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Association Between Novelty-Seeking and the Dopamine D3 Receptor Gene in Bipolar Patients: A Preliminary Report L. Staner, 1 * C. Hilger, 2 F. Hentges, 3 J. Monreal, 1 A. Hoffmann, 3 M. Couturier, 1 O. Le Bon, 4 G. Stefos, 1 D. Souery, 5 and J. Mendlewicz 5 1 Department of Psychiatry, Centre Hospitalier de Luxembourg, Luxembourg, Grand Duchy of Luxembourg 2 CRP-Sante ´, Luxembourg, Grand Duchy of Luxembourg 3 Laboratory of Immuno-Allergology, Centre Hospitalier de Luxembourg, Luxembourg, Grand Duchy of Luxembourg 4 Department of Psychiatry, University Hospital Brugmann, Brussels, Belgium 5 Department of Psychiatry, Erasme Hospital, Free University of Brussels, Brussels, Belgium Recent studies in healthy controls suggest an association between novelty-seeking (NS) and the dopamine D4 receptor (DRD4) gene. In this study, we further investigated the relationship between genes implicated in dopamine as well as serotonin neuro- transmission and personality traits in bi- polar (BP) disorder. Scores on the Tridi- mensional Personality Questionnaire were examined in 37 recovered Research Diag- nostic Criteria-diagnosed BP patients geno- typed for DRD3, DRD4, and serotonin 2A re- ceptor (5HTR2a) polymorphisms. Carriers of DRD3 allele 1 showed significantly lower NS values compared to patients without this allele. Scores on NS and on harm-avoidance were not related to DRD4 or 5HTR2a poly- morphisms. These preliminary results sug- gest a role for D3 receptor in NS expression in BP patients. Am. J. Med. Genet. (Neuro- psychiatr. Genet.) 81:192–194, 1998. © 1998 Wiley-Liss, Inc. KEY WORDS: novelty-seeking; bipolar dis- order; TPQ; DRD3; DRD4; HTR2a INTRODUCTION In his tridimensional theory of personality, Clon- inger [1987] states that three heritable traits are de- termined in part by a specific neurotransmitter (i.e., a dopamine-related novelty-seeking (NS), a serotonin- related harm-avoidance (HA), and a norepinephrine- related reward-dependence (RD) trait), and are sup- posed to underlie basic temperaments in human be- ings. A rating instrument, the Tridimensional Personality Questionnarie (TPQ), has been shown to be a valid and reliable measure of these traits [Cloninger et al., 1991]. The dopamine D4 receptor gene has re- cently been associated with NS in healthy controls [Eb- stein et al., 1996; Benjamin et al., 1996], as was HA with a polymorphism in the serotonin transporter gene regulatory region [Lesch et al., 1996]. Euthymic bipolar (BP) patients have been shown to score significantly higher than healthy controls on the NS and the HA dimensions [Young et al., 1995]. In the present study, we further investigated, in a group of BP patients, the possible relationship between NS and HA and polymor- phisms of genes implicated in dopamine or serotonin neurotransmission. Thus, TPQ scores and polymor- phisms of the serotonin 2A (5HTR2a), the dopamine D3 (DRD3), and dopamine D4 (DRD4) receptor genes were examined in 37 BP patients. SUBJECTS AND METHODS Patients had to be of Caucasian origin and to have experienced a period of euthymia of at least 2 months before fulfilling the TPQ. Bipolar disorder was diag- nosed according to Research Diagnostic Criteria (RDC) [Spitzer et al., 1978], using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version [Spitzer and Endicott, 1979]. The procedure and aims of the study were fully explained to all patients, and informed consent was obtained before drawing venous blood for genomic DNA isolation. Typing of the DRD3, DRD4, and 5HTR2a polymorphisms was done according to Lannfelt et al. [1992], Shaikh et al. [1993], and Warren et al. [1993]. Two alleles were observed for the DRD3 gene, i.e., 1 (304 bp) and 2 (206 + 98 bp), as well as for 5HTR2a, i.e., 1 (372 bp) and 2 (216 + 156 bp). For DRD4, there were seven alleles with 2–8 48-bp repeats (alleles 2–8); genotypes were stratified according to Eb- stein et al. [1996] by the presence or the absence of allele 7 or by 4/4 vs. 4/7 genotypes, the most common *Correspondence to: Dr. L. Staner, FORENAP, Centre Hospi- talier de Rouffach, 29 rue du 4e `me R.S.M., F-68250 Rouffach, France. E-mail: [email protected] Received 15 July 1997; Revised 13 November 1997 American Journal of Medical Genetics (Neuropsychiatric Genetics) 81:192–194 (1998) © 1998 Wiley-Liss, Inc.

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Page 1: Association between novelty-seeking and the dopamine D3 receptor gene in bipolar patients: A preliminary report

Association Between Novelty-Seeking and theDopamine D3 Receptor Gene in Bipolar Patients: APreliminary Report

L. Staner,1* C. Hilger,2 F. Hentges,3 J. Monreal,1 A. Hoffmann,3 M. Couturier,1 O. Le Bon,4 G. Stefos,1D. Souery,5 and J. Mendlewicz5

1Department of Psychiatry, Centre Hospitalier de Luxembourg, Luxembourg, Grand Duchy of Luxembourg2CRP-Sante, Luxembourg, Grand Duchy of Luxembourg3Laboratory of Immuno-Allergology, Centre Hospitalier de Luxembourg, Luxembourg, Grand Duchy of Luxembourg4Department of Psychiatry, University Hospital Brugmann, Brussels, Belgium5Department of Psychiatry, Erasme Hospital, Free University of Brussels, Brussels, Belgium

Recent studies in healthy controls suggestan association between novelty-seeking(NS) and the dopamine D4 receptor (DRD4)gene. In this study, we further investigatedthe relationship between genes implicatedin dopamine as well as serotonin neuro-transmission and personality traits in bi-polar (BP) disorder. Scores on the Tridi-mensional Personality Questionnaire wereexamined in 37 recovered Research Diag-nostic Criteria-diagnosed BP patients geno-typed for DRD3, DRD4, and serotonin 2A re-ceptor (5HTR2a) polymorphisms. Carriersof DRD3 allele 1 showed significantly lowerNS values compared to patients without thisallele. Scores on NS and on harm-avoidancewere not related to DRD4 or 5HTR2a poly-morphisms. These preliminary results sug-gest a role for D3 receptor in NS expressionin BP patients. Am. J. Med. Genet. (Neuro-psychiatr. Genet.) 81:192–194, 1998.© 1998 Wiley-Liss, Inc.

KEY WORDS: novelty-seeking; bipolar dis-order; TPQ; DRD3; DRD4;HTR2a

INTRODUCTIONIn his tridimensional theory of personality, Clon-

inger [1987] states that three heritable traits are de-termined in part by a specific neurotransmitter (i.e., adopamine-related novelty-seeking (NS), a serotonin-related harm-avoidance (HA), and a norepinephrine-related reward-dependence (RD) trait), and are sup-

posed to underlie basic temperaments in human be-ings. A rating instrument, the TridimensionalPersonality Questionnarie (TPQ), has been shown to bea valid and reliable measure of these traits [Cloningeret al., 1991]. The dopamine D4 receptor gene has re-cently been associated with NS in healthy controls [Eb-stein et al., 1996; Benjamin et al., 1996], as was HAwith a polymorphism in the serotonin transporter generegulatory region [Lesch et al., 1996]. Euthymic bipolar(BP) patients have been shown to score significantlyhigher than healthy controls on the NS and the HAdimensions [Young et al., 1995]. In the present study,we further investigated, in a group of BP patients, thepossible relationship between NS and HA and polymor-phisms of genes implicated in dopamine or serotoninneurotransmission. Thus, TPQ scores and polymor-phisms of the serotonin 2A (5HTR2a), the dopamine D3(DRD3), and dopamine D4 (DRD4) receptor genes wereexamined in 37 BP patients.

SUBJECTS AND METHODS

Patients had to be of Caucasian origin and to haveexperienced a period of euthymia of at least 2 monthsbefore fulfilling the TPQ. Bipolar disorder was diag-nosed according to Research Diagnostic Criteria (RDC)[Spitzer et al., 1978], using the Schedule for AffectiveDisorders and Schizophrenia-Lifetime Version [Spitzerand Endicott, 1979]. The procedure and aims of thestudy were fully explained to all patients, and informedconsent was obtained before drawing venous blood forgenomic DNA isolation. Typing of the DRD3, DRD4,and 5HTR2a polymorphisms was done according toLannfelt et al. [1992], Shaikh et al. [1993], and Warrenet al. [1993]. Two alleles were observed for the DRD3gene, i.e., 1 (304 bp) and 2 (206 + 98 bp), as well as for5HTR2a, i.e., 1 (372 bp) and 2 (216 + 156 bp). ForDRD4, there were seven alleles with 2–8 48-bp repeats(alleles 2–8); genotypes were stratified according to Eb-stein et al. [1996] by the presence or the absence ofallele 7 or by 4/4 vs. 4/7 genotypes, the most common

*Correspondence to: Dr. L. Staner, FORENAP, Centre Hospi-talier de Rouffach, 29 rue du 4eme R.S.M., F-68250 Rouffach,France. E-mail: [email protected]

Received 15 July 1997; Revised 13 November 1997

American Journal of Medical Genetics (Neuropsychiatric Genetics) 81:192–194 (1998)

© 1998 Wiley-Liss, Inc.

Page 2: Association between novelty-seeking and the dopamine D3 receptor gene in bipolar patients: A preliminary report

genotypes found for the DRD4 gene. DRD4 genotypeswere also inventoried according to Benjamin et al.[1996] in short (s, 2–5 repeats) and long (1, 6–8 repeats)allele classification. Conservative nonparametric sta-tistics were used, and no correction was made in theobtained P values for multiple testing, since we had ana priori hypothesis about the association of NS and HAscores with polymorphisms of dopamine receptor genesand 5HTR2a, respectively.

RESULTS

Twenty-three female and 14 male bipolar patients,aged 44.89 ± 13.45 years, were included in the study.Their mean age of illness onset was 26.6 ± 9.7, andtheir mean number of episodes was 9.8 ± 7.4 (depres-sive episodes, 4.5 ± 4.4; manic episodes, 5.4 ± 5.2).Seven patients (19%) received another RDC diagnosis,and 17 (46%) had at least one bipolar first-degree rela-tive. Prophylactic medication consisted of lithium (n 426), carbamazepine (n 4 4), valproic acid (n 4 2), andlithium with carbamazepine (n 4 5). Gender and agedid not affect TPQ scores, except for a nonsignificanteffect for age on NS (r 4 −.3086, P 4 .063). Table Ishows the scores on the three TPQ dimensions in pa-tient groups sorted by DRD3, DRD4, and 5HTR2a al-leles and genotypes. A significant difference in NSscores was observed between patients with the allele 1of the DRD3 gene in comparison to patients lackingthis allele, the latter exhibiting higher scores. A trendwas also found for DRD3 genotypes, patients with the1-1 genotype showing the lowest scores, and those withthe 2-2 genotype the highest. However, there were noassociation of NS scores with DRD4 (with vs. withoutallele 7, 4/4 vs. 4/7 genotypes, and s/s vs. s/l vs. l/l geno-types) or 5HTR2a polymorphisms. Scores for HA andRD were statistically indistinguishable between pa-tient groups sorted by DRD3, DRD4, or 5HTR2a allelesor genotypes.

DISCUSSION

These preliminary results suggest that allelic varia-tion at the DRD3 gene may be involved in NS expres-sion in bipolar disorder. The BalI polymorphism of theDRD3 gene results in a glycine-to-serine substitutionin the first exon, leading to a modified sequence of un-known functional significance in the extracellular partof the receptor [Lannfelt et al., 1992]. However, thedopamine D3 receptor, almost exclusively expressed inthe limbic structure [Sokoloff et al., 1990], is of particu-lar interest with regard to NS because nafatopride, aD3 antagonist drug, has been shown to increase spon-taneous locomotor activity in rats [Sautel et al., 1995],whereas D3 agonists were found to inhibit locomotoractivity [Svensson et al., 1994]. Moreover, DRD3-deficient mice displayed increased locomotor activityand rearing behavior [Accili et al., 1996]. Neverthelessand up to now, most evidence for the implication ofgenes related to dopamine neurotransmission in NSexpression has come from DRD4. Ebstein and Bel-maker [1997] reviewed the available studies in humanvolunteers (4 positives and 3 negatives) and in sub-stance abusers (5 positives and 3 negatives) and con-cluded in favor of a probable modest effect of DRD4genotypes on the NS phenotype. It must be acknowl-edged that our 37 patients had a limited statisticalpower to exclude a true association, i.e., in the region of80% to detect a three-point difference in NS score at aP < .05 level. On the other hand, it can be argued thatmore than one dopamine receptor polymorphism is in-volved in NS expression, both in controls and in bipolarpatients. Nevertheless, the present study seems to in-dicate that the D3 and not the D4 receptor is impli-cated in NS expression in BP patients: although theyneed to be replicated in a larger sample, these resultssuggest that a relationship between a personality traitin BP patients and BalI polymorphism of the DRD3gene has to be taken into account when conducting

TABLE I. TPQ Dimension Scores in Subject Groups Sorted by DRD3, DRD4, and 5HTR2a Alleles andGenotypes†

Subject group Novelty-seeking Reward-dependence Harm-avoidance

DRD3 BalI polymorphism1 allele present (n 4 22) 13 (5–23)* 16.5 (6–23) 17 (7–32)1 allele absent (n 4 15) 17 (12–27)* 18 (9–24) 16 (6–31)1-1 genotype (n 4 2) 12 (6–18)** 11.5 (10–13) 20.5 (18–23)1-2 genotype (n 4 20) 13 (5–23)** 17 (6–23) 15.5 (7–32)2-2 genotype (n 4 15) 17 (12–27)** 18 (9–24) 16 (6–31)DRD4 exon III polymorphism7 allele present (n 4 6) 12 (9–23) 16.5 (12–23) 14.5 (12–30)7 allele absent (n 4 31) 15 (5–27) 17 (6–24) 19 (6–32)4-4 genotype (n 4 21) 15 (6–27) 17 (9–24) 20 (6–32)4-7 genotype (n 4 5) 11 (9–23) 17 (12–23) 14 (12–30)5HTR2a T102C polymorphism2 allele present (n 4 26) 15 (6–27) 16.5 (6–23) 17 (6–32)2 allele absent (n 4 11) 12 (5–21) 17 (10–24) 16 (7–27)1-1 genotype (n 4 11) 12 (5–21) 17 (10–24) 16 (7–27)1-2 genotype (n 4 23) 15 (6–27) 16 (6–23) 18 (6–23)2-2 genotype (n 4 3) 16 (12–16) 18 (13–18) 16 (11–30)

†TPQ results are reported as median scores, with minimum and maximum in parentheses.*Mann-Whitney test significance: P 4 0.0155.**Kruskal-Wallis ANOVA significance: P 4 0.0534.

Novelty-Seeking and DRD3 in Bipolar Patients 193

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