Institute of Clinical Neuroscience, Department of Psychiatry and Neurochemistry, Sahlgren University Hospital/Mölndal, Göteborg University, SE-431 80 Mölndal
1 Department of Psychology, Göteborg University, P.O. Box 500, SE-405 30 Göteborg, Sweden
Received 25 January 2000; in revised form 11 April 2000; accepted 28 April 2000
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ABSTRACT |
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INTRODUCTION |
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Another major research area involves studies of platelet monoamine oxidase (MAO)-B activity in alcoholism. As a result of several studies, low platelet MAO-B activity has been proposed as a biological marker for alcoholism, especially in the type 2 alcoholism with personality traits such as sensation-seeking behaviour (Wiberg et al., 1977; Sullivan et al., 1978
, 1990
; von Knorring et al., 1984
; Faraj et al., 1987
; Pandey et al., 1988
; Devor et al., 1993
; Rommelspacher et al., 1994
; Hallman et al., 1996
; von Knorring and Oreland, 1996
). Also in this research area, there are studies where no such association have been observed (Tabakoff et al., 1988
; Parsian et al., 1995
; Anthenelli et al., 1998
; Farren et al., 1998
).
Since both platelet MAO-B activity and alleles for the DRD2 receptor reflect in different ways central dopaminergic neurotransmission, a transmitter system considered important for the central nervous system reward (Wise and Rompre, 1989) and motivation, it seems reasonable to investigate whether platelet MAO-B activity and the DRD2 A1 allele are associated. The aim of this preliminary study was therefore to investigate platelet MAO-B activity in alcoholics both with and without the DRD2 A1 allele.
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MATERIALS AND METHODS |
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Study design
On the investigation day, the subjects were examined physically and psychiatrically by a psychiatrist using a semi-structured interview at an alcoholism treatment unit of the University Hospital. Their social background data were collected and they were assessed for alcohol-dependence according to the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV) criteria of the American Psychiatric Association (1994). The daily alcohol consumption during the last 2 weeks was estimated using the method of TimeLine Follow Back (Sobell et al., 1980). Anxiety and depressive symptoms were assessed using the Hamilton Anxiety Scale (HAS; range of scores 056; Hamilton, 1960) and the Hamilton Depression Scale (HDS; range of scores 052; Hamilton, 1967) respectively. Personality characteristics were assessed using the Karolinska Scales of Personality self-rating instrument (KSP; Schalling, 1993). Blood samples were collected for the determination of platelet MAO-B activity, the A1/A2 allele, as well as liver function tests [aspartate aminotransferase (AST), alanine aminotransferase (ALT) and
-glutamyltransferase (GGT); upper laboratory reference limit for all liver enzymes: 0.8 µkat/l], renal and haematological functions and carbohydrate deficient transferrin (CDT; upper laboratory reference limit: 1.7%). Determination of narcotic drugs (including benzodiazepines) in urine samples was also performed, using suitable laboratory screening procedures.
Biochemical analyses
Platelets were isolated from EDTAblood as previously described (Svennerholm et al., 1982). The cell homogenate used as enzyme source in the assay of MAO-B was prepared by sonication in ice-chilled water for 60 s. The protein content of the homogenate was determined by the bicinchoninic acid procedure (Smith et al., 1985
). The enzyme activity was assayed radiochemically with ß-phenylethylamine as substrate with a concentration of 5.0 µM in the final assay (Fowler and Tipton, 1981
). The specific enzyme activity is expressed as µkat/kg cell protein. The intra-assay variation was 46%, calculated on assayed duplicates of different samples. For determination of the inter-assay precision, a pool of platelets was aliquoted and stored at 80°C. Fresh aliquots were assayed on seven different occasions during a 5-month period. The inter-assay variation of the pooled platelet samples was 10%.
The DRD2 TaqA polymerase chain reaction (PCR) was performed as described by Grandy et al. (1993) with minor modifications. In short, genomic DNA was extracted from venous blood samples, and the DRD2 gene was amplified by PCR using the primers 5'CCGTCGACGGCTGGCCAAGTTGTCTA and 5'CCGTCGACCCTTCCTGAGTGTCATCA. The 310 bp PCR product was cleaved with TaqI, resulting in cleavage of the DRD2* 2 allele into two fragments of 180 and 130 bp, whereas the DRD2* 1 allele was not cleaved (Fig. 1).
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RESULTS |
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Results of liver function tests were for AST 0.60 ± 0.49 µkat/l, ALT 0.89 ± 0.79 µkat/l, GGT 1.47 ± 1.25 µkat/l, and CDT 2.4 ± 2.6%. Platelet MAO-B activity in the total group was 5.2 ± 1.9 µkat/kg protein (laboratory reference value: 5.1 ± 1.3 µkat/kg protein). There were no correlations between age or years of drinking problems vs levels of platelet MAO-B activity (r = 0.04 and 0.19 respectively). In the alcohol-dependent subjects platelet MAO-B activity was 5.1 ± 2.0 and in those subjects who only fulfilled one or two of DSM-IV criteria for alcohol dependence 5.4 ± 1.8 µkat/kg protein. There was also no difference between nicotine users and non-users in platelet MAO-B activity (5.2 ± 1.7 and 5.2 ± 2.1 µkat/kg protein respectively). Among the smokers, no correlation was observed between amount of current smoking (daily numbers of cigarettes) and levels of platelet MAO-B activity (r = 0.19). Renal and haematological function tests were all within their normal ranges.
DRD2 A1 allele (A1+) and (A1)
In the total group of 37 subjects, eight subjects (22%) were carriers of the DRD2 A1 allele (A1+), of whom one was a homozygote. Consequently, the remaining 29 subjects (78%) were non-carriers of the DRD2 A1 allele (A1). In the alcohol-dependent subjects (n = 27), six subjects were A1+, whereas 21 were A1, and in those subjects who only fulfilled one or two of DSM-IV criteria for alcohol dependence (n = 10) two were A1+ and eight A1 (n.s.). Of the eight carriers with A1+, three were nicotine users, and, among the 29 subjects with A1, 15 were nicotine users.
There were no differences in background data between the A1+ and A1 groups (Table 1). Nor were there any differences in scores of the personality variables of the KSP (to be published). Furthermore, no differences were found in liver function between the groups, with the exception of GGT: the A1+ group had higher levels of GGT, compared to the A1 group [F(1,35) = 6.21; P < 0.05; Table 1
].
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DISCUSSION |
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The percentage of subjects who were carriers of the DRD2 A1 allele was about 20% (22% in the alcohol-dependent subjects and 20% in those subjects who only fulfilled one or two of the DSM-IV criteria for alcohol dependence). In a recent review by Noble (1998), in which a meta-analysis of several studies has been performed, it was reported that 47.7% of more severe alcoholics, 31.6% of less severe alcoholics, and 15.7% of controls (alcoholics and/or drug abusers excluded) are carriers of this allele. The relatively low frequency of the DRD2 A1 allele in the present study is somewhat surprising. One explanation could be that this study includes a fairly low number of subjects. Furthermore, 27% of the subjects were non-dependent according to DSM-IV, i.e. they fulfilled only one or two of the criteria and have therefore been characterized as diagnostic orphans according to Hasin and Paykin (1999) and Pollock and Martin (1999). None, however, fulfilled the DSM-IV criteria for alcohol abuse. Finally, few subjects reported any degree of medical complications related to their alcoholism and thus could not be defined as severe according to the concept of severity (medically ill), as suggested for subjects with the presence of the DRD2 A1 allele (see Noble, 1998). It should also be emphasized that the aim of this study was not to investigate the prevalence of the DRD2 A1 allele in alcoholics.
We found that platelet MAO-B activity was significantly lower in subjects having the DRD2 A1 allele, compared to those not having this allele. This relationship remained unchanged when only subjects who fulfilled the DSM-IV criteria for alcohol dependence were considered. Furthermore, as can be seen in Fig. 2, subjects with platelet MAO-B activity above 5.6 µkat/kg protein (mean value for platelet MAO-B activity in the A1-group) were all non-carriers of the A1 allele. This finding that alcoholics who are carriers of the DRD2 A1 allele have lower platelet MAO-B activity has to our knowledge not been reported earlier. The contradictory findings about whether alcoholism is associated with low platelet MAO-B activity or not may at least be partly explained by the results of the present study. Thus, if a study population contains an abundance of individuals carrying the DRD2 A1 allele the mean level of platelet MAO-B activity could be expected to be low.
Besides a possible relationship to alcoholism, low platelet MAO-B activity has also been reported in smokers (von Knorring et al., 1984; Anthenelli et al., 1995
). In recent reports, Anthenelli et al. (1998, 1999) suggested that low platelet MAO-B activity is a state marker for cigarette smoking, rather than a trait marker for alcoholism or its subgroups. In the present study, there was no evidence for a difference in platelet MAO-B activity between nicotine users and non-users, although the number of subjects might have been too small to detect a difference. However, our results are in line with a study by Farren et al. (1998), who used a larger number of subjects (46 abstinent alcoholics and 22 controls) and found no correlation between platelet MAO-B activity and smoking status. Thus, in our opinion, the relationship between platelet MAO-B activity and smoking status in alcoholics needs to be further clarified. Furthermore, it should be noted that, according to Noble et al. (1994a), the prevalence of the A1 allele is higher in active as well as ex-smokers, compared to non-smokers.
MAO-B is important for the degradation of dopamine in the brain. Whether the platelet MAO-B activity reflects central MAO-B activity in the brain has been discussed. In a previous study, using positron emission tomography, brain and platelet MAO-B activity were shown to be highly correlated (Bench et al., 1991). Furthermore, the expression of the A1 polymorphism of the DRD2 receptor gene is not fully understood. There is, however, evidence for a reduced DRD2 receptor density in the striatal region in the brain in A1+ subjects (Pohjalainen et al., 1996
; Noble, 1998
), suggesting a down-regulated receptor function in this region. Subjects with the DRD2 A1 allele may therefore hypothetically maintain their homeostasis in dopaminergic neurotransmission through a compensatory decrease in the central MAO-B activity. It is noteworthy in this context that alcohol-dependent subjects with neuroendocrine evidence for reduced postsynaptic DRD2 receptor function have decreased platelet MAO-B activity (Berggren et al., 2000
), as opposed to findings reported in studies by Balldin et al. (1994) and Farren and Dinan (1996).
To our knowledge, this is the first report of lower platelet MAO-B activity in alcoholics carrying the DRD2 A1 allele polymorphism. The number of subjects in the present study is, however, relatively small and it is therefore important to further investigate if this association could be replicated, not only in alcoholism but also in individuals with other psychiatric disorders and in healthy subjects. If replicated, our finding suggests that future studies on platelet MAO-B activity in different groups of alcoholism should include determination of the DRD2 A1 allele frequency.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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