Pharmacological Reports Copyright © 2012 2012, 64, 11261134 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences
Influence of DRD2 and ANKK1 polymorphisms on the manifestation of withdrawal syndrome symptoms in alcohol addiction
Anna Grzywacz1, Andrzej Jasiewicz1, Iwona Ma³ecka1, Aleksandra Suchanecka1, El¿bieta Grochans2, Beata Karakiewicz3, Agnieszka Samochowiec1,4, Przemys³aw Bieñkowski5, Jerzy Samochowiec1
1Department of Psychiatry, Pomeranian Medical University, Broniewskiego 26, PL 71-460 Szczecin, Poland
2Laboratory of Propedeutics in Nursing, 3Department of Public Health, Pomeranian Medical University, ¯o³nierska 48, PL 71-210 Szczecin, Poland
4Department of Clinical Psychology, Institute of Psychology, University of Szczecin, Szwole¿erów 18, PL 71-062 Szczecin, Poland
5Department of Pharmacology, Institute of Psychiatry and Neurology, Sobieskiego 9, PL 02-957 Warszawa, Poland
Correspondence: Anna Grzywacz, e-mail: [email protected]
Abstract: Background: We investigated the relationship between withdrawal syndrome symptoms and dopamine receptor 2 DRD2 gene poly- morphisms -141 C I/D (rs1799732) exon 8 G/A (rs6276) and ANKK1 (Ankyrin Repeat and Kinase Domain Containing 1) gene poly- morphism Taq1A (rs1800497). Material: A total number of 213 patients who met the ICD 10 criteria for given phenotypes were enrolled in the study. Those phenotypes included: dissocial personality disorder, early onset, alcohol withdrawal syndrome with seizures, alcohol withdrawal syndrome with delirium tremens, and alcohol withdrawal syndrome with seizures and delirium tremens. Results: Our results show statistically significant associations between SNP in exon 8 A/G in the DRD2 gene and alcohol withdrawal syndrome with seizures, and between SNP in promoter -141 C I/D in the DRD2 gene and early onset of alcohol dependence (AD). The A/A genotype in exon 8 A/G polymorphism seems to be a positive predictive factor for the presence or the lack of seizures in al- cohol withdrawal syndrome. The A/G genotype is possibly a protective factor for this AD phenotype. Conclusions: These results suggest that both investigated DRD2 polymorphisms have an impact on the AD phenotype. The findings of the presented study reconfirm that dopamine receptor 2 gene polymorphisms are associated with alcohol addiction and alcohol withdrawal syndrome.
Key words: DRD2, ANKK1, alcohol addiction, withdrawal syndrome
Introduction metabolic and neurological factors [9]. Along with the progress in clinical genetics, it has been ascer- Alcohol dependence (AD) is an etiologically complex tained that many anomalies responsible for alcohol- disorder, whose development involves biochemical, ism are determined by genetics and can be inherited.
1126 Pharmacological Reports, 2012, 64, 11261134 DRD2 and ANKK1 genes in alcohol dependence syndrome Anna Grzywacz et al.
It is estimated that about 40–60% of predisposition ANKK1 (containing RIP kinase and ankyrin repeats), to alcoholism is the genetic contribution [30]. To es- the ANKK1-kinase, and the ANKK1-ankyrin [18]. tablish which genes are associated with this disorder, One of the most commonly studied polymorphisms of the candidate gene strategy was used. Its purpose was this gene is Taq1A placed in 8 exon of the ANKK1 to identify genes involved in the etiology of alcohol gene [35]. addiction. Presupposition was that the knowledge of these genes would enable population screening tests Polymorphism Taq 1A in ANKK1 gene and the identification of people with a higher risk of alcoholism. This, in turn, might result in the provision The Taq1A (E713K) polymorphism causes glutamine of accurate primary and secondary medical attention. to lysine substitution in the 11th ankyrin repeat of The essence of the candidate gene strategy is to evalu- ANKK1. The possibility that it affects peptide struc- ate the relationship between being a carrier of a given ture is very small, but it might change the substrate gene polymorphism and the presence of a nosological specificity. The electrostatic potential analysis of the entity. This approach helps to identify genes partici- ANKK1 crystal structure shows that some regions of pating in biochemical processes, which may cause the protein surface are negatively charged [38]. The pres- addiction. They are mainly genes encoding enzymes ence of negatively charged amino acids on the peptide that synthesize and metabolize catecholamines [1, surface and the combination of amino acids with par- 23]. So far, research has not shown that one of these ticular charges are very conservative. Padmanabhan et genes is a universal marker of the enhanced predispo- al. [38] imply that a specific charge on the peptide sition to alcohol addiction [7, 46]. A multigenic etiol- surface is functionally significant for the peptide- ogy interferes with the identification of one specific peptide interaction. The change of amino acid se- gene that could be used in alcoholism predisposition quence from negatively charged glutamine to posi- screening tests. It seems that determination of a marker tively charged lysine in the ANKK1 peptide at posi- related to a phenotype is now a long-term trend in ge- tion 713 might alter its function. The presence of the netic research on AD [21]. The identification of alle- A1 allele (amino acid: K, nucleotide base: T) implies lic variants associated with the development of addic- a lower density of D2 receptors in striatum. Further- tion may be useful while qualifying patients to differ- more, the A1 allele affects glucose metabolism in ent forms of therapy. It may also result in new brain regions with a high density of the D2 receptor treatment methods. [20, 27, 41, 47, 48]. The dopaminergic system plays an essential role in the pathogenesis of addictions, including AD [24, 42]. The -141 C Ins/Del polymorphism in Research shows that ANKK1 (Ankyrin Repeat and Ki- the dopamine receptor DRD2 gene nase Domain Containing 1) and DRD2 genes might be genetic prognostic factors for an alcoholism phe- This polymorphism results in the insertion (ins, I) or notype [24]. The DRD2 (11q 22-23) gene consists of the deletion (del, D) of cytosine (C) in the promoter 8 exons and 7 introns. Changes in the dopamine re- region of the DRD2 gene at position -141. The -141 C ceptor 2 function are due to polymorphisms in the Ins allele demonstrates higher activity than del allele DRD2 gene. The results that have been reported so far and is responsible for a higher density of D2 receptors suggest that given polymorphic variants might be as- in striatum. These findings were described by Jönsson sociated with an alcohol addiction-prone phenotype. et al. [20], but Pohjalainen et al. [41] did not confirm These results are inconclusive, especially that the them. Thus, the functionality of this polymorphism is analyses were performed mainly on small groups. The still under discussion. Lower levels of DRD2 gene ANKK1 (11q23.2) gene [28], which has about 13 kb, expression in striatum may be a consequence of the consists of 8 exons and is expressed in the placenta, linkage between this particular polymorphism and an- the spinal cord [13] and, according to the latest find- other one in the same gene [20, 27, 39]. ings, also in astrocytes [18]. A peptide encoded by the ANKK1 gene consists of 765 amino acids and is Polymorphism in exon 8 A/G in the DRD2 gene a member of a signal peptide family; it has 11 ankyrin repeats and a serine/threonine kinase domain (EC The next polymorphism in the DRD2 gene is located 2.7.10) [35]. There are at least 3 peptide isoforms of in the exon 8 SNP and causes an adenine (A) to gua-
Pharmacological Reports, 2012, 64, 11261134 1127 nine (G) substitution. This substitution affects gene on genetic contribution to the above-mentioned with- expression [27]. The association between given SNP drawal symptoms. (and haplotypes build with it and other SNPs in the The frequency of the following AD phenotypic fea- DRD2 gene) and more frequent relapse in alcoholics tures was determined in the participants to the study: were found; also a statistical trend with early onset, 1) Dissocial personality disorder (F60.2 according to suicidal attempts and depression was shown [34]. ICD10); 2) Early onset, defined as losing control of the amount of the consumed alcohol or the time spend on alcohol consumption before 26 years of age; Materials and Methods 3) At least one episode of grand mal seizures after al- cohol discontinuation – alcohol withdrawal syndrome with seizures (F10.31 according to ICD10); The group examined consisted of 213 male and fe- 4) At least one episode of delirium tremens – alcohol male patients, whose alcoholism was diagnosed using withdrawal syndrome with delirium tremens (F10.4 the Polish version of SSAGA (Semi-Structured according to ICD10); Assessment for the Genetics of Alcoholism) question- 5) Withdrawal syndrome with seizures and delirium naire [16]. Subjects were recruited among patients of tremens. the Clinic of Psychiatry, the Pomeranian Medical Uni- The purpose of this research was to establish the versity, as well as in hospitals and detox clinics in contribution of three polymorphisms in the ANKK1 western Poland in the years 2000–2010. Patients were and DRD2 genes to the development of alcohol addic- qualified to the research by well-trained doctors from tion with particular phenotypes. In our analysis, we the Department of Psychiatry in Szczecin. Alcohol- did not use the control group of healthy subjects and dependent subjects were women (n = 14, 6.6%) and the study group of patients with alcohol dependence men (n =199, 94.4%), aged 33 ± 9 years. The mean al- (typical association analysis) because our priority was cohol consumption was 224 ± 108 g per day. The mean to create the genetic profile of each AD phenotype. age of losing control of drinking was 25 ± 7 years. The numbers of subjects in each sub-group depended on the polymorphisms examined and were Genotyping as follows: • Taq1A polymorphism: dissocial personality disorder The DNA was isolated from the full blood in accor- (n = 71), early onset (n = 141), seizures (n = 35), de- dance with standard procedures. lirium (n = 33), delirium/seizures (n = 58); The Taq1A (rs1800497) ANKK1 gene polymor- • Exon 8 A/G polymorphism: dissocial personality phism was examined using the PCR-RFLP (Po- disorder (n = 71), early onset (n = 140), seizures (n = lymerase Chain Reaction – Restriction Fragment 36), delirium (n = 33), delirium/seizures (n = 59); Length Polymorphism) method. The following prim- • 141 I/D polymorphism: dissocial personality disor- ers were used: F: 5’- CTT gCC CTC TAg gAA ggA der (n = 71), early onset (n = 143), seizures (n = 35), CAT; R: 5’- ACC TTC CTg AgT gTC ATC AAC C. delirium (n = 33), delirium/seizures (n = 58). The DNA fragments were amplified in an Eppendorf The research protocol was approved by the Bioeth- Thermal Cycler and then digested overnight with the ics Commission of the Pomeranian Medical Univer- TaqI restriction endonuclease (MBI Fermentas, Can- sity in Szczecin. All participants gave their conscious ada Ontario). The digestion products were separated consent for the participation in the study. Phenotypic on a 3% agarose gel and visualized by ethidium bro- features of AD were established by taking patients mide staining. A band size was determined using the medical history with the use of a standardized medical DNA Marker pUC19 DNA/Msp1 (MBI Fermentas). questionnaire. The undigested PCR product was 310 bp (allele A1). The criterion of severe withdrawal symptoms, Allele A2 was comprised of digested bands of 180 namely delirium tremens and alcohol seizures, was and 130 b.p. used to divide the group examined into two sub- The -141 C Ins/Del (rs1799732) DRD2 gene poly- groups: one with delirium tremens and/or alcohol sei- morphism was examined using the PCR-RFLP method. zures and the other one without these symptoms. The The following primers were used: F: 5’- CAA CCC basis for this particular division were literature data Tgg CTT CTg AgT CC; R: 5’- gAg CTg TAC CTC
1128 Pharmacological Reports, 2012, 64, 11261134 DRD2 and ANKK1 genes in alcohol dependence syndrome Anna Grzywacz et al.
CTC ggC gAT C. The DNA fragments were amplified The following primers were used: F: 5’- gCC TgT in an Eppendorf Thermal Cycler and then digested CCT CCC Cgg CTCTg; R: 5’- ggC AgT gAg gAg overnight with the MvaI restriction endonuclease CAT ggA gCC AAC. The DNA fragments were am- (MBI Fermentas). The digestion products were sepa- plified in an Eppendorf Thermal Cycler and then di- rated on a 3% agarose gel and visualized by ethidium gested overnight with the Hpa II restriction endonu- bromide staining. A band size was determined using clease (MBI Fermentas). The digestion products were the DNA Marker pUC19 DNA/Msp1 (MBI Fermen- separated on a 3% agarose gel and visualized by tas). The undigested PCR product was 207 b.p. (allele ethidium bromide staining. A band size was deter- del). Allele ins was comprised of digested bands of mined using the DNA Marker pUC19 DNA/Msp1 177 and 30 b.p. (MBI Fermentas). The undigested PCR product was The exon 8 A/G (rs6276) DRD2 gene polymor- 349bp (allele A). Allele G was comprised of digested phism was examined using the PCR-RFLP method. bands of 282 and 67 b.p.
Tab. 1. The frequency and distribution of AD phenotype features in Tab. 2. The frequency and distribution of AD phenotype features in DRD2 exon 8 A/G polymorphism genotype carriers ANKK1 Taq1A polymorphism genotype carriers
n = 200 n = 205
Phenotype A/A (+) n = 86 A/A (–) n = 114 p Phenotype A1/A1 (+) n = 9 A1/A1 (–) n = 196 p
n % n % n % n % Dissocial 33 38.4 38 33.3 0.460 Dissocial 2 22.2 69 35.2 0.341 personality personality dissorder dissorder Early onset 57 66.3 83 72.9 0.318 Early onset 5 55.6 136 69.4 0.296 Seizures 21 24.4 15 14.5 0.040 Seizures 1 11.1 34 17.3 0.526 Delirium 15 17.4 18 15.8 0.755 Delirium 1 11.1 32 16.3 0.559 Seizures 31 36.05 28 24.6 0.778 Seizures 1 11.1 57 29.1 0.222 + delirium + delirium A/G (+) n = 100 A/G (–) n = 100 A1/A2 (+) n = 66 A1/A2 (–) n = 139 Phenotype p Phenotype p n % n % n % n % Dissocial 34 34.0 37 37.0 0.657 Dissocial 25 37.9 46 33.1 0.302 personality personality dissorder dissorder Early onset 71 71.0 69 69.0 0.757 Early onset 42 63.6 99 71.2 0.175 Seizures 11 11.0 25 25.0 0.009 Seizures 14 21.2 21 15.1 0.187 Delirium 16 16.0 17 17.0 0.848 Delirium 12 18.2 21 15.1 0.356 Seizures 24 24.0 35 35.0 0.088 Seizures 23 34.8 35 25.2 0.103 + delirium + delirium G/G (+) n = 14 G/G (–) n = 186 A2/A2 (+) n = 130 A2/A2 (–) n = 75 Phenotype p Phenotype p n % n % n % n % Dissocial 4 28.6 67 36.02 0.574 Dissocial 44 33.8 27 36.0 0.435 personality personality dissorder dissorder Early onset 12 85.8 128 68.9 0.183 Early onset 94 72.3 47 62.7 0.101 Seizures 4 28.6 32 17.2 0.285 Seizures 20 15.4 15 20.0 0.255 Delirium 2 14.3 31 16.7 0.816 Delirium 20 15.4 13 17.3 0.429 Seizures 4 28.6 55 29.6 0.937 Seizures 34 26.2 24 32.0 0.231 + delirium + delirium
Pharmacological Reports, 2012, 64, 11261134 1129 Statistical analysis Tab. 3. The frequency and distribution of AD phenotype features in DRD2 -141 C ins/del polymorphism genotype carriers Continuous variables are shown as the means and standard deviation. The normality of distribution was n = 206 2 analyzed with the Shapiro-Wilk test. The Pearson c Phenotype I/I (+) n = 170 I/I (–) n = 36 p test and the exact Fischer test were used to compare n % n % genotypes in each phenotype subgroup. Statistica 7.0 (StatSoft, Poland) was used. A statistical significance Dissocial 57 33.5 14 38.9 0.333 level was p £ 0.05. personality dissorder Early onset 112 65.9 31 86.1 0.011 Seizures 32 18.8 3 8.3 0.095 Delirium 27 15.9 6 16.7 0.538 Results Seizures 50 29.4 8 22.2 0.256 + delirium The genotype of exon 8 A/G polymorphism in the I/D (+) n = 35 I/D (–) n = 171 Phenotype p DRD2 gene is associated with the presence of alcohol n % n % withdrawal syndrome with seizures (Tab. 1). We found no association between Taq1A ANKK1 Dissocial 13 37.1 58 33.9 0.427 personality polymorphism and phenotype features (Tab. 2). dissorder The genotype of the -141C Ins/Del polymorphism Early onset 30 85.7 113 66.1 0.015 in the DRD2 gene promoter region is associated with Seizures 3 8.6 32 18.7 0.109 the early onset of AD (Tab. 3). Delirium 6 17.1 27 15.8 0.506 Seizures 8 22.9 50 29.2 0.293 + delirium D/D (+) n = 1 D/D (–) n = 205 Discussion Phenotype p n % n % Dissocial 1 100.0 70 34.1 0.345 Our results show statistically significant associations personality between SNP in the exon 8 A/G in the DRD2 gene and dissorder alcohol withdrawal syndrome with seizures, as well Early onset 1 100.0 142 69.3 0.694 as between SNP in the -141 C Ins/Del promoter in the Seizures 0 0.0 35 17.1 0.830 DRD2 gene and an early onset of AD. The A/A geno- Delirium 0 0.0 33 16.1 0.840 type in exon 8 A/G polymorphism seems to be a posi- Seizures 0 0.0 58 28.3 0.719 tive predictive factor for the presence or the lack of + delirium seizures in alcohol withdrawal syndrome. The A/G genotype is possibly a protective factor for this AD phenotype. Most literature in this field concentrates on the phe- notype variety concerning dopamine receptor gene sion about genetic research methodology in psychia- polymorphisms and substance addiction. The first re- try and pharmacology [7, 46]. search [7] on the association between the Taq1A poly- The heterogeneity of genotyped SNPs both within morphism and alcoholism with severe withdrawal a population and between populations suggests con- symptoms was replicated many times [2, 5, 9, 17, 19]. ducting a haplotype analysis. It is important to re- Other genetic variants of the dopamine receptor 2 member that the relationship between AD susceptibil- gene are also related to AD: Taq1B1, 311 Cys and ity and DRD2 allelic variants is modulated by envi- -141 C Ins [10]. However, these findings were not ronmental factors and probably other genetic factors confirmed by other researchers analyzing these asso- involved in the metabolism and pharmacodynamic ef- ciations. The data inconsistency has provoked discus- fects of alcohol [11, 26, 49].
1130 Pharmacological Reports, 2012, 64, 11261134 DRD2 and ANKK1 genes in alcohol dependence syndrome Anna Grzywacz et al.
The role of genetic factors in severe withdrawal 3) Insignificant effects of one polymorphism on such syndrome was investigated by Sander et al. [44]. a multigenic and multifactor disease as AD, whose Their main thesis was that genetic factors signifi- development is strongly related also to environmental cantly contribute both to alcohol addiction and with- factors; drawal syndrome. The dopaminergic system was ana- 4) Effects of Taq1A on the amount of alcohol intake in lyzed and psychotomimetic effects of the dopamine non-addicts. transporter were confirmed. Polymorphism in the do- Moreover, Noble et al. [37] suggest that the diver- pamine transporter DAT1 was analyzed. As a result, gence in the results concerning the incidence of nine repeats of VNTR (Variable Number Tandem Re- Taq1A may result from different populations and dif- peats) polymorphism were found to be associated ferent AD types analyzed. with severe withdrawal syndrome [44], which was In our previous paper [43], we presented the results also confirmed by our results. indicating to the preferential transmission of the A2 According to Finckh et al. [12] A/A genotype carri- allele from parents to their offspring affected with ers in exon 8 DRD2 polymorphism predispose to se- AD. This result was statistically significant in sub- vere forms of alcohol addiction. groups with early onset and severe withdrawal symp- The results reported by Samochowiec et al. [43] in- toms. A case-control analysis did not reveal any asso- dicate to the association between the DRD2 gene exon ciations. This confirms the validity of the Taq1A 8 polymorphism and certain neurobiological and psy- analysis performed in homogenous subgroups, since chiatric features such as pusillanimity, depressiveness the division into subgroups has a significant influence and severe AD. The A/A genotype seems to be more on the presence or the lack of association. common in subjects with severe withdrawal syndrome. The -141 C Ins/Del polymorphism in the DRD2 Dopamine is a basic neurotransmitter in the reward gene seems to play a role in the etiology of early onset system. Therefore, genes which encode synthesizing AD. I/D genotype carriers might be predisposed to and degrading enzymes, receptors and transporters of early onset AD (86% of I/D and D/D carriers), but this neurotransmitter are candidate genes in alcohol still 66% of I/I genotype carriers have early onset AD addiction research [8]. as well (p = 0.011). These results are consistent with The metaanalysis of research on Caucasian race those reported by Duan et al. [10], however, there are shows a statistically significantly higher frequency of also contradictory findings [14]. SNP -141 C I/D the A1 allele of the Taq1A polymorphism in alcoholics modulates DRD2 gene expression [4, 40]. The pres- than in the control group. DRD2 gene variants are ence of the D allele reduces expression by ~68% in vi- also related to obesity as well as cocaine, nicotine and tro. The I allele might, on the other hand, cause dopa- opioid addiction [36]. minergic hyperactivity [15]. It is difficult to establish The Taq1A polymorphism A1 variant is associated the role of this polymorphism in AD. One theory is with a lower density of D2 receptors in striatum and that the I/I genotype, which increases DRD2 expres- A2 variant is related to higher alcohol consumption sion, forces a carrier to produce more dopamine in or- by alcoholics [37]. der to saturate all receptors. This might be an impor- A higher frequency of the A1 allele Taq1A SNP in tant contributor to substance addiction and risky be- alcohol addicts than in controls was confirmed by: haviors resulting in the increased dopaminergic Blum et al. [7]; Comings et al. [9]; Gelernter and output, especially in adolescents, who have not devel- Kranzler [14]; Parsian et al. [39]; Amadeo et al. [2]; oped the delayed gratification mechanism yet [6]. Noble et al. [37]; Hietala et al. [17]; Samochowiec et Our research does not show any associations be- al. [43]. There are no reports on association research tween the Taq1A polymorphism and phenotype fea- similar to that described by Nobe [36]. tures of AD or withdrawal syndrome. A widely dis- In spite of many association analyses, statistically sig- cussed contribution of the Taq1A polymorphism to al- nificant associations between the A1 allele and AD were cohol and nicotine addictions is a consequence of the not found in every case. We can hypothesize that the re- role that DRD2 and probably ANKK1 genes play in sults of the Taq1A analysis may be associated with: the reward system functioning. Studies on the rela- 1) AD type; tionship between nicotine addiction and Taq1A that 2) The type of the control group; have been performed so far are not conclusive, but
Pharmacological Reports, 2012, 64, 11261134 1131 there are two metaanalyses [25, 33] which point to the to predict, was the frequency of genotypes. In particu- A1 allele as predisposing to this addiction. lar, D/D (-141 C I/D) and A1/A1 (Taq1A) were very Klein et al. [22] used neuroimaging techniques to rare. The low penetration of these two genotypes might investigate the role of dopamine in learning from have been a factor disrupting the analysis. It may also one’s own mistakes. A1 allele carriers with a lower explain why the role of these genotypes in the patho- D2 receptor density learned how to avoid actions with genesis of AD have not been demonstrated. Irrespec- negative consequences less effectively than A2 allele tive of these limitations, the analysis was conducted on carriers. The decreasing amount of D2 receptors the adequate number of genotyped subjects and inter- seems to reduce sensitivity to negative outcomes of esting data were obtained. actions. This might also explain a higher risk of ad- Our discovery creates perspectives to develop sim- diction in the group of A1 allele carriers. ple screening tests to genotype chosen genes. These The Taq1A polymorphism and the haplotype which tests could help to find those AD children who are in- contains this polymorphism affect cognitive function- clined to early onset and to identify alcoholics predis- ing in patients after traumatic brain injury [13, 29]. posed to severe withdrawal syndrome with seizures. Our results confirm previous findings of Shaikh et Perhaps further analysis of mechanisms which enable al. [45] concerning the lack of associations between polymorphisms of the DRD2 gene to modulate the this SNP and AD onset. progress of alcohol addiction, would allow to apply There is a strong linkage disequilibrium (LD) be- new therapeutic and preventive measures for this dis- tween SNP rs711890 (Thr239Ala) and Taq1A [18], order. which suggests that this polymorphism has an effect on the activity of the ANKK1 protein kinase domain. Acknowledgment: Threonine at position 239 creates an additional phos- This work was supported by MNiSW: NN 402466540. phorylation point, which might modify protein func- tion in astrocytes and neurons. What is worth men- tioning is the fact that both ANKK1 and DRD2 genes have sequences binding the same transcription factors References: related to cell growth, proliferation and differentiating in promoter regions. 1. Agarwal DP, Seitz HK: Alcohol in Health and Disease, The discovery of the fact that the ANKK1 gene is ex- Marcel Dekker Inc, New York, 2001. 2. pressed in the central nervous system (CNS) in astro- Amadeo S, Abbar M, Fourcade ML, Waksman G, Leroux MG, Madec A, Selin M et al.: D2 dopamine receptor gene cytes only creates new perspectives for understanding and alcoholism. J Psychiatr Res, 1993, 27, 173–179. the basis of pathophysiology in Taq1A-related pheno- 3. Araque A, Parpura V, Sanzgiri RP, Haydon PG: Tripar- types. Because of bilateral communication between as- tite synapses: Glia, the unacknowledged partner. Trends trocytes and neurons, astrocytes are considered to be Neurosci, 1999, 22, 208–215. 4. Arinami T, Gao M, Hamaguchi H, Toru M: A functional a part of synapse [3]. The above-mentioned glia cells polymorphism in the promoter region of dopamine D2 take part in the pathophysiology of the learning process receptor gene is associated with schizophrenia. Hum Mol and the rewarding effect of addictive substances [31]. Genet, 1997, 6, 577–582. 5. In mice the ANKK1 protein is located in astroglia of Arinami T, Itokawa M, Komiyama T, Mitsushio H, Mori H, Mifime H, Hamaguchi H, Toru M: Association the developing CNS [18]. Human astroglia is a source between severity of alcoholism and the A l allele of of neuronal progenitor cells in the cortex [32]. Avail- the dopamine D2 receptor gene Taql A RFLP in Japa- able data suggest that polymorphic variants of genes nese. Biol Psychiatry, 1993, 33, 108–114. engaged in astroglia function play an important part. 6. Beauregard M, Levesque J, Bourgouin P: Neural corre- lates of conscious self-regulation of emotion. J Neurosci, These polymorphisms may create small changes in 2001, 21, RC165. brain cytoarchitecture, which might be a reason for in- 7. Blum K, Noble N, Sheridan P, Montgomery A, Richie T, dividual differences in brain function. Jagadeeswaran P, Nogami H et al.: Allelic association of The advantage of this research was that the genetic human dopamine D2 receptor gene in alcoholism. J Am analysis of DRD2 and ANKK1 genes was performed in Med Assoc, 1990, 263, 2055–2060. 8. Comings D, Blum K: Reward deficiency syndrome: ge- quite a big and homogenous group of alcohol addicts. netic aspects of behavioral disorders. Prog Brain Res, A potential limitation, which however was impossible 2000, 126, 325–341.
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