Differential cytokine levels between early withdrawal and remission states in patients with alcohol dependence.

Alcohol dependence (AD) leads to altered innate and adaptive immune responses, and frequently co-occurs with inflammation. Therefore, inflammatory cytokines potentially play a crucial role in the development of alcohol-related illnesses. This study evaluated changes in plasma cytokine concentrations, liver function, cravings, depression severity, and cognitive function in male patients with AD, during the course of an alcohol-detoxification program. A total of 78 male patients with AD were recruited for a conservative detoxification program; and cytokine levels, depressive score, and cognitive impairment applying the Trail Making Test (TMT) were evaluated during early withdrawal (baseline) and after 4 weeks of abstinence from alcohol. Healthy volunteers (86 males) were also recruited as controls. Inflammatory cytokine expression in all participants was assessed by multiplex magnetic bead assay. AD patients during early withdrawal demonstrated higher cytokine levels than the healthy controls (P≤0.001 for all cytokines). However, the levels of cytokine expression were significantly lower after 4 weeks of abstinence from alcohol (P≤0.001, except for IL-1ß and IL-5). Higher liver function marker levels, depressive severity, and TMT times were observed in patients at the beginning of the detoxification program than in healthy controls. Fortunately, these functions significantly ameliorated after 4 weeks of abstinence. (P≤0.001). Levels of circulating cytokines, liver function, and cognitive function may markers of alcohol use disorder.

Incongruent reduction of dopamine transporter availability in different subgroups of alcohol dependence.

The dopamine transporter (DAT) plays a crucial role in the pathogenesis of alcohol dependence (AD) and major depression (MD), and males have more risk factors for the development of AD. However, imaging studies on brain DAT availability in males with AD comorbid with MD (AD/MD) are limited, and the association of DAT availability with cognitive function and depressive scores in patients with AD/MD has not been analyzed. Hence, this study examined the relationship between brain DAT availability, cognitive function, and depressive symptoms in different subgroups of males with AD.Single-photon emission computed tomography imaging with Tc-TRODAT-1 as a ligand was used to measure striatal DAT availability in 49 patients with AD (28 pure AD and 21 AD/MD) and 24 age- and sex-matched healthy volunteers. The Wisconsin Card Sorting Test (WCST) and 17-item Hamilton Depression Rating Scale were used to assess neurocognitive function and depressive scores, respectively. Patients with AD showed a significant reduction of DAT availability in 3 brain regions (P < 0.001), and this reduction was more pronounced in the patients with pure AD compared to healthy controls. The patients with AD showed significantly poorer performance on the WCST, but only in the control group was DAT availability significantly negatively correlated with total errors and perseverative errors (P < 0.001).These preliminary findings suggest that DAT availability is associated with neurocognitive function, and incongruent reduction of DAT may play a pathophysiological role in different subgroups of AD. In addition, decreased DAT availability may be associated with the severity of depressive symptoms in patients with AD/MD.

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 [(99m) Tc]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.

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 may not contribute to susceptibility and the specific personality traits of amphetamine dependence.

BACKGROUND: A 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. METHODS: Eighteen 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. RESULTS: A 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. CONCLUSIONS: This 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.

Dopamine transporter gene may be associated with bipolar disorder and its personality traits.

Dopamine transporter and its genetic factors have been suggested to play a critical role in the development of bipolar disorder (BPD). However, the importance of the dopamine transporter gene (DAT1) in the pathogenesis of BPD remains unclear. The aims of this study were to assess 18 polymorphisms of the DAT1 gene to determine whether this gene is associated with BPD and whether it influences personality traits of patients with BPD. DAT1 polymorphisms were analyzed in 492 BPD (374 BPDI and 118 BPDII) patients and 436 controls. All participants were screened using the same assessment tool, and all met the criteria for BPD. The Tridimensional Personality Questionnaire was used to assess personality traits in both patients and controls. Several polymorphisms had a weak association with BPD, including rs2550948, rs2652511, and rs2975226 in allele distribution analysis (P < 0.05). Furthermore, the promoter G-A-C-G haplotype (rs6350-rs2975226-rs2652511-rs6413429) was over-represented in the BPD patients compared to the controls (P = 0.007). In personality assessment, the BPDII patients had the highest harm avoidance score, followed by the BPDI patients and controls (P = 3.7 × 10(-32)). In addition, a significant association between rs40184 and harm avoidance was found in the patients with BPD. The DAT1 promoter may be associated with vulnerabilities in BPD. The BPD patients had a higher rate of harm avoidance personality traits than the controls, and DAT1 variants may influence personality traits in patients with BPD.

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 (p corrected = 0.05 for rs2550948 and p corrected = 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.

Association study of serotonin transporter availability and SLC6A4 gene polymorphisms in patients with major depression.

The serotonin transporter (SERT) is hypothesized to be an important component of the pathophysiology of major depression (MD). The aim of this study was to use [(123)I]ADAM single-photon emission computed tomography (SPECT) to explore whether SERT availability in four regions of the brain (striatum, thalamus, midbrain and pons) is different in patients with MD and healthy individuals. The effects of three genetic variants (rs25531, rs6354 and STin2) of the serotonin transporter gene (SLC6A4) on SERT availability were also investigated. This study included 40 MD patients and 12 controls. The mean specific uptake ratio (SUR) values in the thalamus differed significantly between MD patients and controls. Genetic variants of SLC6A4, age, gender, severity of depression, and smoking behavior did not influence SERT availability. SERT availability might be a useful biomarker of the development of MD; however, a larger sample size is needed to provide more concrete evidence.

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.

A possible association of the norepinephrine transporter gene in the development of heroin dependence in Han Chinese.

OBJECTIVE: Noradrenergic pathways have been suggested to play a crucial role in the motivation-reward system of heroin dependence (HD), but so far, the role of the human norepinephrine transporter (NET; SLC6A2) gene in the pathogenesis of HD has never been investigated. The purpose of this study was to examine whether the NET gene is associated with the development of HD, and whether the NET gene influences specific personality traits. METHODS: Twelve single-nucleotide polymorphisms of the NET gene were analyzed in a case-control study of 965 Han Chinese participants (603 patients and 362 controls). All participants were screened using a Chinese version of the modified Schedule of Affective Disorder and Schizophrenia-Lifetime and all patients met the criteria for HD. A Chinese version of the Tridimensional Personality Questionnaire was used to assess personality traits and examine the association between specific personality traits and NET polymorphisms. RESULTS: No statistically significant differences in allele or genotype frequencies were observed in any of the investigated NET variants between HD patients and controls. After logistic regression analyses, no statistically significant effect of NET variants in the development of HD was found. In haplotype analysis, the frequency of AATA haplotype in rs1532701-rs40434-rs13333066-rs187714 was significantly different between HD patients and controls. These NET polymorphisms did not influence novelty seeking and harm avoidance scores. CONCLUSION: This study suggests that the NET gene may be associated with the development of HD, but not associated with specific personality traits among Han Chinese.

Availability of the serotonin transporter in patients with alcohol dependence.

OBJECTIVES: Evidence has suggested that the serotonin transporter (SERT) plays a role in the pathogenesis of alcohol dependence, anxiety and depression and that polymorphisms of the serotonin-transporter-linked promoter region (5-HTTLPR) may influence the SERT. This study evaluated the differences in SERT availability between healthy controls and alcoholic patients and the impact of 5-HTTLPR polymorphisms on SERT availability. METHODS: Eleven healthy controls and 28 alcoholic patients were recruited. SERT availability was measured in vivo with single photon emission computed tomography and (123)I-labelled 2-((2-((dimethyl-amino)methyl)phenyl)thio)-5-iodophenylamine in the midbrain, thalamus and striatum. Each subject was genotyped for the 5-HTTLPR polymorphism. RESULTS: Compared to healthy controls, there was a significantly lower availability of SERT in the midbrain among patients with pure alcohol dependence (pure ALC). Of patients with anxiety, depression and alcohol dependence (ANX/DEPALC), the carriers of one L(A) allele showed a significantly higher availability of SERT in the striatum compared to non-L(A) carriers. After Bonferroni correction, these significances vanished. There were no significant differences in SERT availability between controls and ANX/DEP ALC. CONCLUSIONS: The results suggest that pure alcoholics may have lower SERT availability in the midbrain; the 5HTTLPR polymorphism may influence SERT availability in ANX/DEP ALC. These findings may serve as a springboard for future large-scale studies.