Heroin-dependent Subjects Research Articles

Serum brain-derived neurotrophic factor in relation to craving and duration of abstinence in patients with heroin dependence-A case-control study.

Addiction is a chronic disorder that comes with emotional and financial burdens. Several neurobiological factors were correlated to opiate-use disorder which is brain-derived neurotrophic factor (BDNF). BDNF has been found to be involved in long-term potentiation of synaptic strength, a mechanism that is thought to motivate both natural adaption mechanisms as well as the development of addictive behavior. In this study, we aimed to address the relation between BDNF serum level and heroin craving and the effect of duration of abstinence on them. A case study was conducted on 80 subjects from Kasr Al-Ainy Psychiatry and Addiction Treatment Hospital with a history of heroin dependence and were divided into two groups: Group A had 40 active heroin-dependent subjects while in Group B, 40 subjects with 1-year heroin abstinence. Severity of addiction was assessed by the addiction severity index, heroin craving was measured by Brief Substance Craving Scale and serum BDNF level was investigated using an enzyme-linked immunosorbent assay. The findings show that active heroin users had significantly higher serum BDNF which is associated with high heroin craving in comparison to the abstinent group. This study revealed a significant positive correlation between serum BDNF levels and craving in active heroin users versus 1-year abstinent subjects. It is the first study to address the relationship between craving and serum BDNF level in a 1-year abstinent participants. These findings help to determine the brain alterations associated with illness and recovery in heroin dependence.

Heroin use and neuropsychological impairments: comparison of intravenous and inhalational use.

Injection and inhalational heroin use are associated with different levels of brain exposure to heroin and its metabolites and differences in the severity of dependence, which might lead to differential impacts on neuropsychological functions. We examined the difference and the magnitude of difference in the neuropsychological functions between inhalational and injection heroin-dependent subjects and also compared them with healthy controls. The study sample comprised three groups: 73 subjects with injection heroin dependence, 74 with inhalational heroin dependence, and 75 healthy controls (HC). We excluded patients with HIV, head injury, epilepsy, and severe mental illness. Neuropsychological assessments were done by Standard Progressive Matrices, Wisconsin Card Sorting Test (WCST), Iowa Gambling Task, Trail-Making Tests A and B (TMT), and Verbal and Visual Memory 1 and 2 Backtests (NBT). We estimated independent effects of the groups on various neuropsychological test parameters, adjusted for age and duration of dependence. In the WCST, the inhalational heroin-dependent group took more trials to complete the first category and had higher scores in the failure to maintain set than controls. The intravenous group had higher total errors than controls in verbal working memory tests and Visual Working Memory 2 Backtest. This group scored higher commission errors in the Verbal 2 Backtest than the controls. The two groups of heroin users differed in failure to maintain set and Verbal Working Memory 2 Backtests. The effect sizes of the group differences were modest. Either route of heroin use is associated with cognitive impairments; inhalational and injection use involve different cognitive domains.

Increased Amplitude of Low-Frequency Fluctuation in Right Angular Gyrus and Left Superior Occipital Gyrus Negatively Correlated With Heroin Use.

Abnormal amplitude of low-frequency fluctuation has been implicated in heroin addiction. However, previous studies lacked consistency and didn’t consider the impact of confounding factors such as methadone and alcohol. Fifty-one heroin-dependent (HD) individuals and 40 healthy controls underwent resting-state functional magnetic resonance imaging. The ‘amplitude of low-frequency fluctuation’ (ALFF) value was calculated and support vector machine (SVM) classification analysis was applied to analyze the data. Compared with healthy controls, heroin addicts exhibited increased ALFF in the right angular gyrus (AG) and left superior occipital gyrus (SOG). A negative correlation was observed between increased ALFF in the right angular gyrus and left superior occipital gyrus and the duration of heroin use (p 1=0.004, r 1=-0.426; p 2=0.009, r 2=-0.361). Moreover, the ALFF in the right AG and left SOG could discriminate the HD subjects from the controls with acceptable accuracy (Acc1=64.85%, p 1=0.004; Acc2=63.80%, p 2=0.005). HD patients showed abnormal ALFF in the brain areas involved in semantic memory and visual networks. The longer HD individuals abused heroin, the less the ALFF of associated brain regions increased. These observed patterns suggested that the accumulative effect of heroin’s neurotoxicity overpowered self-recovery of the brain and may be applied as a potential biomarker to identify HD individuals from the controls.

QT length during methadone maintenance treatment: gene×dose interaction.

Methadone is known to be a risk factor for sudden death by enlarging ECG QT corrected (QTc) interval. For other medical conditions, QTc lengthening has been described as the result of interactions between pharmacological treatments and genetic factors. Former heroin-dependent subjects under methadone maintenance treatment in remission for at last 3months were recruited. We studied the association between QTc length (Bazett formula) and 126 SNPs located on five genes (KCNE1, KCNQ1, KCNH2, NOS1AP and SCN5A) previously associated with drug-induced QT prolongation. Both SNP-based and gene-based approaches were used, and we tested also the interaction of the top SNP with methadone dosage to predict the QTc length. In our sample of 154 patients, current methadone daily dose was associated with QTc length (rPearson =0.26; P=10-3 ). Only one SNP, rs11911509 on KCNE1, remained significantly associated with QT length after correction for multiple testing (P=3.84×10-4 ; pcorrected =0.049). Using a gene-based approach, KCNE1 was also significantly associated with QTc length (pempirical =0.02). We found a significant interaction between methadone dosage and rs11911509 minor allele count (allele A vs. C; P=0.01). Stratified analysis revealed that the correlation between QTc length and methadone dosage was restricted only to AA carriers of this top SNP. Patients' genetic background should be taken into account in the case of clinically relevant QT enlargement during methadone maintenance treatment.

Support vector machine-based multivariate pattern classification of methamphetamine dependence using arterial spin labeling.

Arterial spin labeling (ASL) magnetic resonance imaging has been widely applied to identify cerebral blood flow (CBF) abnormalities in a number of brain disorders. To evaluate its significance in detecting methamphetamine (MA) dependence, this study used a multivariate pattern classification algorithm, ie, a support vector machine (SVM), to construct classifiers for discriminating MA-dependent subjects from normal controls. Forty-five MA-dependent subjects, 45 normal controls, and 36 heroin-dependent subjects were enrolled. Classifiers trained with ASL-CBF data from the left or right cerebrum showed significant hemispheric asymmetry in their cross-validated prediction performance (P<0.001 for accuracy, sensitivity, specificity, kappa, and area under the curve [AUC] of the receiver operating characteristics [ROC] curve). A classifier trained with ASL-CBF data from all cerebral regions (bilateral hemispheres and corpus callosum) was able to differentiate MA-dependent subjects from normal controls with a cross-validated prediction accuracy, sensitivity, specificity, kappa, and AUC of 89%, 94%, 84%, 0.78, and 0.95, respectively. The discrimination map extracted from this classifier covered multiple brain circuits that either constitute a network related to drug abuse and addiction or could be impaired in MA-dependence. The cerebral regions contribute most to classification include occipital lobe, insular cortex, postcentral gyrus, corpus callosum, and inferior frontal cortex. This classifier was also specific to MA-dependence rather than substance use disorders in general (ie, 55.56% accuracy for heroin dependence). These results support the future utilization of ASL with an SVM-based classifier for the diagnosis of MA-dependence and could help improve the understanding of MA-related neuropathology.

Association between genetic polymorphisms of XRCC4 insertion/deletion in intron 3 and G-1394T of XRCC4 and susceptibility to dependency to heroin

The ubiquitously expressed X-ray repair cross complementing group 4 (XRCC4, OMIM: 194363) is essential in the non-homologous end-joining pathway. Since genetic polymorphisms in the XRCC4 might be associated with a reduction in cellular DNA repair capacity, it is hypothesized that the XRCC4 G-1394T (rs6869366) and Insertion/Deletion (Ins/Del, polymorphism in intron 3 of the gene; rs28360071) polymorphisms may be a risk factor for heroin dependency (HD). Considering that there is no study on association between the rs6869366 and rs28360071 polymorphisms and the risk of HD, the present case-control study was carried out on 1241 participants (442 heroin dependent subjects and 799 healthy blood donors). The genotypes were determined by PCR based methods. The Ins/Del (OR = 1.41, CI = 1.08–1.85, P = 0.012) and Del/Del (OR = 1.95, CI = 1.39–2.76, P < 0.001) genotypes increased the risk of HD. Analysis of the G-1394T polymorphism showed that the TG genotype significantly decreased the risk of HD (OR = 0.73, CI = 0.54–0.99, P = 0.043). It should be noted that the linear trend between the number of the G allele and the risk of HD was significant (χ2 = 6.42, P = 0.011). The study polymorphisms showed strong linkage disequilibrium in both control and HD patients. There were significant associations between the Ins-G (OR = 0.45, CI = 0.23–0.88, P = 0.020), Ins-T (OR = 0.63, CI = 0.53–0.76, P < 0.001), and Del-G (OR = 0.54, CI = 0.40–0.74, P < 0.001) haplotypes and the risk of HD. These results also suggest that genetic variants of the rs6869366 and rs28360071 polymorphisms are involved in etiology of HD and could be novel markers for HD.

Characteristics of empathy and psychopathy among patological Internet users and opiate-dependent persons

Background/Aim. The debate about diagnostic criteria for differences and similiraties as psychosocial characteristics of pathological Internet users and Internet and substance addicts still continued. The aim of the study was to investigate the differences between empathy and psychopathy among subjects with pathological Internet use (PIU) and opiate dependence. Methods. The cross sectional study was performed at the Methadone Center of the Clinical Centre of Vojvodina, Novi Sad, Serbia, with 40 consecutively recruited patients with opiate dependence (OD group) and compared to age matched (25 to 35 years) random online recruited subjects (n = 80). They were divided into two groups: 40 subjects with PIU and 40 controls according to cut-off score of 39 or less obtained at Questionnaire regarding the Internet use assessment. The questionnaires for sociodemographic data, Emotion Specific Empathy (EMI) questionnaire and Psychopathy Assessment Questionnaire (PAQ) were applied. Descriptive statistics, _2-tests, ANOVA and MANOVA analysis were used for data assessment which was performed by the SPSS software (version 20.0) and p &lt; 0.05 was applied. Results. There were more differences among psychopathy dimensions than empathy dimensions among PIU subjects, controls and heroin dependent subjects. The PIU group demonstrated the lowest psychopathy dimensions except for the lifestyle dimension which was higher than in the control group. On the contrary, the PIU group showed the highest empathy, with two dimensions as the most prominent ones: empathy with negative emotions and emotional reactions provoked by empathy. Conclusion. The PIU subjects are characterized by high empathy and low psychopathy. These findings suggest that it would be useful to consider seriously the dimensions of empathy and psychopathy when developing strategies to prevent PIU and planning educational programs for persons with problems related to the Internet overuse disorder.

Contribution of Genetic Polymorphisms and Haplotypes in DRD2, BDNF, and Opioid Receptors to Heroin Dependence and Endophenotypes Among the Han Chinese.

Heroin and drug dependence are major contributors to global health burden worldwide, but their underlying mechanisms remain elusive and may vary from population to population. Reward- and memory-related candidate genes dopamine D2 receptor (DRD2) and brain-derived neurotrophic factor (BDNF), as well as the opioid receptor genes (OPRM1, OPRD1, and OPRK1), have been implicated in drug dependence, but relatively little is known on their contributions to heroin dependence in populations worldwide. Hence, we evaluated the contributions of the above five candidate genes in heroin dependence and several important related endophenotypes (the onset age of heroin use and subjective response to first heroin use), at single single-nucleotide polymorphism as well as haplotype levels, in a Han Chinese population sample. We genotyped 546 unrelated and heroin-dependent subjects for the candidate genes noted, and 228 sex- and age-matched unrelated controls. The G allele of rs4654327 (OPRD1), DRD2 haplotype block CCGCCGTT (rs6277-rs1076560-rs2283265-rs2734833-rs2075652-rs1079596-rs4436578-rs11214607), and OPRD1 haplotypes TACG (rs6669447-rs2236857-rs508448-rs4654327), CG (rs508448-rs4654327), and TG (rs6669447-rs4654327) were significantly associated with heroin dependence phenotype. Homozygotes AA at rs6265 (BDNF), TT at rs16917234 (BDNF), and CC at rs508448 (OPRD1) also appeared as risk factors for the endophenotype earlier age of onset for heroin use. Two OPRM1 haplotypes, AG (rs1799971-rs1381376) and AT (rs1799971-rs3778151), were observed as potential protective factors. These emerging findings contribute to the literature on genetic biomarkers of drug dependence and related endophenotypes, and call for replication in independent population.

Availability of dopamine transporters in heroin-dependent subjects: A 18F-FECNT PET imaging study

This study was to reconfirm the reduced dopamine transporter (DAT) availability in heroin-dependent subjects and validate the use of 2β-carbomethoxy-3β-(4-chlorophenyl)−8-(2-fluoroethyl)-nortropane (18F-FECNT) as a PET radiotracer to assess the changes of striatal DAT in drug addicted subjects. Herein, we assessed DAT standardized uptake values (SUV) of 18F-FECNT in the striatum and cerebellum of 20 heroin-dependent subjects and 10 healthy controls and analyzed the correlation between DAT availability and heroin withdrawal symptom scores and anxiety/depression rating scales in heroin-dependent subjects, as well as the relationship between the withdrawal symptoms scores and age. The striatal DAT availability in heroin-dependent subjects was significantly lower (by ~15.7–17.6%) than that in healthy controls. Age was positively related to heroin withdrawal symptom scores. The withdrawal symptom scores in older patients (Age: 49.5±2.5) were significantly higher (by ~20%) than those in younger patients (Age: 30.9±4.8). These results confirm that chronic heroin use induces striatal DAT reduction, suggesting that 18F-FECNT could be used as an alternative PET imaging radioligand for in vivo imaging of DAT in drug addicted subjects. Moreover, older patients might suffer more severe withdrawal symptoms than younger patients, suggesting that older patients with heroin withdrawal could be given more medication.

Polymorphisms in the 5-hydroxytryptamine receptor 3B gene are associated with heroin dependence in the Chinese Han population

Previous studies suggested that the 5-hydroxytryptamine receptor 3B (HTR3B) is involved in heroin dependence by modulating dopamine (DA) release in the reward pathway and that the genetic polymorphisms in HTR3B play plausible role in modulating the risk of developing heroin addiction. To identify markers that contribute to the genetic susceptibility to heroin dependence, we examined the potential associations between heroin dependence and 7 single nucleotide polymorphisms (SNPs) of the HTR3B gene using multiplex SNaPshot technology in a Chinese Han population. Participants included 418 heroin-dependent subjects and 422 healthy controls. The results suggested that the genotype distribution of HTR3B rs1176746 and rs1185027 were significantly different between heroin dependent subjects and healthy controls (both p=0.004). The frequency of the GG of rs1176746 and AA of rs1185027 genotype in heroin-dependent subjects were significantly higher than that of healthy controls, while the GA of rs1176746 and AT of rs1185027 genotype distributions were much lower. Another SNP, rs10789970, showed a nominally significant p-value in the genotype distribution between heroin dependent subjects and controls (p=0.022). These findings indicate the important role of HTR3B polymorphisms in heroin dependence among the Chinese Han population and provide valuable information for further genetic and neurobiological investigations of heroin dependence.

Major Depressive Disorder and Heroin-dependent Patients Share Decreased Frontal Gray Matter Volumes: A Voxel-Based Morphometry Study

Background: Heroin addiction has been occurring in comorbidity with depression. These conditions are thought to result from common neurobiological basis. However, to date, little is known on the common volumetric changes in the multiple gray matter regions in these two patients groups. Methods: The study comprised samples of 15 depressed patients, 15 heroindependent subjects and 15, age- and sex-matched healthy controls. The gray matter volumes (GMV) abnormalities of these samples were identified and compared among them by using voxel-based morphometry method. The two resulted images were interpolated to locate the common areas of GMV alterations in the two subjects groups. Results: Common GMV abnormalities were found in superior frontal gyrus (SFG), right Middle prefrontal cortex (MPFC) and Middle frontal gyrus (MFG) in both heroin-dependent subjects and patients with depression. Moreover, we found decreased GMV in MPFC to positively correlate with HAMD scores. The decreased GMV in SFG was found to be positively correlated with daily doses of heroin in patients with heroin addiction. Conclusions: The Common disruptions of GMV in frontal lobe might be the neuroanatomical substrate for impairments of motivational drive, decision-making and behavioral control that characterizes individuals with heroin dependence and depression.

Suicide Risk of Heroin Dependent Subjects in Lebanon.

The aim is to determine the frequency of suicidal behavior and associated factors among heroin dependent inpatients. 61 heroin dependent inpatients (vs. 61 controls) were assessed on their pattern of substance use, impulsivity, depression and suicidal behavior. 37.7% of patients had a personal history of suicidal attempt (SA), 14.8% had current suicidal ideation. SA was associated to younger age at first substance use and to higher rates of depression and impulsivity. IV heroin overdose was the most frequent mode of SA (47.8%). Long duration, multiple drug use, and family history of suicide were associated with higher risk of suicide among lebanese patients.

Methadone maintenance dose modulates anterior cingulate glutamate levels in heroin-dependent individuals: A preliminary in vivo1H MRS study

Mu-opioid receptor agonists alter brain glutamate (GLU) levels in laboratory animals. This clinical study used proton magnetic resonance spectroscopy (1H MRS) to examine regional brain GLU levels during experimental manipulation of methadone (MTD) maintenance dose under double-blind, within-subject conditions in seven heroin-dependent volunteers. Subjects were scanned first at a high MTD dose (100mg/day), underwent a 3-week outpatient MTD dose taper, and then were scanned again at a low MTD dose (10–25mg/day; modified for participant comfort). Five age- and cigarette smoking-matched controls were scanned once. In vivo short echo time (TE=22ms), single voxel 1H MRS data from midline pregenual anterior cingulate cortex (ACC) and thalamus (4.5cm3 each) were collected using PRESS on a 4-Tesla MRI system. Absolute metabolite levels were quantified. GLU levels in the ACC, but not the thalamus, were higher at the low relative to the high MTD dose in heroin-dependent subjects. No other metabolites differed by MTD dose, or between control vs. heroin-dependent subjects (at either MTD dose). GLU levels in the ACC were inversely related to the duration of cigarette smoking (controls) and heroin use (experimental group). Future studies are warranted to investigate the relationship between GLU levels during treatment (and detoxification), and withdrawal symptoms or relapse.

Nature of functional links in valuation networks differentiates impulsive behaviors between abstinent heroin-dependent subjects and nondrug-using subjects

Advanced neuroimaging studies have identified brain correlates of pathological impulsivity in a variety of neuropsychiatric disorders. However, whether and how these spatially separate and functionally integrated neural correlates collectively contribute to aberrant impulsive behaviors remains unclear. Building on recent progress in neuroeconomics toward determining a biological account of human behaviors, we employed resting-state functional MRI to characterize the nature of the links between these neural correlates and to investigate their impact on impulsivity. We demonstrated that through functional connectivity with the ventral medial prefrontal cortex, the δ-network (regions of the executive control system, such as the dorsolateral prefrontal cortex) and the β-network (regions of the reward system involved in the mesocorticolimbic pathway), jointly influence impulsivity measured by the Barratt impulsiveness scale scores. In control nondrug-using subjects, the functional link between the β- and δ-networks is balanced, and the δ-network competitively controls impulsivity. However, in abstinent heroin-dependent subjects, the link is imbalanced, with stronger β-network connectivity and weaker δ-network connectivity. The imbalanced link is associated with impulsivity, indicating that the β- and δ-networks may mutually reinforce each other in abstinent heroin-dependent subjects. These findings of an aberrant link between the β- and δ-networks in abstinent heroin-dependent subjects may shed light on the mechanism of aberrant behaviors of drug addiction and may serve as an endophenotype to mark individual subjects' self-control capacity.

Implicit processing of heroin and emotional cues in abstinent heroin users: early and late event-related potential effects

Background: The abnormal cognitive processing of drug cues is a core characteristic of drug dependence. Previous research has suggested that the late positive potential (LPP) of heroin users is increased by heroin-related stimuli because of the attention-grabbing nature of such stimuli. Objectives: The present research used a modified emotional Stroop (eStroop) task to examine whether there was an early posterior negativity (EPN) modulation to heroin cues compared with emotional or neutral stimuli in heroin dependent subjects. Methods: Fifteen former heroin users and 15 matched controls performed the eStroop task, which was composed of positive, negative, heroin-related, and neutral pictures with superimposed color squares. Participants responded to the color of the square and not to the picture while behavioral data and event-related potentials were recorded. Results: There were no significant differences of EPN amplitudes to emotional and neutral stimuli between heroin users and controls. However, heroin users displayed increased EPN modulation for heroin cues, whereas this modulation was absent in controls. Conclusions: Drug-related cues acquire motivational salience and automatically capture the attention of heroin users at early processing stages, even when engaged in a non-drug-related task. The EPN to heroin cues could represent a novel electrophysiological index with clinical implications for selecting abstinent drug users who are at increased risk of relapse or to evaluate treatment interventions.

Neural correlates of adherence to extended-release naltrexone pharmacotherapy in heroin dependence.

Injectable extended-release naltrexone (XRNTX) presents an effective therapeutic strategy for opioid addiction, however its utility could be hampered by poor adherence. To gain a better insight into this phenomenon, we utilized blood oxygenation level-dependent functional magnetic resonance imaging (fMRI) in conjunction with a validated cue-induced craving procedure to examine neural correlates of XRNTX adherence. We operationalized treatment adherence as the number of monthly XRNTX injections (range: 0–3) administered to a group of fully detoxified heroin-dependent subjects (n=32). Additional outcomes included urine toxicology screening and self-reported tobacco use. The presented heroin-related visual cues reliably elicited heroin craving in all tested subjects. Nine, five, three and 15 of the participants, respectively, received zero, one, two and three XRNTX injections, predicted by the individual baseline fMRI signal change in response to the cues in the medial prefrontal cortex, a brain region involved in inhibitory self-control and emotional appraisal. The incidence of opioid-positive urines during the XRNTX therapy was low and remained about half the pre-treatment rate after the XRNTX ended. During the treatment, cigarette smoking behaviors followed patterns of opioid use, while cocaine consumption was increased with reductions in opioid use. The present data support the hypothesis that medial prefrontal cortex functions are involved in adherence to opioid antagonist therapy. A potential role of concurrent non-opioid addictive substances consumption during the XRNTX pharmacotherapy warrants further investigation. Our findings set the stage for further bio-behavioral investigations of the mechanisms of relapse prevention in opioid dependence.

Abnormal gray matter volume and resting-state functional connectivity in former heroin-dependent individuals abstinent for multiple years.

Previous studies have suggested that heroin addiction is associated with structural and functional brain abnormalities. However, it is largely unknown whether these characteristics of brain abnormalities would be persistent or restored after long periods of abstinence. Considering the very high rates of relapse, we hypothesized that there may exist some latent neural vulnerabilities in abstinent heroin users. In this study, structural and resting-state functional magnetic resonance imaging data were collected from 30 former heroin-dependent (FHD) subjects who were drug free for more than 3 years and 30 non-addicted control (CN) volunteers. Voxel-based morphometry was used to identify possible gray matter volume differences between the FHD and CN groups. Alterations in resting-state functional connectivity in FHD were examined using brain areas with gray matter deficits as seed regions. Significantly reduced gray matter volume was observed in FHD in an area surrounding the parieto-occipital sulcus, which included the precuneus and cuneus. Functional connectivity analyses revealed that the FHD subjects showed reduced positive correlation within the default mode network and visual network and decreased negative correlation between the default mode network, visual network and task positive network. Moreover, the altered functional connectivity was correlated with self-reported impulsivity scores in the FHD subjects. Our findings suggest that disruption of large-scale brain systems is present in former heroin users even after multi-year abstinence, which could serve as system-level neural underpinnings for behavioral dysfunctions associated with addiction.

RsfMRI effects of KB220Z™ on neural pathways in reward circuitry of abstinent genotyped heroin addicts

Recently, Willuhn et al. reported that cocaine use and even non-substance-related addictive behavior increases as dopaminergic function is reduced. Chronic cocaine exposure has been associated with decreases in D2/D3 receptors and was also associated with lower activation of cues in occipital cortex and cerebellum, in a recent PET study by Volkow’s et al. Therefore, treatment strategies, like dopamine agonist therapy, that might conserve dopamine function may be an interesting approach to relapse prevention in psychoactive drug and behavioral addictions. To this aim, we evaluated the effect of KB220Z™ on reward circuitry of 10 heroin addicts undergoing protracted abstinence (average 16.9 months). In a randomized placebo-controlled crossover study of KB220Z, five subjects completed a triple-blinded experiment in which the subject, the person administering the treatment, and the person evaluating the response to treatment were blinded to the treatment that any particular subject was receiving. In addition, nine subjects were genotyped utilizing the GARSDX™ test. We preliminarily report that KB220Z induced an increase in BOLD activation in caudate-accumbens-dopaminergic pathways compared to placebo following 1-hour acute administration. Furthermore, KB220Z also reduced resting-state activity in the putamen of abstinent heroin addicts. In the second phase of this pilot study of all 10 abstinent heroin-dependent subjects, we observed that three brain regions of interest were significantly activated from resting state by KB220Z compared to placebo (p < 0.05). Increased functional connectivity was observed in a putative network that included the dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. These results and other quantitative electroencephalogy (qEEG) study results suggest a putative anti-craving/anti-relapse role of KB220Z in addiction by direct or indirect dopaminergic interaction. Due to small sample size, we caution definitive interpretation of these preliminary results, and confirmation with additional research and ongoing rodent and human studies of KB220Z is required.

Altered intrinsic hippocmapus declarative memory network and its association with impulsivity in abstinent heroin dependent subjects

Converging evidence suggests that addiction can be considered a disease of aberrant learning and memory with impulsive decision-making. In the past decades, numerous studies have demonstrated that drug addiction is involved in multiple memory systems such as classical conditioned drug memory, instrumental learning memory and the habitual learning memory. However, most of these studies have focused on the contributions of non-declarative memory, and declarative memory has largely been neglected in the research of addiction.Based on a recent finding that hippocampus, as a core functioning region of declarative memory, was proved biased the decision-making process based on past experiences by spreading associated reward values throughout memory. Our present study focused on the hippocampus. By utilizing seed-based network analysis on the resting-state functional MRI datasets with the seed hippocampus we tested how the intrinsic hippocampal memory network altered toward drug addiction, and examined how the functional connectivity strength within the altered hippocampal network correlated with behavioral index ‘impulsivity’.Our results demonstrated that HD group showed enhanced coherence between hippocampus which represents declarative memory system and non-declarative reward-guided learning memory system, and also showed attenuated intrinsic functional link between hippocampus and top-down control system, compared to the CN group. This alteration was furthered found to have behavioral significance over the behavioral index ‘impulsivity’ measured with Barratt Impulsiveness Scale (BIS). These results provide insights into the mechanism of declarative memory underlying the impulsive behavior in drug addiction.

The association of 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR gene polymorphisms and borderline personality disorder in female heroin-dependent Chinese subjects

To explore the association between the 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR polymorphisms with co-morbid borderline personality disorder (BPD) in female heroin-dependent patients. In a case control study, we compared the polymorphic distributions of 5-HTR2A-1438A/G, COMTVal158Met, MAOA-LPR, DATVNTR and 5-HTTVNTR in 296 female heroin-dependent patients (including 61 patients with BPD and 235 without BPD) and 101 normal females by genotypes, alleles, and interaction between genes. Female heroin-dependent subjects with BPD have lower frequency of the high activity allele (L: 4 repeats (4R)) of MAOA-LPR than those female heroin-dependent subjects without BPD, and have higher 5-HTTVNTR 10R/10R genotype frequency than normal female controls, with adjusted P-value<0.05 (after adjusted for multiple testing by 1000-fold permutation tests) respectively. By MDR (Multifactor Dimensionality Reduction) analyses, the interactive effects between MAOA-LPR and 5-HTTVNTR, and among MAOA-LPR, 5-HTTVNTR and rs6311 were close to the significance level (P=0.05) in predicting the risk of co-morbidity of BPD and heroin dependence relative to normal female controls, with 1000-fold permutation testing P-value<0.06 however >0.05 respectively. 5-HTTVNTR and MAOA-LPR may have independent predictive effects on co-morbid BPD in female heroin-dependent patients; the gene-gene interactions between MAOA-LPR and 5-HTTVNTR, and among MAOA-LPR, 5-HTTVNTR and rs6311 might also be involved in the etiology of this co-morbidity.