儿茶酚胺类激素在海洛因成瘾中的作用

目的：探索儿茶酚胺类激素在海洛因成瘾中的作用。方法：肌肉注射利血平后再给予海洛因,用放射免疫法检测血液和脑组织中多巴胺（dopamine,DA）、环磷酸腺苷（cMAP）、环磷酸鸟苷（cMGP）水平。结果：利血平组大鼠未出现明显的戒断反应症状。放射免疫法检测发现,血液、中脑腹侧背盖区（ventral tegmental area,VTA）、大脑前额叶皮（prefrontal cortex,PFC）、海马（hippocampus,Hipp）中cAMP水平：利血平纽比对照组和海洛因组分别升高35．36％和15．53％、24．08％和8．53％、15．66％和8．13％、21．95％和8．40％;PFC、Hipp、纹状体（striatum）、伏隔核（nueleus aceumbens,NAc）中DA水平：利血平组比对照组和海洛因组分别降低74．09％和82．86％、81．06％和82．23％、91．62％和86．55％、84．35％和90．63％;脑组织cGMP的含量均低于对照组。神经电生理检测发现,海洛因和利血平组,大鼠的脑电图、心电图和肌梭放电图与对照组比,均发生明显的改变。结论：儿茶酚胺类激素是引起海洛因成瘾的关键因素。     

Decreased serum testosterone concentration in male heroin and methadone addicts

The serum concentrations of testosterone, estradiol-17β, FSH and LH were measured in 22 male subjects addicted to heroin or methadone. Serum testosterone concentration was decreased in many of these subjects without consistent abnormalities in the other hormones. It is suggested that decreased sexual function in male addicts may be partially due to a decrease in serum testosterone concentration.     

Aminopeptidase activity in the postmortem brain of human heroin addicts

Several studies have reported that the chronic administration of opioids induces changes in the biosynthesis of endogenous opioid peptides or their precursors in specific brain regions of the adult central nervous system. However, little is known about the catabolic regulation of opioid peptides and its contribution to neuroadaptative changes underlying drug addiction. In the present study, we have analyzed the activity of two enkephalin-degrading enzymes (puromycin-sensitive aminopeptidase or PSA and aminopeptidase N or APN) and two functionally different, soluble aminopeptidases (aminopeptidase B and aspartyl-aminopeptidase) in postmortem samples of prefrontal cortex and caudate nucleus of eight human heroin addict brains and eight matched-controls. Enzyme activities were fluorimetrically measured using beta-naphthylamide derivatives. An increase in the activity of soluble PSA in the prefrontal cortex of heroin abusers was observed (heroin addict group: 51,452+/-3892 UAP/mg protein versus control group: 42,003+/-2597 UAP/mg protein; P<0.05), while the activity of the other peptidases in both brain regions remained unaltered. This result agrees with previous findings in morphine-tolerant rats, and indicates that soluble PSA may be involved in neurobiological processes which underlie heroin addiction.     

Induction of sister-chromatid exchanges in heroin-cannabis, heroin and cannabis addicts

The aim of this study was to determine the frequency of sister-chromatid exchanges (SCEs) in heroin-cannabis, heroin and cannabis addicts. The group of 84 subjects consisted of 42 controls, 16 heroin-cannabis addicts, 12 heroin addicts and 14 cannabis addicts. The mean number of SCEs/cell was 12.95 in heroin-cannabis addicts, 12.05 in heroin addicts and 11.99 in cannabis addicts. These values are significantly (P less than 0.002) higher than the mean values found in controls. This increase in SCEs may be related to reduced DNA repair in chronic drug addicts, which would allow the fixation or retention of a greater fraction of the DNA lesions caused by normal environmental exposure.     

Adipocyte-derived hormones in heroin addicts: the influence of methadone maintenance treatment

Heroin addiction markedly affects the nutritional and metabolic status and frequently leads to malnutrition. The aim of our study was to compare circulating concentration of adipose tissue-derived hormones leptin, adiponectin and resistin in 12 patients with heroin addiction before and after one-year methadone maintenance treatment with the group of 20 age- and body mass index-matched healthy subjects. Basal serum leptin and adiponectin levels in heroin addicts were significantly decreased (3.4+/-0.4 vs. 4.5+/-0.6 ng/ml and 18.9+/-3.3 vs. 33.9+/-3.1 ng/microl, respectively; p 0.05) while serum resistin concentrations were increased compared to healthy subjects (10.1+/-1.2 vs. 4.6+/-0.3 ng/ml; p 0.05). Moreover, positive correlation of serum leptin levels with body mass index was lost in the addicts in contrast to control group. One year of methadone maintenance treatment normalized serum leptin, but not serum adiponectin and resistin concentrations. In conclusion, circulating concentrations of leptin, adiponectin and resistin are markedly altered in patients with chronic heroin addiction. These alterations appear to be relatively independent of nutritional status and insulin sensitivity.     

Enhanced assays detect increased chromosome damage and sister-chromatid exchanges in heroin addicts

To refine previous studies of chromosome damage (CD) and sister-chromatid exchanges (SCE) in heroin addicts, we applied new methods developed in our laboratory to enhance detection of the cytogenetic effects of low-level radiation exposure in hospital workers. For CD analysis, we applied our thymidine-fluorodeoxyuridine-caffeine (TFC) enhancement procedure in which cells at setup receive 1 x 10(-7) M fluorodeoxyuridine to inhibit thymidylate synthetase and 4 X 10(-5) M thymidine to satisfy the induced requirement, and then in G2 receive 2.2 mM caffeine to modulate DNA repair. For SCE enhancement, caffeine treatment was initiated in G1 at 19 h before harvest. Using both standard and enhanced procedures for CD and SCE analysis, blood samples were evaluated from 20 street heroin addicts and 22 controls. Standard 2-day CD and 3-day SCE assays showed small, insignificant genotoxic increases in addicts while the enhanced CD and SCE assays showed highly significant increases. Most CD events were in the form of chromatid and chromosome breaks. There were no rings and only a few dicentrics were observed in the TFC-enhanced cultures. Although quadriradials are rare, 10 were found in addict TFC-cultures and 3 in control TFC-cultures. With the standard CD assay, the mean number of chromosome breaks per 100 cells was 0.727 for controls and 1.056 for addicts (not significant). With the TFC-enhanced assay, the same measure showed 1.483 chromosome breaks for controls and 5.143 for addicts (highly significant, ANOVA: p less than 0.0001). A highly significant difference was also observed for chromatid-type damage with the TFC-enhanced assay (chromatid breaks per 100 cells: 16.793 for controls; 48.191 for addicts). The SCE data also showed significant differences with the enhanced assay. Scoring 25 cells/condition, standard SCE cultures showed 10.892 SCE/cell for controls and 11.732 SCE/cell for addicts (not significant). With CAF enhancement there were 13.08 SCE/cell for controls and 17.05 SCE/cell for addicts (ANOVA: p less than 0.008). These findings indicate that detection of CD and SCE effects can be significantly enhanced by the use of these new procedures. The finding of greatly increased chromatid damage in the addicts with the TFC procedure suggests that at least part of the CD detected occurred in vitro and is not a product of prior in vivo damage. Therefore exposure to this drug and perhaps other environmental agents may not only leave a residue of DNA or chromosome damage but may also induce a sensitivity to further genotoxic damage that is revealed by using the enhanced procedures.     

Interaction between dysfunctional connectivity at rest and heroin cues-induced brain responses in male abstinent heroin-dependent individuals

Background

The majority of previous heroin cue-reactivity functional magnetic resonance imaging (fMRI) studies focused on local function impairments, such as inhibitory control, decision-making and stress regulation. Our previous studies have demonstrated that these brain circuits also presented dysfunctional connectivity during the resting state. Yet few studies considered the relevance of resting state dysfunctional connectivity to task-related neural activity in the same chronic heroin user (CHU).

Methodology/Principal Findings

We employed the method of graph theory analysis, which detected the abnormality of brain regions and dysregulation of brain connections at rest between 16 male abstinent chronic heroin users (CHUs) and 16 non-drug users (NDUs). Using a cue-reactivity task, we assessed the relationship between drug-related cue-induced craving activity and the abnormal topological properties of the CHUs'' resting networks. Comparing NDUs'' brain activity to that of CHUs, the intensity of functional connectivity of the medial frontal gyrus (meFG) in patients'' resting state networks was prominently greater and positively correlated with the same region''s neural activity in the heroin-related task; decreased functional connectivity intensity of the anterior cingulate cortex (ACC) in CHUs at rest was associated with more drug-related cue-induced craving activities.

Conclusions

These results may indicate that there exist two brain systems interacting simultaneously in the heroin-addicted brain with regards to a cue-reactivity task. The current study may shed further light on the neural architecture that supports craving responses in heroin dependence.     

Seven-year follow-up of heroin addicts: abstinence and continued use compared.

Data from a seven-year follow-up study of drug addicts were examined to see whether there were any differences between those who had stopped using opiates and those who had continued to use them. Information about the addicts when they first entered the study in 1969 was also reviewed to determine whether any of their characteristics would have predicted whether they would stop using opiates or continue. Those who had stopped using opiates by 1976-7 were more likely than the continuing addicts to have a job and legitimate source of income, to be in good health, and to have a stable address and less likely to have problems with the law or contact with addicts. In 1969, however, there were few differences between those who eventually stopped using drugs and those who continued, though the former group were younger, had a shorter period of heroin use, and had worked less since they became addicted. Over the seven years'' follow-up the addicts who stopped taking drugs changed most, while those who stayed on opiates changed their life-style very little.     

Serum concentrations of macro and trace elements in heroin addicts of the Canary islands

Na, K, Ca, Mg, P, Fe, Cu, Zn and Se concentrations were determined in the serum of 106 heroin addicts and were compared with the concentrations obtained in a control group formed of 186 apparently healthy individuals. Heroin addicts displayed K and Se mean concentrations lower (p < 0.05), and Na, Mg, P mean concentrations and a Cu/Zn ratio higher (p < 0.05) than those mean values observed in the control group. The Mg and P concentrations in the serum of heroin addicts tended to normalize when age increased. The heroin addicts included in the methadone maintenance treatment program had higher serum mean concentrations of K and Mg than the heroin addicts in the detoxification process. The Na, K and Mg concentrations displayed highly significant correlations, with a different behavior for the heroin addicts group and the control group. When applying factor analysis and representing the scores of the first and second factors, the heroin addicts tended to differentiation from the control group. However, methadone substitution treatment was not able to normalize these concentrations.     

Event-related potentials in a Go/Nogo task of abnormal response inhibition in heroin addicts

Inhibitory control dysfunction is regarded as a core feature in addicts. The major objective of this study was to explore the time course of response inhibition in chronic heroin addicts and provide the neu-rophysiological evidence of their inhibitory control dysfunction. The amplitudes and latencies of ERP components were studied in fourteen heroin addicts (mean duration of heroin use being (13.54±5.71) years (Mean±SD), average abstinence being ((4.67±6.44) months)) and fourteen matched healthy con-trols with a visual Go/Nogo task. Our results showed that heroin addicts demonstrated significantly larger Go-N2 amplitudes which results in a decreased N2 Go/Nogo effect, but no statistically significant differences were found between heroin addicts and controls in P3. The ERP data suggest that fronto-central areas of heroin addicts were impaired during the inhibition process (200—300 ms) and over-activated to targets. The impaired early process might reflect an abnormal conflict monitoring process in heroin addicts. These results consolidate the inhibitory control dysfunction hypothesis in chronic heroin users.     

The personality traits and social characteristics of Croatian heroin addicts and cannabis users

The purpose of this study was to investigate differences in social characteristics (level of education, working and family status, and criminal record) between heroin addicts, cannabis users and a control group. Additional goal was to explore the possibility of discerning subjects of different addiction status (of both gender) based on their scores on Eysenck Personality Questionnaire (EPQ). In comparison to the control group, heroin addicts and cannabis users had lower level of education, were more frequently unemployed and with criminal record, and more often came from dysfunctional families. In cannabis users the frequency of these characteristics was generally lower than in heroin addicts. Proportion of correct classification of subjects in groups of different addiction status based on the EPQ scores was 23.3% for males (higher than by chance alone), and 30% for females.     

Ethnic diversity of DNA methylation in the OPRM1 promoter region in lymphocytes of heroin addicts

The μ-opioid receptor is the site of action of many endogenous opioids as well as opiates. We hypothesize that differences in DNA methylation of specific CpG dinucleotides between former severe heroin addicts in methadone maintenance treatment and control subjects will depend, in part, upon ethnicity. DNA methylation analysis of the μ-opioid receptor gene (OPRM1) promoter region was performed on African-Americans (118 cases, 80 controls) and Hispanics (142 cases, 61 controls) and these were compared with a similar Caucasian cohort from our earlier study. In controls, a higher methylation level was found in the African-Americans compared with the Hispanics or Caucasians. Significant experiment-wise differences in methylation levels were found at the −25 and +12 CpG sites in the controls among the three ethnicities. The overall methylation level of the CpG sites were significantly higher in the former heroin addicts when compared with the controls (point-wise P = 0.0457). However, in the African-Americans, the degree of methylation was significantly decreased experiment-wise in the former heroin addicts at the +12 CpG site (P = 0.0032, Bonferroni corrected general estimating equations). In Hispanics, the degree of methylation was increased in the former heroin addicts at the −25 (P < 0.001, experiment-wise), −14 (P = 0.001, experiment-wise), and +27 (P < 0.001, experiment-wise) CpG sites. These changes in methylation of the OPRM1 promoter region may lead to altered expression of the μ-opioid receptor gene in the lymphocytes of former heroin addicts who are stabilized in methadone maintenance treatment.