be principally associated with type II alcoholism (Cloninger et al., 1981; von Knorring et al., 1985
; Sullivan et al., 1990
; Anthenelli et al., 1995
). According to a suggested classification, type I alcoholism is characterized by late onset alcohol dependence in both men and women as a consequence of adverse psychosocial factors and low heritability. Type I alcoholics have been reported to have normal MAO levels (von Knorring et al., 1985
; Sullivan et al., 1990
). Type II alcoholism seems to be highly heritable, and limited to males. Type II alcoholics have an early onset of dependence, some social complications, more impulsive, more sensation-seeking, disinhibited characteristics, and significantly lower levels of platelet MAO-B than type I alcoholics (Cloninger et al., 1981
; von Knorring et al., 1985
; Sullivan et al., 1990
). However, some studies found no difference between Type I and II alcoholic patients with regard to MAO activity (Anthenelli et al., 1998
; Farren et al., 1998
). In accordance with this division of alcoholics, an association has been reported between low platelet MAO-B activity, which represents an index of brain serotonergic function (Oreland and Shaskan, 1983
; Diaz-Marsa et al., 2000
), and some personality traits such as aggressiveness, sensation-seeking behaviour and impulsiveness (Fowler et al., 1980
; Zuckerman, 1984
; Schalling et al., 1987
; Rommelspacher et al., 1994
; Stalenheim et al., 1997
). In contrast to these studies, we did not find any correlation between MAO-B values and lifetime aggression scores, although we observed a non-significant tendency for a decrease in MAO-B levels in the high-aggression group, compared to the low-aggression group, during the first week. In other words, our results did not confirm the association of low platelet MAO-B activity and type II alcoholism, or lifetime aggression history. Instead, we found that low MAO-B activity was limited to the first week of the withdrawal period in both the low- and high-aggression groups. However, it must be kept in mind that this discrepancy may have been caused by the facts that these two samples were quite small and that even patients in the high-aggression group were not actually aggressive (at least during the study), being represented by inpatients who were eager to stop drinking and who did not fully meet the criteria of antisocial or borderline personality disorder. If we had been able to compare the low-aggression alcoholic group with, for example, imprisoned violent alcoholics, the results might have been different.
It has been reported in some recent animal studies that there is a higher degree of correlation between aggressiveness and MAO-A activity rather than MAO-B activity (Shih and Chen, 1999; Shih et al., 1999
). MAO-A gene knock-out mice showed elevated brain levels of serotonin, norepinephrine and dopamine, and manifested aggressive behaviour. However, since only the B-form of MAO is present in blood platelets (Donnelly and Murphy, 1977
), it was impossible to measure MAO-A activity in the periphery with our method.
In conclusion, our data showed that platelet MAO activity was lower during the first week of withdrawal in alcohol-dependent patients, compared with that in controls, and approached control values by the fourth week of withdrawal as symptoms were subsiding. The findings of the present study also indicated no difference between patients with high- and low-aggression history in terms of platelet MAO activity during withdrawal. If we had found a difference in MAO activity between these two subgroups, it might have suggested that this trait is related to the serotonergic system. Our results suggest that low platelet MAO activity may be a state marker of alcohol withdrawal or a result of high alcohol consumption, rather than a trait marker of alcoholism. Nevertheless, since we did not measure platelet MAO activity during active alcohol consumption or later than 1 month after alcohol cessation, we cannot readily exclude the hypothesis that low platelet MAO activity may be a trait marker of alcoholism. The fact that only smoking subjects were included in the study allows us to eliminate the smoking effect on platelet MAO activity and thus strengthens our results. Although a 4-week duration is usually adequate for relieving withdrawal symptoms, one cannot be sure that enzyme activity will remain stable after the fourth week of withdrawal. Therefore, longer-term longitudinal studies in larger samples are needed to clarify this issue.
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FOOTNOTES |
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Report presented at the 13th European College of Neuropsychopharmacology Congress, 9 September 2000, Munich, Germany.
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