Norepinephrine Transporter Polymorphism and Personality Trait of Reward Dependence in Male Alcoholics

Cloninger et al. proposed a model of personality based on three dimensions: Novelty Seeking (NS), Harm Avoidance (HA) and Reward Dependence (RD), which were assessed using the Tridimensional Personality Questionnaire [1]. Novelty seeking was defined as the tendency to respond actively to new stimuli, harm avoidance as a tendency toward inhibitory response to aversive stimuli. Reward dependence is a multifaceted, higher-order temperament trait consisting of the following three aspects or lower order traits: sentimentality vs. tough-mindedness (RD1), attachment vs. detachment (RD3), and dependence vs. independence (RD4). Individuals high in reward dependence tend to be tender-hearted, loving and warm, sensitive, dedicated, dependent and sociable. They seek social contact and are open to communication with other people. A major advantage of high reward dependence is the sensitivity to social cues. A major disadvantage of high reward dependence involves the ease with which other people can influence the dependent person’s views and feelings, possibly leading to loss of objectivity and a tendency for a positive response to signals of reward [1]. It was assumed that these personality traits could be related to different neurotransmitter systems, and accordingly to dopaminergic, serotonergic and norepinephrinergic neurones. Previous studies have given evidence for the correlation between the reward dependence trait and urinary levels of the main norepinephrine metabolite - 3-methoxy-4-hydroxyphenylglycol (MHPG) [2] [4]. It was hypothesised that norepinephrine activity may contribute to the personality dimension of RD. Norepinephrine turnover in the brain is regulated with norepinephrine transporter (NET), a transmembrane protein responsible for the reuptake of the transmitter from the synaptic cleft. Recently, the gene for this protein was mapped on the chromosome 16q12.2, and a highly polymorphic site within this locus was described [10]. The study by Jönsson et al. revealed that this SLC6A2 (Sau 96I) polymorphism (NET 8 G1287A RFLP in exon 9) is associated with high MHPG levels in the cerebrospinal fluid, which might reflect a genetic influence on norepinephrine metabolism [6].

The aim of this study was to test the hypothesis that allelic variation of norepinephrine transporter gene might influence the personality trait of reward dependence in alcohol dependent subjects. The Ethics Committee of the University Hospital Rudolf Virchow at the Free University of Berlin approved the study protocol. Written informed consent was obtained from all participants, who were unrelated individuals of German descent. The study included 72 males (age 44 ± 10, abstinent for 3 months, without any neurological or somatic disorders) fulfilling the criteria of the alcohol dependence syndrome according to ICD-10. Alcohol and substance abuse history was assessed by Composite International Diagnostic Interview [7]. Comorbidity was assessed by a psychiatric interview and a sociodemographic questionnaire. All subjects answered the German version of TPQ [3] assessing personality dimensions novelty seeking (34 items), harm avoidance (34 items), and reward dependence (30 items). Subjects with history of a primary major psychiatric disorder or substance dependence other than alcohol or nicotine dependence were excluded. In our group, 48.4 % of the patients were single, and 52.4 % had finished primary school only. 33.9 % of patients examined had a family history positive for alcohol dependence. The age of alcohol initiation was 17.5 ± 5.9 and the age of onset was 32.7 ± 9.9 years. Mean alcohol consumption was 224.7 ± 140.8 g of pure alcohol per day. The mean number of patient detoxifications was 4.6 ± 6.2. An exonic silent RFLP (1287A) in the NET gene was analysed as previously described by Stöber [10].

There were no significant differences between means of TPQ dimensions of novelty seeking and harm avoidance (NS, HA) in groups carrying the A [f (A) = 0.29] allele and G allele, whereas reward dependence (RD) showed a significant increase in A allele carriers (15.26 ± 4.05 vs. 12.46 ± 4.05; p = 0.02, df = 1) compared using the Mann-Whitney U-Test. None of the observed genotype counts deviated from the Hardy-Weinberg equilibrium.

Samochowiec et al. and Stöber et al. [9] [10] estimated the A allele frequency in controls at 0.35; n = 92 and n = 109 respectively, which is in good agreement with our present results. According to the study by Waller et al. on 1,236 controls without psychiatric disorders [12], the mean value of reward dependence was 11.7 ± 3.8. According to the study by Sullivan et al. on 56 alcohol dependent subjects according to Cloninger’s type I and type II [11], reward dependence was 20.2 and 21 points respectively. This result was obtained during the treatment; therefore, the scores might be increased compared to those in our group, which had been abstinent for a longer period (three months).

Our finding is consistent with results of some previous studies. They showed that RD might be associated with higher levels of MPHG in urine, and that the NET polymorphism analysed might correspond with high MPHG levels in CSF. Also, Gerra et al. performed the clonidine challenge in healthy volunteers, and demonstrated that reward dependence scores correlated positively with clonidine stimulated growth hormone release [5].

Our study has two important limitations. We only analysed small numbers of male alcohol-dependent subjects; thus, we probably cannot generalise our results to the global population. However, our study confirms previous reports that included only male subjects [2] or showed significant associations only for male subgroup [6]. It is not known whether the analysed polymorphism affects the protein structure via a silent mutation. However, we cannot exclude the existence of linkage disequilibrium with other functional polymorphism in NET gene (for example Gly478Ser) [8].

In conclusion, our results are in good agreement with the Cloninger theory on personality traits [1], and give further evidence for the association between reward dependence and the norepinephrinergic system.

References

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