Showing papers in "Addiction Biology in 2013"
TL;DR: The findings support the diffuse brain hypothesis and suggest that cognitive dysfunction may linger for up to an average of 1 year post‐detoxification from alcohol.
Abstract: The cognitive repercussions of alcohol dependence are well documented. However, the literature remains somewhat ambiguous with respect to which distinct cognitive functions are more susceptible to impairment in alcoholism and to how duration of abstinence affects cognitive recovery. Some theories claim alcohol negatively affects specific cognitive functions, while others assert that deficits are more diffuse in nature. This is the first meta-analysis to examine cognition in alcohol abuse/dependence and the duration of abstinence necessary to achieve cognitive recovery. A literature search yielded 62 studies that assessed cognitive dysfunction among alcoholics. Effect size estimates were calculated using the Comprehensive Meta-Analysis V2, for the following 12 cognitive domains: intelligence quotient, verbal fluency/language, speed of processing, working memory, attention, problem solving/executive functions, inhibition/impulsivity, verbal learning, verbal memory, visual learning, visual memory and visuospatial abilities. Within these 12 domains, three effect size estimates were calculated based on abstinence duration. The three groups were partitioned into short- ( 1 year) term abstinence. Findings revealed moderate impairment across 11 cognitive domains during short-term abstinence, with moderate impairment across 10 domains during intermediate term abstinence. Small effect size estimates were found for long-term abstinence. These results suggest significant impairment across multiple cognitive functions remains stable during the first year of abstinence from alcohol. Generally, dysfunction abates by 1 year of sobriety. These findings support the diffuse brain hypothesis and suggest that cognitive dysfunction may linger for up to an average of 1 year post-detoxification from alcohol.
432 citations
TL;DR: In this article, the authors used activation likelihood estimation, a quantitative, coordinate-based meta-analytic method, to analyze the brain areas activated by alcohol-related cues across studies, and examined whether these areas were differentially activated between cases and controls.
Abstract: A comprehensive understanding of the neurobiology of alcohol cue reactivity is critical in identifying the neuropathology of alcohol use disorders (AUD) and developing treatments that may attenuate alcohol craving and reduce relapse risk. Functional neuroimaging studies have identified many brain areas in which alcohol cues elicit activation. However, extant studies have included relatively small numbers of cases, with AUD of varying severity, and have employed many different cue paradigms. We used activation likelihood estimation, a quantitative, coordinate-based meta-analytic method, to analyze the brain areas activated by alcohol-related cues across studies, and to examine whether these areas were differentially activated between cases and controls. Secondarily, we reviewed correlations between behavioral measures and cue-elicited activation, as well as treatment effects on such activation. Data analyzed were from 28 studies of 679 cases and 174 controls. Among cases, alcohol cues elicited robust activation of limbic and prefrontal regions, including ventral striatum, anterior cingulate and ventromedial prefrontal cortex. As compared to controls, cases demonstrated greater activation of parietal and temporal regions, including posterior cingulate, precuneus and superior temporal gyrus. Cue-elicited activation of ventral striatum was most frequently correlated with behavioral measures and most frequently reduced by treatment, but these results were often derived from region-of-interest analyses that interrogated only limbic regions. These findings support long-standing theories of mesolimbic involvement in alcohol cue processing, but suggest that cue-elicited activation of other brain areas may more clearly differentiate cases from controls. Prevention and treatment for AUD should consider interventions that may reduce cue-elicited activation of these areas.
422 citations
TL;DR: Brain correlates of cue‐induced craving to play online games in subjects with Internet gaming addiction, subjects in remission from IGA and controls showed that bilateral dorsolateral prefrontal cortex (DLPFC), precuneus, left parahippocampus, posterior cingulate and right anterior cingulates were activated in response to gaming cues and their activation was stronger in the IGA group than those in the control group.
Abstract: This study aimed to evaluate brain correlates of cue-induced craving to play online games in subjects with Internet gaming addiction (IGA), subjects in remission from IGA and controls. The craving response was assessed by event-related design of functional magnetic resonance images (fMRIs). Fifteen subjects with IGA, 15 in remission from IGA and 15 controls were recruited in this study. The subjects were arranged to view the gaming screenshots and neutral images under investigation of fMRIs. The results showed that bilateral dorsolateral prefrontal cortex (DLPFC), precuneus, left parahippocampus, posterior cingulate and right anterior cingulate were activated in response to gaming cues in the IGA group and their activation was stronger in the IGA group than those in the control group. Their region-of-interest was also positively correlated with subjective gaming urge under cue exposure. These activated brain areas represent the brain circuit corresponding to the mechanism of substance use disorder. Thus, it would suggest that the mechanism of IGA is similar to substance use disorder. Furthermore, the IGA group had stronger activation over right DLPFC and left parahippocampus than did the remission group. The two areas would be candidate markers for current addiction to online gaming and should be investigated in future studies.
223 citations
TL;DR: Bilateral optical inhibition of the PL, NAcore or the PL fibers in the NAcore inhibited the reinstatement of cocaine seeking.
Abstract: Inhibitory optogenetics was used to examine the roles of the prelimbic cortex (PL), the nucleus accumbens core (NAcore) and the PL projections to the NAcore in the reinstatement of cocaine seeking. Rats were microinjected into the PL or NAcore with an adeno-associated virus containing halorhodopsin or archaerhodopsin. After 12 days of cocaine self-administration, followed by extinction training, animals underwent reinstatement testing along with the presence/absence of optically induced inhibition via laser light. Bilateral optical inhibition of the PL, NAcore or the PL fibers in the NAcore inhibited the reinstatement of cocaine seeking.
215 citations
TL;DR: Preliminary results suggest that some smokers may be able to use neurofeedback via rtfMRI to voluntarily regulate ACC activation and temporarily reduce smoking cue‐induced craving.
Abstract: Numerous research groups are now using analysis of blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) results and relaying back information about regional activity in their brains to participants in the scanner in 'real time'. In this study, we explored the feasibility of self-regulation of frontal cortical activation using real-time fMRI (rtfMRI) neurofeedback in nicotine-dependent cigarette smokers during exposure to smoking cues. Ten cigarette smokers were shown smoking-related visual cues in a 3 Tesla MRI scanner to induce their nicotine craving. Participants were instructed to modify their craving using rtfMRI feedback with two different approaches. In a 'reduce craving' paradigm, participants were instructed to 'reduce' their craving, and decrease the anterior cingulate cortex (ACC) activity. In a separate 'increase resistance' paradigm, participants were asked to increase their resistance to craving and to increase middle prefrontal cortex (mPFC) activity. We found that participants were able to significantly reduce the BOLD signal in the ACC during the 'reduce craving' task (P=0.028). There was a significant correlation between decreased ACC activation and reduced craving ratings during the 'reduce craving' session (P=0.011). In contrast, there was no modulation of the BOLD signal in mPFC during the 'increase resistance' session. These preliminary results suggest that some smokers may be able to use neurofeedback via rtfMRI to voluntarily regulate ACC activation and temporarily reduce smoking cue-induced craving. Further research is needed to determine the optimal parameters of neurofeedback rtfMRI, and whether it might eventually become a therapeutic tool for nicotine dependence.
161 citations
TL;DR: It is demonstrated that individuals with more severe alcohol dependence exhibit less frontal connectivity with the striatum, a component of cognitive control networks important for response inhibition, which suggests that the fronto‐striatal pathway underlying response inhibition is weakened as alcoholism progresses.
Abstract: Poor response inhibition has been implicated in the development of alcohol dependence, yet little is known about how neural pathways underlying cognitive control are affected in this disorder. Moreover, endogenous opioid levels may impact the functionality of inhibitory control pathways. This study investigated the relationship between alcohol dependence severity and functional connectivity of fronto-striatal networks during response inhibition in an alcohol-dependent sample. A secondary aim of this study was to test the moderating effect of a functional polymorphism (A118G) of the μ-opioid receptor (OPRM1) gene. Twenty individuals with alcohol dependence (six females; 90% Caucasian; mean age = 29.4) who were prospectively genotyped on the OPRM1 gene underwent blood oxygen level-dependent functional magnetic resonance imaging while performing a Stop-Signal Task. The relationship between alcohol dependence severity and functional connectivity within fronto-striatal networks important for response inhibition was assessed using psychophysiological interaction analyses. Analyses revealed greater alcohol dependence severity was associated with weaker functional connectivity between the putamen and prefrontal regions (e.g. the anterior insula, anterior cingulate and medial prefrontal cortex) during response inhibition. Furthermore, the OPRM1 genotype was associated with differential response inhibition-related functional connectivity. This study demonstrates that individuals with more severe alcohol dependence exhibit less frontal connectivity with the striatum, a component of cognitive control networks important for response inhibition. These findings suggest that the fronto-striatal pathway underlying response inhibition is weakened as alcoholism progresses.
139 citations
TL;DR: It is found that cannabis cues activate areas associated with addiction pathology in frequent cannabis users compared with sporadic users and controls, and among frequent users, cue‐reactivity seems to be primarily associated with problem severity, not with amount of cannabis use.
Abstract: Cue-reactivity reflects enhanced motivational processing underlying continued substance use and relapse in substance use disorders. Substance use disorders are associated with greater cue-reactivity in orbitofrontal cortex, anterior cingulate cortex, striatum, ventral tegmental area and amygdala. Here we examine whether this also holds for frequent cannabis users. Using functional magnetic resonance imaging (fMRI), neural responses to neutral and cannabis-related cues were compared between frequent cannabis users (n = 31), sporadic cannabis users (n = 20) and cannabis-naive controls (n = 21). In addition, fMRI findings were correlated with the level of cannabis use, problem severity and craving. In frequent users compared with sporadic users and controls, cannabis images engendered higher activation than control images in the ventral tegmental area. Activation of the orbitofrontal cortex, anterior cingulate cortex and striatum was only higher in a subgroup of frequent users with high compared with low-problem severity. Activity in the right putamen and right dorsolateral prefrontal cortex correlated negatively with subjective craving in frequent users. Activity was not correlated with level of cannabis use. These findings indicate that cannabis cues activate areas associated with addiction pathology in frequent cannabis users compared with sporadic users and controls. However, among frequent users, cue-reactivity seems to be primarily associated with problem severity, not with amount of cannabis use. These findings imply neural cue-reactivity as a tool in assessing problem severity of cannabis use.
128 citations
TL;DR: It is suggested that identically designed RCTs conducted in different parts of the world may help improve the external validity of RCTS by comparing a new double–blind, placebo‐controlled randomized trial conducted in Germany with data from the US COMBINE Study.
Abstract: The results of placebo-controlled trials (RCTs) with acamprosate or naltrexone vary substantially. Those differences have been attributed to differing patient characteristics, recruitment strategies, treatment settings and remuneration systems. We tested these assumptions by comparing a new double–blind, placebo-controlled randomized trial conducted in Germany (called PREDICT Study) with data from the US COMBINE Study. PREDICT was designed according to the protocol of the COMBINE Study. A total of 426 alcohol-dependent patients were compared to 459 COMBINE Study patients corresponding to the treatment cells in PREDICT. All patients received acamprosate, naltrexone or placebo for 3 months (PREDICT) or 4 months (COMBINE). Biweekly manualized ‘medical management’ to enhance compliance was delivered in both studies. Time until the first occurrence of heavy drinking was the main outcome measure. PREDICT found neither acamprosate nor naltrexone to supply any additional benefit compared with placebo, which is at variance with a positive naltrexone effect being reported in the COMBINE Study. A secondary comparison between both studies showed better overall treatment outcomes in PREDICT, although these patients had been more severely affected than their COMBINE counterparts. The divergence in results may be attributable to basic differences in the treatment environments (such as in-patient pre-treatment versus primary outpatient care). We suggest that identically designed RCTs conducted in different parts of the world may help improve the external validity of RCTs. This approach could be called ‘comparative efficacy research’.
109 citations
TL;DR: Fasting ghrelin levels may generally enhance subjective craving when confronted with reward cues, and brain activation and subjective appetite ratings suggest that gh Relin elevates the hedonic effects of food pictures.
Abstract: Ghrelin figures prominently in the regulation of appetite in normal-weighed individuals. The apparent failure of this mechanism in eating disorders and the connection to addictive behavior in general demand a deeper understanding of the endogenous central-nervous processes related to ghrelin. Thus, we investigated processing of pictures showing palatable food after overnight fasting and following a standardized caloric intake (i.e. a 75-g oral glucose tolerance test) using functional magnetic resonance imaging and correlated it with blood plasma levels of ghrelin. Twenty-six healthy female and male volunteers viewed food and control pictures in a block design and rated their appetite after each block. Fasting levels of ghrelin correlated positively with food-cue reactivity in a bilateral network of visual processing-, reward- and taste-related regions, including limbic and paralimbic regions. Notably, among those regions were the hypothalamus and the midbrain where ghrelin receptors are densely concentrated. In addition, high fasting ghrelin levels were associated with stronger increases of subjective appetite during the food-cue-reactivity task. In conclusion, brain activation and subjective appetite ratings suggest that ghrelin elevates the hedonic effects of food pictures. Thereby, fasting ghrelin levels may generally enhance subjective craving when confronted with reward cues.
108 citations
TL;DR: The findings indicate that cannabidiol does not exhibit reinforcing properties in the ICSS paradigm at any of the doses tested, while it decreases the reward‐facilitating effects of morphine, while these effects were mediated by activation of 5‐HT1A receptors in the dorsal raphe.
Abstract: Cannabidiol is a non-psychotomimetic constituent of Cannabis sativa, which induces central effects in rodents. It has been shown that cannabidiol attenuates cue-induced reinstatement of heroin seeking. However, to the best of our knowledge, its effects on brain stimulation reward and the reward-facilitating effects of drugs of abuse have not yet been examined. Therefore, we investigated the effects of cannabidiol on brain reward function and on the reward-facilitating effect of morphine and cocaine using the intracranial self-stimulation (ICSS) paradigm. Rats were prepared with a stimulating electrode into the medial forebrain bundle (MFB), and a guide cannula into the dorsal raphe (microinjection experiments), and were trained to respond for electrical brain stimulation. A low dose of cannabidiol did not affect the reinforcing efficacy of brain stimulation, whereas higher doses significantly elevated the threshold frequency required for MFB ICSS. Both cocaine and morphine lowered ICSS thresholds. Cannabidiol inhibited the reward-facilitating effect of morphine, but not cocaine. This effect was reversed by pre-treatment with an intra-dorsal raphe injection of the selective 5-HT1A receptor antagonist WAY-100635. The present findings indicate that cannabidiol does not exhibit reinforcing properties in the ICSS paradigm at any of the doses tested, while it decreases the reward-facilitating effects of morphine. These effects were mediated by activation of 5-HT1A receptors in the dorsal raphe. Our results suggest that cannabidiol interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids, thus indicating that cannabidiol may be clinically useful in attenuating the rewarding effects of opioids.
105 citations
TL;DR: Evidence is provided of stimulant‐typical abuse liability for 4‐MMC in the traditional pre‐clinical self‐administration model and the number of responses and/or the total amount of drug self-administered varied as a function of dose.
Abstract: Recreational use of the drug 4-methylmethcathinone (mephedrone; 4-MMC) became increasingly popular in the United Kingdom in recent years, spurred in part by the fact that it was not criminalized until April 2010. Although several fatalities have been associated with consumption of 4-MMC and cautions for recreational users about its addictive potential have appeared on Internet forums, very little information about abuse liability for this drug is available. This study was conducted to determine if 4-MMC serves as a reinforcer in a traditional intravenous self-administration model. Groups of male Wistar and Sprague-Dawley rats were prepared with intravenous catheters and trained to self-administer 4-MMC in 1-hour sessions. Per-infusion doses of 0.5 and 1.0 mg/kg were consistently self-administered, resulting in greater than 80% discrimination for the drug-paired lever and mean intakes of about 2-3 mg/kg/hour. Dose-substitution studies after acquisition demonstrated that the number of responses and/or the total amount of drug self-administered varied as a function of dose. In addition, radiotelemetry devices were used to show that self-administered 4-MMC was capable of increasing locomotor activity (Wistar) and decreasing body temperature (Sprague-Dawley). Pharmacokinetic studies found that the T1/2 of 4-MMC was about 1 hour in vivo in rat plasma and 90 minutes using in vitro liver microsomal assays. This study provides evidence of stimulant-typical abuse liability for 4-MMC in the traditional pre-clinical self-administration model.
TL;DR: The mean methadone doses required by subjects homozygous for the variant alleles of the CYP2B6 SNPs 785A>G and 516G>T were significantly lower than those of the heterozygotes and the non‐carriers and the results remain significant after controlling for age, sex and the ABCB1 SNP 1236C>T.
Abstract: Adequate methadone dosing in methadone maintenance treatment (MMT) for opioid addiction is critical for therapeutic success. One of the challenges in dose determination is the inter-individual variability in dose-response. Methadone metabolism is attributed primarily to cytochrome P450 enzymes CYP3A4, CYP2B6 and CYP2D6. The CYP2B6*6 allele [single nucleotide polymorphisms (SNPs) 785A>G (rs2279343) and 516G>T (rs3745274)] was associated with slow methadone metabolism. To explore the effects of CYP2B6*6 allele on methadone dose requirement, it was genotyped in a well-characterized sample of 74 Israeli former heroin addicts in MMT. The sample is primarily of Middle Eastern/European ancestry, based on ancestry informative markers (AIMs). Only patients with no major co-medication that may affect methadone metabolism were included. The stabilizing daily methadone dose in this sample ranges between 13 and 260mg (mean 140±52mg). The mean methadone doses required by subjects homozygous for the variant alleles of the CYP2B6 SNPs 785A>G and 516G>T (88, 96mg, respectively) were significantly lower than those of the heterozygotes (133, 129mg, respectively) and the non-carriers (150, 151mg, respectively) (nominal P=0.012, 0.048, respectively). The results remain significant after controlling for age, sex and the ABCB1 SNP 1236C>T (rs1128503), which was previously shown to be associated with high methadone dose requirement in this population (P=0.006, 0.030, respectively). An additional 77 CYP2B6, CYP3A4 and CYP2D6 SNPs were genotyped. Of these, 24 SNPs were polymorphic and none showed significant association with methadone dose. Further studies are necessary to replicate these preliminary findings in additional subjects and other populations.
TL;DR: It is suggested that top‐down inhibitory processes might suppress the cue reactivity‐related neural activity in long‐presentation trials in PCGPs.
Abstract: Despite a rising social relevance of pathological computer game playing, it remains unclear whether the neurobiological basis of this addiction-like behavioral disorder and substance-related addiction are comparable. In substance-related addiction, attentional bias and cue reactivity are often observed. We conducted a functional magnetic resonance study using a dot probe paradigm with short-presentation (attentional bias) and long-presentation (cue reactivity) trials in eight male pathological computer game players (PCGPs) and nine healthy controls (HCs). Computer game-related and neutral computer-generated pictures, as well as pictures from the International Affective Picture System with positive and neutral valence, served as stimuli. PCGPs showed an attentional bias toward both game-related and affective stimuli with positive valence. In contrast, HCs showed no attentional bias effect at all. PCGPs showed stronger brain responses in short-presentation trials compared with HCs in medial prefrontal cortex (MPFC) and anterior cingulate gyrus and in long-presentation trials in lingual gyrus. In an exploratory post hoc functional connectivity analyses, for long-presentation trials, connectivity strength was higher between right inferior frontal gyrus, which was associated with inhibition processing in previous studies, and cue reactivity-related regions (left orbitofrontal cortex and ventral striatum) in PCGPs. We observed behavioral and neural effects in PCGPs, which are comparable with those found in substance-related addiction. However, cue-related brain responses were depending on duration of cue presentation. Together with the connectivity result, these findings suggest that top-down inhibitory processes might suppress the cue reactivity-related neural activity in long-presentation trials.
TL;DR: Evidence is presented that alterations in DNA methylation may be associated with AD, which is consistent with epigenetic theory.
Abstract: Genetic, epigenetic, and environmental factors influence the development of alcohol dependence (AD). Recent studies have shown that DNA methylation markers in peripheral blood may serve as risk markers for AD. Yet a genome-wide epigenomic approach investigating the role of DNA methylation in AD has yet to be performed. We conducted a population-based, case-control study of genome-wide DNA methylation to determine if alterations in gene-specific methylation were associated with AD in a Chinese population. Using the Illumina Infinium Human Methylation27 BeadChip, we assessed gene-specific methylation in over 27 000 CpG sites from DNA isolated from lymphocytes in 63 male AD in-patients and 65 male healthy controls. Using a multi-factorial statistical model, we observed differential methylation between cases and controls at multiple CpG sites with the majority of the methylated CpG sites being hypomethylated. Analyses with the online gene set analysis toolkit WebGestalt revealed that the genes of interest were enriched in multiple biological processes involved in AD development. Gene Ontology function annotation showed that stress, immune response and signal transduction were highly associated with AD. Further analysis by the Kyoto Encyclopedia of Genes and Genomes revealed associations with multiple pathways involved in metabolism through cytochrome P450, cytokine-cytokine receptor interaction and calcium signaling. Associations with canonical pathways previously shown to be involved in AD were also observed, such as dehydrogenases 1A (ADH1A), ADH7, aldehyde dehydrogenases 3B2 (ALDH3B2) and cytochrome P450 2A13. We present evidence that alterations in DNA methylation may be associated with AD, which is consistent with epigenetic theory.
TL;DR: The results are suggestive of WM recovery with sustained abstinence and point to the need for further investigation of factors related to treatment‐seeking status and length of abstinence.
Abstract: Atrophy of brain white matter (WM) often is considered a signature injury of alcohol use disorders (AUDs). However, investigations into AUD-related changes in WM volume have yielded complex findings that are difficult to synthesize in a narrative review. The objective of this study was to obtain an averaged effect size (ES) for WM volume reduction associated with AUD diagnosis and to test potential moderators of ES. Study inclusion criteria were: (1) English language; (2) peer reviewed; (3) published before December 2011; (4) use of magnetic resonance imaging (MRI); (5) human participants; (6) inclusion of AUD group; (7) inclusion of non-AUD comparison group; and (8) reporting or testing of total or cerebral WM volume. Moderators included study design, MRI methodology and AUD characteristics. Nineteen studies with a total of 1302 participants (70% male) were included, and calculated ESs were confirmed by the corresponding author for 12 studies. The magnitude of the averaged ES adjusted for small sample bias (Hedges' g) for WM reduction in AUDs was 0.304 (standard error = 0.134, range = -0.57-1.21). Hierarchical linear modeling indicated that the overall ES differed significantly from 0, t(18) = 2.257, P = 0.037, and that the distribution of the 19 ESs showed significant heterogeneity beyond sampling error, χ(2) (18) = 52.400, P Language: en
TL;DR: Results suggest that chronic psychosocial stress enhances EtOH consumption, and baclofen and OXT differentially affect EtOH intake in mice.
Abstract: Chronic stress is known to enhance the susceptibility for addiction disorders including alcoholism. While these findings have been recapitulated in animal models, the majority of these studies have utilized non-social rather than social stress paradigms; the latter of which are believed to be more relevant to the human situation. Therefore, the major aim of this study was to investigate, if 14 days of chronic subordinate colony housing (CSC), a pre-clinically validated psychosocial stress paradigm relevant for human psychiatric and somatic disorders, enhances ethanol (EtOH) consumption in male mice. To assess this, we employed the well-established two-bottle free-choice paradigm where mice were given access to water and 2, 4, 6 and 8% EtOH solutions (with the concentrations increasing each fourth day) following termination of the stress procedure. After 14 days of CSC, stressed mice consumed significantly more EtOH at all concentrations tested and displayed increased EtOH preference at concentrations of 6 and 8%. This effect was not due to an altered taste preference in CSC mice as assessed by saccharine- and quinine-preference tests, but was accompanied by increased anxiety-related behavior. Systemic administration of baclofen (2.5 mg/kg) or oxytocin (OXT; 10 mg/kg) reduced the EtOH intake in single housed control (baclofen, OXT) and CSC (baclofen) mice, whereas intracerebroventricular OXT (0.5 μg/2 μl) was ineffective in both groups. Taken together, these results suggest that (i) chronic psychosocial stress enhances EtOH consumption, and (ii) baclofen and OXT differentially affect EtOH intake in mice.
TL;DR: The first genome‐wide association study for disordered gambling using a quantitative factor score in 1312 twins from 894 Australian families is reported, and gene‐based analysis of 24 candidate genes for dopamine agonist‐induced gambling in individuals with Parkinson's disease suggested an enrichment of SNPs associated with dis ordered gambling.
Abstract: adb_463 1..12 Disorderedgamblingisamoderatelyheritabletrait,buttheunderlyinggeneticbasisislargelyunknown.Weperformed a genome-wide association study (GWAS) for disordered gambling using a quantitative factor score in 1312 twins from 894 Australian families. Association was conducted for 2 381 914 single-nucleotide polymorphisms (SNPs) using the family-based association test in Merlin followed by gene and pathway enrichment analyses. Although no SNP reached genome-wide significance, six achieved P-values < 1 ¥ 10 -5 with variants in three genes (MT1X, ATXN1 and VLDLR) implicated in disordered gambling. Secondary case-control analyses found two SNPs on chromosome 9 (rs1106076 and rs12305135 near VLDLR) and rs10812227 near FZD10 on chromosome 12 to be significantly associated with lifetime Diagnostic and Statistical Manual of Mental Disorders, fourth edition pathological gambling and South Oaks Gambling Screen classified probable pathological gambling status. Furthermore, several addiction-related pathways were enriched for SNPs associated with disordered gambling. Finally, gene-based analysis of 24 candidate genes for dopamine agonist-induced gambling in individuals with Parkinson's disease suggested an enrichment of SNPs asso- ciated with disordered gambling. We report the first GWAS of disordered gambling. While further replication is required, the identification of susceptibility loci and biological pathways will be important in characterizing the biological mechanisms that underpin disordered gambling.
TL;DR: The results indicated that chronic alcohol drinking enhanced extracellular glutamate concentrations in the mesolimbic system, as a result, in part, of reduced clearance, suggesting that enhanced glutamate neurotransmission may contribute to the maintenance of alcohol drinking.
Abstract: The present study determined the effects of voluntary ethanol drinking and deprivation on basal extracellular glutamate concentrations and clearance in the mesolimbic system and tested the hypothesis that chronic ethanol drinking would persistently increase basal glutamate neurotransmission. Three groups of alcohol-preferring (P) rats were used: 'water group (WG),' 'ethanol maintenance group (MG; 24-hour free choice water versus 15% ethanol)' and 'ethanol deprivation group (DG; 2 weeks of deprivation).' Quantitative microdialysis and Western blots were conducted to measure basal extracellular glutamate concentrations, clearance and proteins associated with glutamate clearance. Chronic alcohol drinking produced a 70-100% increase of basal extracellular glutamate concentrations in the posterior ventral tegmental area (4.0 versus 7.0 μM) and nucleus accumbens shell (3.0 versus 6.0 μM). Glutamate clearances were reduced by 30-40% in both regions of MG rats compared with WG rats. In addition, Western blots revealed a 40-45% decrease of excitatory amino transporter 1 (EAAT1) protein, but no significant changes in the levels of EAAT2 or cystine-glutamate antiporter in these regions of MG versus WG rats. The enhanced glutamate concentrations returned to control levels, accompanied by a recovery of glutamate clearance following deprivation. These results indicated that chronic alcohol drinking enhanced extracellular glutamate concentrations in the mesolimbic system, as a result, in part, of reduced clearance, suggesting that enhanced glutamate neurotransmission may contribute to the maintenance of alcohol drinking. However, because the increased glutamate levels returned to normal after deprivation, elevated glutamate neurotransmission may not contribute to the initiation of relapse drinking.
TL;DR: A new systems medicine approach is used to define individual neurobehavioral risk profiles in adolescents that are predictive of alcohol use disorders later in life and to identify new pharmacological targets and molecules for the treatment of alcoholism.
Abstract: According to the World Health Organization, about 2 billion people drink alcohol. Excessive alcohol consumption can result in alcohol addiction, which is one of the most prevalent neuropsychiatric diseases afflicting our society today. Prevention and intervention of alcohol binging in adolescents and treatment of alcoholism are major unmet challenges affecting our health-care system and society alike. Our newly formed German SysMedAlcoholism consortium is using a new systems medicine approach and intends (1) to define individual neurobehavioral risk profiles in adolescents that are predictive of alcohol use disorders later in life and (2) to identify new pharmacological targets and molecules for the treatment of alcoholism. To achieve these goals, we will use omics-information from epigenomics, genetics transcriptomics, neurodynamics, global neurochemical connectomes and neuroimaging (IMAGEN; Schumann et al. ) to feed mathematical prediction modules provided by two Bernstein Centers for Computational Neurosciences (Berlin and Heidelberg/Mannheim), the results of which will subsequently be functionally validated in independent clinical samples and appropriate animal models. This approach will lead to new early intervention strategies and identify innovative molecules for relapse prevention that will be tested in experimental human studies. This research program will ultimately help in consolidating addiction research clusters in Germany that can effectively conduct large clinical trials, implement early intervention strategies and impact political and healthcare decision makers.
TL;DR: A new finding is that individuals who are biased toward immediate rewards have a higher probability of increasing drug use, highlighting the importance of the relative balance between motivational processes and regulatory executive processes in the development of substance use disorders.
Abstract: Decision-making deficits are thought to play an important role in the development and persistence of substance use disorders. Individual differences in decision-making abilities and their underlying neurocircuitry may, therefore, constitute an important predictor for the course of substance use and the development of substance use disorders. Here, we investigate the predictive value of decision making and neural mechanisms underlying decision making for future cannabis use and problem severity in a sample of heavy cannabis users. Brain activity during a monetary decision-making task (Iowa gambling task) was compared between 32 heavy cannabis users and 41 matched non-using controls using functional magnetic resonance imaging. In addition, within the group of heavy cannabis users, associations were examined between task-related brain activations, cannabis use and cannabis use-related problems at baseline, and change in cannabis use and problem severity after a 6-month follow-up. Despite normal task performance, heavy cannabis users compared with controls showed higher activation during wins in core areas associated with decision making. Moreover, within the group of heavy cannabis users, win-related activity and activity anticipating loss outcomes in areas generally involved in executive functions predicted change in cannabis use after 6 months. These findings are consistent with previous studies and point to abnormal processing of motivational information in heavy cannabis users. A new finding is that individuals who are biased toward immediate rewards have a higher probability of increasing drug use, highlighting the importance of the relative balance between motivational processes and regulatory executive processes in the development of substance use disorders.
TL;DR: Data show that mGluR5 inhibition and stimulation in the NAcore can regulate cocaine‐seeking, and demonstrate that one mechanism for this effect is via interactions with Homer proteins.
Abstract: In animal models of addiction, reducing glutamate stimulation of the metabotropic glutamate receptor 5 (mGluR5) inhibits drug-seeking. The present study used the reinstatement model of cocaine-seeking to show that blockade of mGluR5 directly in the core subcompartment of the nucleus accumbens (NAcore) prevented both conditioned cue- and cocaine-reinstated drug-seeking. Consistent with this finding, microinjection of the mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine into the NAcore produced modest reinstatement of lever pressing when given alone and significantly potentiated cue-induced reinstatement. Homer proteins are contained in the post-synaptic density and regulate mGluR5 intracellular signaling and trafficking to the membrane. Microinjecting a membrane permeable peptide antagonist of Homer binding to mGluR5 into the NAcore also inhibited cue- and cocaine-reinstated lever pressing. However, this peptide did not change the surface expression of mGluR5, indicating that the peptide inhibitor did not alter the surface trafficking of mGluR5. Taken together, these data show that mGluR5 inhibition and stimulation in the NAcore can regulate cocaine-seeking, and demonstrate that one mechanism for this effect is via interactions with Homer proteins.
TL;DR: It is reported that systemic or local administration of SB‐277011A into the NAc or the CeA, but not the dorsal striatum or basolateral amygdala, significantly inhibits expression of incubation of cocaine craving in rats after 2–30 days of withdrawal from previous cocaine self‐administration.
Abstract: Cue-induced drug seeking progressively increases over time of withdrawal from drug self-administration in rats, a phenomenon called 'incubation of craving'. The underlying mechanisms have been linked to increased expression of brain-derived neurotrophic factor and GluR2-lacking AMPA receptors in the mesolimbic dopamine (DA) system and also to increased extracellular signal-regulated kinase activation in the central amygdala (CeA). However, it remains unclear whether any DA mechanism is also involved in incubation of craving. Recent research demonstrates that cue-induced cocaine seeking appears to parallel increased DA D3 , but not D1 or D2 , receptor expression in the nucleus accumbens (NAc) of rats over time of withdrawal, suggesting possible involvement of D3 receptors (D3 Rs) in incubation of cocaine craving. Here, we report that systemic or local administration of SB-277011A, a highly selective D3 R antagonist, into the NAc (core and shell) or the CeA, but not the dorsal striatum or basolateral amygdala, significantly inhibits expression of incubation of cocaine craving in rats after 2-30 days of withdrawal from previous cocaine self-administration but had no effect on sucrose-seeking behavior in rats after 10-30 days of withdrawal. These data suggest that DA D3 Rs in both the NAc and the CeA play an important role in incubation of cocaine craving in rats and support the potential utility of D3 R antagonists in the treatment of cocaine addiction.
TL;DR: Although intermittent ethanol access resulted in escalated ethanol intake in all tested genotypes, the robustness of the effect varied across genotypes and there was no evidence that the effects of intermittent access are correlated with either binge‐like drinking or withdrawal severity, and only weak evidence for a genetic correlation with baseline ethanol preference.
Abstract: Experimental animals offered continuous 24-hour free choice access to ethanol rarely display voluntary ethanol consumption at levels sufficient to induce intoxication or to engender dependence. One of the simplest ways to increase voluntary ethanol intake is to impose temporal limitations on ethanol availability. Escalation of ethanol intake has been observed in both rats and mice under a variety of different schedules of alternating ethanol access and deprivation. Although such effects have been observed in a variety of rat and mouse genotypes, little is known concerning possible genetic correlations between responses to intermittent ethanol access and other ethanol-related phenotypes. In the present study, we examined the effects of intermittent ethanol access in mouse genotypes characterized by divergent responses to ethanol in other domains, including ethanol preference (C57BL/6J and C3H/HeJ mice), binge-like ethanol drinking (High Drinking in the Dark and HS/Npt mice) and ethanol withdrawal severity (Withdrawal Seizure-Prone and Withdrawal Seizure-Resistant mice). Although intermittent ethanol access resulted in escalated ethanol intake in all tested genotypes, the robustness of the effect varied across genotypes. On the other hand, we saw no evidence that the effects of intermittent access are correlated with either binge-like drinking or withdrawal severity, and only weak evidence for a genetic correlation with baseline ethanol preference. Thus, these different ethanol-related traits appear to depend on largely unique sets of genetic mediators.
TL;DR: Activation of the κ‐opioid receptor by up‐regulated dynorphins in alcoholics may underlie in part neurocognitive dysfunctions relevant for addiction and disrupted inhibitory control.
Abstract: The endogenous opioid system (EOS) plays a critical role in addictive processes. Molecular dysregulations in this system may be specific for different stages of addiction cycle and neurocircuitries ...
TL;DR: Free‐choice drinking demonstrated by the HAP1 and cHAP lines may provide a unique opportunity for modeling the excessive intake that often occurs in alcohol‐dependent individuals, and allow for exploration of predisposing factors for excessive consumption, as well as the development of physiological, behavioral and toxicological outcomes following alcohol exposure.
Abstract: Multiple lines of High Alcohol Preferring (HAP) mice were selectively bred for their intake of 10% ethanol (v/v) during 24-h daily access over a four-week period, with the highest drinking lines exhibiting intakes in excess of 20 g/kg/day. We observed circadian drinking patterns and resulting blood ethanol concentrations in the HAP lines. We also compared the drinking rhythms and corresponding blood ethanol concentrations (BEC) of the highest drinking HAP lines to those of the C57BL/6J (B6) inbred strain. Adult male and female crossed HAP (cHAP), HAP replicate lines 1, 2, 3, and B6 mice had free-choice access to 10% ethanol and water for 3 weeks prior to bi-hourly assessments of intake throughout the dark portion of the light-dark cycle. All HAP lines reached and maintained a rate of alcohol intake above the rate at which HAP1 mice metabolize alcohol, and BECs were consistent with this finding. Further, cHAP and HAP1 mice maintained an excessive level of intake throughout the dark portion of the cycle, accumulating mean BEC levels of 261.5 ± 18.09 and 217.9 ± 25.02 mg/dl, respectively. B6 mice drank comparatively modestly, and did not accumulate high BEC levels (53.63 + 8.15 mg/dl). Free-choice drinking demonstrated by the HAP1 and cHAP lines may provide a unique opportunity for modeling the excessive intake that often occurs in alcohol-dependent individuals, and allow for exploration of predisposing factors for excessive consumption, as well as the development of physiological, behavioral, and toxicological outcomes following alcohol exposure.
TL;DR: The present data indicate that changes in DA and GABA neurotransmission during maintenance phase mirror the motivational aspects of cocaine intake.
Abstract: We investigated the changes in dopamine (DA), glutamate and γ-aminobutyric acid (GABA) during cocaine self-administration in rats implanted with guide cannulae into the nucleus accumbens and ventral pallidum. After stabilized cocaine self-administration, separate groups of rats underwent extinction (10 days) procedure in which cocaine infusion was replaced by saline injections. With using a 'yoked' procedure, the effects of cocaine or its withdrawal on the level of neurotransmitters were evaluated by dual-probe microdialysis. Repeated cocaine administration reduced basal glutamate levels in the nucleus accumbens and ventral pallidum, whereas it did not affect basal accumbal DA levels. Only rats that self-administered cocaine had increased basal GABA overflow in both examined brain structures. Active or passive cocaine administration elevated extracellular accumbal DA, however, the extent of cocaine-evoked DA level was significantly higher in rats that self-administered cocaine while both groups of animals showed also an attenuation of GABA level in the nucleus accumbens. On day 10 of extinction training, rats previously given cocaine revealed decreases in the basal accumbal concentration of glutamate while the basal GABA levels were significantly enhanced as compared with baseline of saline-yoked controls. Potassium depolarization delayed the reduction of the accumbal and pallidal extracellular glutamate levels in the active and passive cocaine groups. The present data indicate that changes in DA and GABA neurotransmission during maintenance phase mirror the motivational aspects of cocaine intake. Depending on acute (24 hours) or late (10 days) cocaine withdrawal, different neurotransmitter systems (i.e. glutamate or GABA) seem to be involved.
TL;DR: This dual modality magnetic resonance (MR) study indicated that chronic smoking in ALC was associated with significant cortical thinning and NAA abnormalities in anterior brain regions that are implicated in the development and maintenance of addictive disorders.
Abstract: Chronic smoking in alcohol dependence is associated with abnormalities in brain morphology and metabolite levels in large lobar regions (e.g. frontal lobe). Here, we evaluated if these abnormalities are specifically apparent in several cortical and select subcortical components of the extended brain reward system (BRS), a network that is critically involved in the development and maintenance of all forms of addictive disorders. We studied 33 non-smoking and 43 smoking alcohol-dependent individuals (ALC) with 1 week of abstinence and 42 non-smoking Controls. At 1.5 Tesla, we obtained regional measures of cortical thickness and N-acetylaspartate (NAA; a surrogate marker of neuronal integrity) concentration in major components of the BRS as well as the corresponding measures throughout the cortex. Smoking ALC and non-smoking ALC demonstrated decreased thickness compared with Controls in the dorsolateral prefrontal cortex (DLPFC), insula, orbitofrontal cortex (OFC), the total BRS, total frontal cortex and global cortex. Smoking ALC had significantly decreased thickness compared to non-smoking ALC in the ACC, insula, the total BRS and total frontal cortex. Smoking ALC had also lower NAA concentrations than both non-smoking ALC and Controls in the DLPFC, insula, superior corona radiata and the total BRS. Alcohol consumption and common medical and psychiatric co-morbidities did not mediate differences between smoking and non-smoking ALC. This dual modality magnetic resonance (MR) study indicated that chronic smoking in ALC was associated with significant cortical thinning and NAA abnormalities in anterior brain regions that are implicated in the development and maintenance of addictive disorders.
TL;DR: The pattern of alterations observed for the nociceptin system appears to be consistent with its role of functional antagonism towards the actions of ethanol associated with other opioid peptides, which could help to the understanding of how alcohol differentially affects the opioid systems in the brain.
Abstract: Molecular mechanisms of adaptive transformations caused by alcohol exposure on opioid dynorphin and nociceptin systems have been investigated in the rat brain. Alcohol was intragastrically administered to rats to resemble human drinking with several hours of exposure: water or alcohol (20% in water) at a dose of 1.5 g/kg three times daily for 1 or 5 days. The development of tolerance and dependence were recorded daily. Brains were dissected 30 minutes (1- and 5-day groups) or 1, 3 or 7 days after the last administration for the three other 5-day groups (groups under withdrawal). Specific alterations in opioid genes expression were ascertained. In the amygdala, an up-regulation of prodynorphin and pronociceptin was observed in the 1-day group; moreover, pronociceptin and the kappa opioid receptor mRNAs in the 5-day group and both peptide precursors in the 1-day withdrawal group were also up-regulated. In the prefrontal cortex, an increase in prodynorhin expression in the 1-day group was detected. These data indicate a relevant role of the dynorphinergic system in the negative hedonic states associated with multiple alcohol exposure. The pattern of alterations observed for the nociceptin system appears to be consistent with its role of functional antagonism towards the actions of ethanol associated with other opioid peptides. Our findings could help to the understanding of how alcohol differentially affects the opioid systems in the brain and also suggest the dynorphin and nociceptin systems as possible targets for the treatment and/or prevention of alcohol dependence.
TL;DR: The NGF serum levels were significantly associated with the mean methylation of the investigated CpG‐sites and imply an epigenetic regulation of the NGF gene during alcohol withdrawal.
Abstract: We investigated the Cytosin-phosphatidyl-Guanin (CpG) island promoter methylation (mean and methylation of individual CpG-sites) of the nerve growth factor (NGF) gene in the blood of alcohol-dependent patients (57 male patients) during withdrawal (days 1, 7 and 14). Methylation and NGF serum levels did not change significantly from days 1–7. From days 7–14, mean methylation increased (F = 30.55, P < 0.001), whereas the NGF serum levels decreased significantly (days 7–14: F = 17.95, P < 0.001). The NGF serum levels were significantly associated with the mean methylation of the investigated CpG-sites (F = 1.55, P < 0.001). These results imply an epigenetic regulation of the NGF gene during alcohol withdrawal.
TL;DR: Adolescents who smoked their first cigarette at an earlier age reported more pleasurable sensations from the cigarette, and they were more likely to be regular smokers at age 22, and the age at first cigarette also predicted the number of cigarettes smoked and dependence at age22.
Abstract: There is converging evidence suggesting a particular susceptibility to the addictive properties of nicotine among adolescents. The aim of the current study was to prospectively ascertain the relationship between age at first cigarette and initial smoking experiences, and to examine the combined effects of these characteristics of adolescent smoking behavior on adult smoking. It was hypothesized that the association between earlier age at first cigarette and later development of nicotine dependence may, at least in part, be attributable to differences in experiencing pleasurable early smoking sensations. Data were drawn from the participants of the Mannheim Study of Children at Risk, an ongoing epidemiological cohort study from birth to adulthood. Structured interviews at age 15, 19 and 22 years were conducted to assess the age at first cigarette, early smoking experiences and current smoking behavior in 213 young adults. In addition, the participants completed the Fagerstrom Test for Nicotine Dependence. Adolescents who smoked their first cigarette at an earlier age reported more pleasurable sensations from the cigarette, and they were more likely to be regular smokers at age 22. The age at first cigarette also predicted the number of cigarettes smoked and dependence at age 22. Thus, both the age of first cigarette and the pleasure experienced from the cigarette independently predicted aspects of smoking at age 22.