Personality Trait Of Novelty Seeking Research Articles

The dopamine D2 receptor gene TaqI A polymorphism is not associated with Novelty Seeking, Harm Avoidance and Reward Dependence in healthy subjects

Allele A1 of the TaqI A restriction fragment length polymorphism (RFLP) of the dopamine D2 receptor gene has been found to be associated with substance abuse and alcoholism. The personality trait of Novelty Seeking (NS) is also associated with substance abuse and dependence. We hypothesised, on the basis of involvement of dopaminergic mechanisms in substance abuse, that the presence of allele A1 of the dopamine D2 receptor gene may represent a genetic predisposition for the NS personality trait. We investigated, therefore, whether the allele A1 of the TaqI A RFLP of the dopamine D2 receptor gene is associated with the NS dimension of the Tridimensional Personality Questionnaire (TPQ) in healthy Caucasian subjects with no history of alcohol or substance abuse or dependence. We genotyped 204 subjects aged 18 to 30 years. There was no association between any of the alleles of the D2 receptor genes and any of the TPQ scores (NS, Harm Avoidance, Reward Dependence). We conclude that allele A1 of the TaqI A RFLP of the dopamine D2 receptor is not associated with NS personality trait in healthy Caucasian subjects.

Additional evidence for an association between the dopamine D4 receptor (D4DR) exon III seven-repeat allele and substance abuse in opioid dependent subjects: relationship of treatment retention to genotype and personality.

The long form of the dopamine D4 receptor (D4DR) exon III repeat polymorphism has been linked in some but not all studies to impulsive, extravagant and novelty-seeking personality traits that are prominent in affiliated behaviours such as attention deficit disorder and substance abuse. In particular, we have reported previously an increased frequency of the long seven-repeat D4DR exon III allele in a group of 141 opioiddependent subjects compared to 110 control subjects. In order to further substantiate the role of D4DR in contributing to heroin addiction we have genotyped an additional, smaller cohort of opioid-dependent subjects. In this new group of 57 opioid-dependent subjects compared to an expanded group of 143 control subjects a significant difference was observed in overall genotype frequency (p=0.04). An excess of the seven-repeat allele of the D4DR receptor gene was also observed compared to control subjects (p=0.06). The frequency of the seven-repeat allele is 15.8% in the heroin addict population vs. 8.1% in the control group, conferring a relative risk of 2.07 (95% CI: 0.98-4.38). An association between two polymorphisms considered together (D4DR and dopamine D3 receptor) and treatment retention was observed (p=0.02). In a subgroup of 38 opioid-dependent subjects, who were successfully administered the TPQ, higher Harm Avoidance (p< 0.001) and Novelty Seeking (NS3; extravagant vs. reserved, p< 0.001) scores were found. In contrast to some previous reports, no relationship was apparent between TPQ scores and treatment retention in this small group of opioid-dependent subjects.

Human novelty-seeking personality traits and dopamine D4 receptor polymorphisms: a twin and genetic association study

Although it is well-established that genetic variation is important in causing individual differences in many human personality traits or based on family, twin, and adoption studies, the first reports that specific genetic polymorphisms might influence a normal dimension of personality were only recently published. Specifically, two studies have described significant associations between a dopamine D4 receptor (D4DR) exon III 48-base pair (bp) insertion/deletion polymorphism and the personality traits of novelty-seeking and positive emotional experience [Benjamin et al. (1996): Nat Genet 12: 81-84; Ebstein et al. (1996): Nat Genet 12:78-80]. The present study was undertaken to attempt to replicate these important and heuristic initial findings. Personality questionnaires measuring novelty-seeking and positive emotional experience were administered to 306 male and female young adult twins (monozygotic 92 pairs, dizygotic 61 pairs) from the general population, 281 of whom were genotyped for D4DR exon I and III polymorphisms. No significant associations were observed between novelty-seeking or positive emotional experience and these D4DR polymorphisms. This failure to replicate the initial reports seems unlikely to represent measurement or genetic differences across studies, although environmental differences may be possible. Adequate statistical power in the present study suggests that these results are unlikely to be statistical "false negatives" and instead may reduce confidence in the generality of the initial positive findings.

No significant associations between two dopamine receptor polymorphisms and normal temperament

A replicated association has been reported between the normal personality trait of novelty seeking on the Tridimensional Personality Questionnaire (TPQ) and an exon III polymorphism in the dopamine D4 receptor gene (D4DR). Genotyping of a polymorphism in exon I of the same gene was carried out in 124 normal volunteers, and no association was found with any TPQ trait. In the same volunteers a dopamine D3 receptor gene (D3DR) point mutation in exon 1 was genotyped. Again, no overall association between any TPQ trait and alleles or genotype was found. There was a weak association between D3DR exon I genotype and harm avoidance in males only. © 1998 John Wiley & Sons, Ltd.

D4 Dopamine-Receptor (DRD4) Alleles and Novelty Seeking in Substance-Dependent, Personality-Disorder, and Control Subjects

Two reports have been published suggesting an association between the personality trait of novelty seeking and the DRD4*7R allele at the D4 dopamine-receptor locus (with heterozygotes or homozygotes for DRD4*7R having higher novelty seeking). We studied novelty seeking and four coding-sequence polymorphisms affecting protein structure in the D4 dopamine-receptor gene (DRD4) in a sample of 341 American subjects, of whom 224 are of primarily European ancestry and 117 are of primarily African ancestry. These subjects had diagnoses of substance dependence or personality disorder (PD) or were screened to exclude major psychiatric diagnosis. We found that, although the substance-dependent subjects had significantly higher novelty seeking than the control and PD subjects, they did not differ in DRD4*7R allele frequency. There was no association between any DRD4 polymorphism and novelty seeking in any population or diagnostic group, except for a significant association between the DRD4*7R allele and lower novelty seeking among European American females and African American substance abusers. The novelty seeking of subjects heterozygous for a null mutation did not differ from that of subjects with two functional alleles. We conclude that the most likely explanation of these results is that the DRD4 VNTR does not influence directly the trait of novelty seeking, in these samples.

Additional evidence for an association between the dopamine D4 receptor (D4DR) exon III repeat polymorphism and the human personality trait of Novelty Seeking.

The long alleles (> or =6 repeats) of the dopamine D4 dopamine receptor exon III polymorphism have been linked in some, but not all, studies to Novelty Seeking (NS), one of four personality traits defined by Cloninger's tridimensional personality questionnarie (TPQ). In order to further examine the robustness of our original observation we have recruited an additional cohort similar in demographic structure to the original cohort. Although no significant difference in mean NS scores was observed when the new subjects (n=94) were grouped by presence (NS=17.83 +/- 1.16) or absence (NS=16.45 +/- 0.65) of the 7 repeat allele, a significant difference in range of NS scores was observed (non-parametric Moses range test, P = 0.01). The effect of the seven allele was also significant in those individuals scoring highest on NS (>1 standard deviation from the mean; t-test, t=5.13, P=0.002). In the expanded cohort (n=218) a significant effect of the seven allele on NS is demonstrated by both parametric (t=2.26, P=0.01) and non-parametric (range test, P=0.004) statistical tests. The effect is also observed in both principal ethnic groups (Ashkenazi and non-Ashkenazi Jews). In the expanded cohort the effect is significant in female (t=2.2, P=0.03, n=98) but not in male subjects (t=1.12, P>0.1, n=116). We discuss both direct and indirect evidence that in our opinion continues to support a modest role for the long alleles of the dopamine D4 receptor repeat polymorphism in the determination of NS behavior at least in some population groups.

Dopamine D4 receptor exon III alleles and variation of novelty seeking in alcoholics.

A dysfunction of dopaminergic neurotansmission has been implicated in alcohol-seeking behavior. Recently, a significant association between the seven-repeat allele (DRD4*7R) of a 16 amino acid motif in the third exon of the dopamine D4 receptor gene (DRD4) and the personality trait of novelty seeking has been reported. Our population-based association study tested the hypothesis that the DRD4*7R variant predisposes to high levels of novelty seeking, which may underlie alcohol-seeking behavior. The genotypes of the expressed DRD4 exon III polymorphism were determined in 197 German controls and 252 German alcohol-dependent males, of whom 92 alcoholics completed the tridimensional personality questionnaire. We found no significant differences in the DRD4*7R frequencies between controls and alcoholics, including two subgroups (56 alcoholics with dissocial personality disorder according to ICD-10 and 89 alcoholics with severe withdrawal symptoms) with a high level of novelty seeking. The novelty-seeking scores did not differ significantly between alcoholics (including both subgroups) carrying long alleles with six or more repeats compared with those lacking long alleles. The present results do not provide evidence that the DRD4*7R allele contributes a common and relevant effect to alcohol-seeking behavior in our sample of alcoholics.

Excess dopamine D4 receptor (D4DR) exon III seven repeat allele in opioid-dependent subjects.

Only in the past decade has a role of heredity in substance abuse been established as a result of extensive twin and family studies. More recently, several candidate genes have been investigated for their possible role in alcoholism and cocaine abuse. Specific genetic factors in opioid substance abuse have not been investigated in man, although animal studies suggest that quantitative trait loci (QTLs) can be identified that predispose mice both to morphine and alcohol preference. Central dopaminergic pathways figure prominently in drug-mediated reinforcement suggesting that dopamine receptors are likely candiadates for association with substance abuse in man. In addition, we recently reported an association between a human personality trait, Novelty Seeking and the long alleles (represented chiefly by the 7-repeat) of the D4 dopamine receptor (D4DR) exon III polymorphism. The personality trait of Novelty Seeking is also more pronounced in substance abusers, who score higher in this dimension than control subjects. The twin role of dopamine receptors in mediating Novelty Seeking and drugreinforcement prompted us to examine a group of Israeli heroin addicts for prevalence of the D4DR repeat polymorphism. We now show that the 7-repeat allele is significantly over-represented in the opioid-dependent cohort and confers a relative risk of 2.46. To our knowledge this is the first report of an association between a specific genetic polymorphism and opioid addiction.

Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking

Twin and adoption studies suggest that 30 to 60% of the variance in many personality traits is due to inherited factors. However, there is little knowledge of the number or identity of the responsible genes, how they differ between individuals, or how their gene products interact with the developing brain and with environmental and experiential factors to generate the complex blend of attitudes and actions that comprise human temperament1. In the accompanying paper, Ebstein et al.2 have found a population association between a long allele of polymorphic exon III repeat sequence of the D4 dopamine receptor gene (DADR) and the normal personality trait of Novelty Seeking. The possibility of a causal relationship between DADR and Novelty Seeking is further supported by studies showing that the number of exon III repeats can affect the binding of ligands to the receptor3,4; that DADR is expressed in lim-bic areas involved in cognition and emotion5,6; that dopamine mediates exploratory behaviour in experimental animals7–12; that the rewarding effects of amphetamines and cocaine are related to dopamine release13; and that Novelty Seeking is low in dopamine-deficient patients with Parkinson's disease14. We investigated the relationship between DADR exon III sequence variants and personality test scores in a population of 315 mostly male siblings, other family members and individuals from the United States. The association between long alleles of exon III and personality traits related to Novelty Seeking was confirmed. Moreover, family studies showed that this association is the result of genetic transmission rather than of population stratification.

Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking.

Human personality traits which can be reliably measured by any of a number of rating scales, show a considerable heritable component1,2. The tridimensional personality questionnaire (TPQ) is one such instrument and was designed by Cloninger to measure four distinct domains of temperament — Novelty Seeking, Harm Avoidance, Reward Dependence and Persistence — that are hypothesized to be based on distinct neurochemical and genetic substrates. Cloninger proposed that individual variations in the Novelty Seeking trait are mediated by genetic variability in dopamine transmission2. Individuals who score higher than average on the TPQ Novelty Seeking scale are characterized as impulsive, exploratory, fickle, excitable, quick-tempered and extravagant, whereas those who score lower than average tend to be reflective, rigid, loyal, stoic, slow-tempered and frugal. We now show that higher than average Novelty Seeking test scores in a group of 124 unrelated Israeli subjects are significantly associated with a particular exonic polymorphism, the 7 repeat allele in the locus for the D4 dopamine receptor gene (D4DR). The association of high Novelty Seeking and the 7-repeat allele was independent of ethnicity, sex or age of the subjects. This work, together with the accompanying confirmations in this issue3, provides the first replicated association between a specific genetic locus involved in neuro-transmission and a normal personality trait.