Chang-Chih Huang

DRD3 variation associates with early-onset heroin dependence, but not specific personality traits

Dopamine D3 receptor-mediated pathways are involved in the mechanism of addiction, and genetic factors play a role in the vulnerability to heroin dependence. The aim of this study was to examine whether the corresponding gene, DRD3, is associated with the development of heroin dependence and specific personality traits in HD patients. Eight polymorphisms in DRD3 were analyzed in 1067 unrelated Han Chinese subjects (566 heroin dependence patients and 501 controls). All participants were screened using the same assessment tool and all patients met the criteria for heroin dependence. A Tridimensional Personality Questionnaire was used to assess personality traits in 276 heroin dependence patients. In addition, heroin dependence patients were divided into 4 clinical subgroups based on age-of-onset and family history of substance abuse, to reduce the clinical heterogeneity. The rs6280 and rs9825563 variants showed association with the development of early-onset heroin dependence. The GTA haplotype frequency in the block (rs324029, rs6280, rs9825563) was significantly associated with early-onset heroin dependence (p=0.003). However, these significant associations were weaker after Bonferronis correction. In addition, these DRD3 polymorphisms did not influence novelty seeking and harm avoidance scores in HD patients. DRD3 is possibly a genetic factor in the development of early-onset heroin dependence, but is not associated with specific personality traits in these patients among the Han Chinese population.

Association study of the dopamine transporter gene with personality traits and major depressive disorder in the Han Chinese population.

Major depression is a complex psychiatric disorder involving multiple factors, including genetic and personality components. This study used 17 polymorphisms of dopamine transporter gene (DAT1) to explore whether this gene is associated with major depression and whether it influences personality traits in patients with major depression. The DAT1 polymorphisms were analyzed in 1017 unrelated individuals and 459 patients were eligible to assess personality traits. We found a borderline association between controls and total major depression and between major depression with family history versus controls; however, these differences were obscured after correction for multiple testing. Furthermore, the DAT1 polymorphisms were not associated either with major depression in haplotype analysis or with personality traits. Despite the fact that several association tendencies were found between DAT1 and major depression, we did not confirm a major role for DAT1 in the susceptibility to major depression. In addition, DAT1 does not seem to affect personality traits observed in patients with major depression.

Reduced striatal dopamine transporter density associated with working memory deficits in opioid-dependent male subjects: a SPECT study

Research on the effects of repeated opioid use on striatal dopamine transporters has yielded inconsistent results, possibly confounded by a history of methamphetamine or methadone exposure in opioid‐dependent individuals. Previous studies have shown that striatal dopamine transporter density is positively correlated with the cognitive performance of healthy volunteers. This study aimed to investigate changes in striatal dopamine transporter density and their functional significance in opioid‐dependent individuals. Single‐photon emission computed tomography with [99mTc]TRODAT‐1 as a ligand was used to measure striatal dopamine transporter levels in 20 opioid‐dependent individuals and 20 age‐ and sex‐matched healthy controls. Opioid‐dependent individuals had no history of methamphetamine or methadone use. The Wisconsin Card Sorting Test (WCST) was performed to assess neurocognitive function. We found that compared with healthy controls, opioid‐dependent individuals showed a significant reduction in striatal dopamine transporter density. They also showed poorer performance on the WCST in terms of the trials administered, total errors, perseverative responses, perseverative errors, and non‐perseverative errors. Striatal dopamine transporter levels negatively correlated with non‐perseverative errors not only in opioid‐dependent individuals but also in healthy controls. These findings suggest that in human, repeated opioid exposure reduces striatal dopamine transporter density, which can be associated with non‐perseverative errors. Non‐perseverative errors may be one of the more sensitive parameters in WCST to identify working memory deficits associated with striatal dopamine transporter reduction. Moreover, we suggest that whether opioid‐associated neurotoxicity is reversible depends on the brain region.

Suicidal ideation modulates the reduction in serotonin transporter availability in male military conscripts with major depression: A 4-[18F]-ADAM PET study

Objectives. Suicide is an important issue in the military service, since it can influence military morale and create dangerous situations for other personnel. The serotonin transporter (SERT) has been suggested to be involved in the pathophysiology of depression and suicidal behaviours. The aims of this study were to examine whether the brain SERT availability differs between military conscripts with depression and control subjects, and whether suicidal ideation is correlated with SERT availability. Methods.We used N,N-dimethyl-2-(2-amino-4-[18F]-fluorophenylthio)benzylamine (4-[18F]-ADAM) as a radioligand for positron emission tomography (PET) imaging. All participants completed the Hamilton Depression Rating Scale and Beck Scale for Suicide Ideation (BSS) prior to PET imaging. Results. The effect of major depression and BSS scores had an interaction on SERT availability. After adjusting for the BSS score, subjects with depression had lower SERT availability than control subjects (F1,17 = 23.85, P < 0.001). A positive correlation between SERT availability and BSS scores was observed in the depression group (F1,8 = 30.67, P = 0.001). The status of depression and intensity of suicidal ideation exert opposite effects on SERT availability. Conclusions. The extent of suicidal ideation may moderate the reduction effect in SERT binding observed in major depression in male military conscripts.

The dopamine transporter gene may not contribute to susceptibility and the specific personality traits of amphetamine dependence

BACKGROUNDnA substantial amount of evidence suggests that dysfunction of the dopamine transporter may be involved in the pathophysiology of amphetamine dependence (AD). The aim of this study was to examine whether the dopamine transporter gene (DAT1, SLC6A3) is associated with development of AD and whether this gene influences personality traits in patients with AD.nnnMETHODSnEighteen polymorphisms of the DAT1 gene were analyzed in a case-control study that included 909 Han Chinese men (568 patients with AD and 341 control subjects). The patients fulfilled the DSM-IV-TR criteria for AD. The Tridimensional Personality Questionnaire (TPQ) was used to assess personality traits and to examine the association between these traits and DAT1 gene variants.nnnRESULTSnA weak association was found between the rs27072 polymorphism and development of AD, but these borderline associations were unconfirmed by logistic regression and haplotype analysis. Although harm avoidance and novelty seeking scores were significantly higher in patients than in controls, DAT1 polymorphisms did not influence these scores.nnnCONCLUSIONSnThis study suggests that high harm avoidance and novelty seeking personality traits may be a risk factor for the development of AD. However, the DAT1 gene may not contribute to AD susceptibility and specific personality traits observed in AD among Han Chinese men.

Reduced Dopamine Transporter Availability and Neurocognitive Deficits in Male Patients with Alcohol Dependence

Dopamine plays an important role in the development of alcohol dependence, cognitive dysfunction, and is regulated via dopamine transporter activity. Although dopamine transporter activity is critically involved in alcohol dependence, studies observing this relationship are limited. Thus the current study examined whether dopamine transporter availability is associated with developing of alcohol dependence and cognitive dysfunction. Brain imaging with 99mTc-TRODAT-1 as a ligand was used to measure dopamine transporter availability among 26 male patients with pure alcohol dependence and 22 age- and sex- matched healthy volunteers. The Wisconsin Card Sorting Test (WCST) and Tridimensional Personality Questionnaire (TPQ) were administered to assess neurocognitive functioning and personality traits, respectively. Compared to healthy controls, patients with alcohol dependence showed a significant reduction in dopamine transporter availability (p < 0.001), as well as diminished performance on the WCST (p < 0.001). Dopamine transporter availability was negatively correlated with both total and perseverative WCST errors among healthy controls, but only patients with alcohol dependence showed a positive correlation between dopamine transporter availability and a harm avoidance personality profile. Thus, reductions in dopamine transporter availability may play a pathophysiological role in the development of pure alcohol dependence, given its association with neurocognitive deficits. Moreover, personality may influence the development of pure alcohol dependence; however, additional clinical subgroups should be examined to confirm this possibility.

The dopamine transporter gene possibly affects personality traits in patients with early-onset major depressive disorder.

Objective Comorbid personality pathologies may affect the outcome of patients with major depression (MD). The dopamine transporter gene DAT1 (SLC6A3) has been suggested to play a role in both depression and specific personality traits. The aim of this study was to assess five polymorphisms of the DAT1 gene (rs2550948, rs2975226, rs6347, rs27072, and 3′-VNTR) to determine whether this gene influences personality traits in patients with MD or its subgroups. Methods The DAT1 polymorphisms were analysed in 463 unrelated Han Chinese MD patients. The personality traits, novelty seeking (NS), and harm avoidance (HA), were examined using the Tridimensional Personality Questionnaire. The patients were also divided into four clinical subgroups on the basis of differences in their sex (male or female) and age at disease onset (early or late). Results There was no association between the DAT1 gene and either NS or HA in the total MD sample or in the sex-based subgroups. However, early-onset MD patients with the G/G genotype of rs2550948 and the T/T genotype of rs2975226 had lower NS scores than did patients with the other genotypes (pcorrected = 0.05 for rs2550948 and pcorrected = 0.005 for rs2975226). Conclusion Our study suggests that DAT1 promoter variants possibly influence specific personality traits in the early-onset subgroup of depressed patients in the Han Chinese population. Further prospective cohort studies are required to verify our preliminary finding and to confirm the effects of personality susceptibility on long-term disease outcomes.

The relationship between the striatal dopamine transporter and novelty seeking and cognitive flexibility in opioid dependence

ABSTRACT Novelty seeking (NS) is a core personality trait that primes the susceptibility to drug addiction. Striatal dopamine activity contributes to cognitive flexibility, an important cognitive strategy to inhibit impulsivity and compulsive drug‐seeking behavior. Evidence supports the association between dopamine and NS. Opioid‐dependent patients show higher levels of NS, and repeated opioid exposure can cause cognitive deficits including poor cognitive flexibility and impaired impulse control. However, in opioid‐dependent patients, the link between NS, striatal dopamine activity, and cognitive flexibility is still unclear. We recruited 22 opioid‐dependent individuals and 30 age‐ and sex‐matched healthy controls. Single‐photon emission computed tomography with [99mTc]TRODAT‐1 as a ligand was used to measure the striatal dopamine transporter (DAT) availability. The Trail Making Test (TMT) was performed to assess cognitive flexibility. Cloningers Tridimensional Personality Questionnaire (TPQ) was used to measure NS. We found that in opioid‐dependent patients, the striatal DAT availability was lower and negatively associated with TMT Part B ÷ Part A. Moreover, an inverted‐U shape significantly matched the scores of NS as a function of the striatal DAT availability, with maximum NS potential in the midrange of the DAT availability. An extra sum‐of‐squares F test was conducted, indicating that a quadratic model fitted the association between the DAT and NS better than a linear model did. In brief, in opioid‐dependent patients, the striatal DAT availability is nonlinearly linked to NS and linearly linked to cognitive flexibility. The role of the striatal DAT in the transition from controlled to compulsive opioid use warrants further research. Graphical abstract Figure. No caption available. HighlightsHeroin users show high novelty seeking, reduced striatal DAT, and poor cognitive flexibility.In heroin users, the striatal DAT availability is linearly linked to cognitive flexibility.In heroin users, the striatal DAT availability is nonlinearly linked to novelty seeking.An inverted‐U‐shaped relationship exists between novelty seeking and DAT in heroin users.

OPRD1 gene affects disease vulnerability and environmental stress in patients with heroin dependence in Han Chinese

ABSTRACT Exposure to stress not only increases the vulnerability to heroin dependence (HD) but also provokes relapse. The etiology of HD and the role of life stress remain unclear, but prior studies suggested that both genetic and environmental factors are important. Opioid related genes, including OPRM1, OPRD1, OPRK1, and POMC, are obvious candidates for HD. Therefore, this study was conducted to explore whether the genetic polymorphisms of the candidates could affect vulnerability to HD and response to life stress in patients with HD. Ten polymorphisms of the opioid related genes were analyzed in 801 patients and 530 controls. The Life Event Questionnaire was used to assess the perspective and response to life stress in the past year. The genotype distribution and allelic frequency analyses showed that the minor C allele of rs2234918 in OPRD1 is over‐represented in the HD group (P=.006 and P=.002, respectively). This finding was further confirmed by logistic regression analysis, showing that C allele carriers have a 1.42 times greater risk for HD compared to T/T homozygotes. A subgroup of 421 patients and 135 controls were eligible for life stress assessment. Patients with HD have a higher occurrence of negative events (No), negative events score (Ns), and average negative event score (Na) than those of controls (all P<.001), but there was no difference regarding positive recent events between the two groups. Gene‐stress assessment in the HD group showed that T/T homozygotes of OPRD1 rs2236857 have more severe stress than C allele carriers (Ns, P=.004 and Na, P=.047). Our results indicate that the OPRD1 gene may not only play a role in the pathogenesis of HD but also affect the response to life stress among patients with HD in our Han Chinese population. Patients with the risk genotype may need additional psychosocial intervention for relapse prevention. HIGHLIGHTSThe minor C allele of rs2234918 in OPRD1 is considered a risk allele for heroin dependence in Han Chinese.Patients with heroin dependence sustained more negative recent events and more severe life stress than controls.The polymorphism of OPRD1 rs2236857 may affect the response to life stress in patients with heroin dependence.

Differential effect of the DRD3 genotype on inflammatory cytokine responses during abstinence in amphetamine-dependent women

Amphetamine exposure impacts on innate and adaptive immunity and DRD3 may modulate the effect of amphetamine on the immune response. We assessed the immune-cytokine markers in 72 female patients with amphetamine dependence (AD) at baseline and after 4-week drug abstinence and in 51 healthy women. Multiplex magnetic bead assay was used to measure the plasma cytokine expression level simultaneously in all participants and DRD3 rs6280 polymorphism was genotyped in patients. We demonstrated an increase of the T helper 1 (Th1) cytokines (IL-2), Th2 cytokines (IL-4, IL-5, IL-6 and IL-10) and other cytokines (IL-1β) in the entire AD cohort. A similar cytokine pattern, along with a significantly decreased IL-8 and IL-10 levels was observed after 4-week abstinence. Among AD patients with DRD3 rs6280 TT genotype, the cytokine expression profile was consistent with total AD cohort at baseline and revealed a significant down-regulated plasma level of the Th1, Th2, and other cytokines except for IL-6 after 4-week abstinence. In AD group with DRD3 rs6280 C allele carrier, we found IL-2 level was significantly higher than healthy controls at baseline and remained higher, accompanied with a borderline increase in IL-4, IL-6 and IL-1β levels after 4-week abstinence. Our results suggest that chronic use of amphetamine increased both pro- and anti-inflammatory cytokines in AD patients, indicating the immune imbalance that may persist for 4 weeks or more. Besides, DRD3 rs6280 TT genotype may be associated with favorable recovery in general inflammatory cytokines during period of abstinence.