Risk Factors For Substance Dependence Research Articles

Neural Responses to Signals for Behavior Change: Greater Within‐Person Variability is Associated With Risk Factors for Substance Dependence

An impaired ability to change behavior in the face of cues indicating a need for change is one means of defining risk for substance dependence. The present study used a cognitive task administered in a laboratory as a model of this process. It focused on 2 known and related correlates of risk (conduct disorder, borderline personality disorder) and examined their associations with reactivity to cues requesting a change in motor behavior. A total of 224 teenagers, 14 to 19years of age, performed a task during which white noise bursts were used to cue a requirement to reverse the mapping of right and left key press responses onto high- and low-frequency pure tones during a subsequent trial block. The amplitude of the P300 electroencephalographic (EEG) response to each cue was summarized by calculating its across-trial average as well as its intertrial variability (ITV). In addition, the number of motor response reversal failures (perseveration errors) was calculated. The ITV of the P300 response to cues for behavior change was superior to its average amplitude in revealing associations with risk: It was significantly greater among teenagers with more conduct problems and more borderline personality disorder symptoms in comparison with their less-affected peers. ITV was also positively correlated with perseveration errors. No group differences were found in P300 amplitude averaged over trials. The findings suggest that the measurement of intertrial variability in brain activity may be more valuable than the average level for revealing neurophysiological differences associated with impulsivity and personality risk factors for dependence. EEG measures may be particularly valuable in this context because they offer superior temporal resolution and signal-to-noise characteristics.

Transition to substance use disorders: impulsivity for reward and learning from reward.

Substance dependence constitutes a profound societal burden. Although large numbers of individuals use licit or illicit substances, few transition to dependence. The specific factors influencing this transition are not well understood. Substance-dependent individuals tend to be swayed by the immediate rewards of drug taking, but are often insensitive to delayed negative consequences of their behavior. Dependence is consequently associated with impulsivity for reward and atypical learning from feedback. Behavioral impulsivity is indexed using tasks measuring spontaneous decision-making and capacity to control impulses. While evidence indicates drug taking exacerbates behavioral impulsivity for reward, animal and human studies of drug naïve populations demonstrate it might precede any drug-related problems. Research suggests dependent individuals are also more likely to learn from rewarding (relative to punishing) feedback. This may partly explain why substance-dependent individuals fail to modify their behavior in response to negative outcomes. This enhanced learning from reward may constitute a further pre-existing risk factor for substance dependence. Although impulsivity for reward and preferential learning from rewarding feedback are both underpinned by a compromised dopaminergic system, few studies have examined the relationship between these two mechanisms. The interplay of these processes may help enrich understanding of why some individuals transition to substance dependence.

DISC1 as a Possible Genetic Contribution to Opioid Dependence in a Polish Sample.

Disrupted-in-schizophrenia 1 (DISC1) has been linked to vulnerability to a variety of psychiatric disorders and neuropsychiatric phenotypes. However, DISC1 has not been frequently examined as a potential risk factor for substance dependence. An association between opioid dependence and DISC1 rs2738888 polymorphism has been recently reported. In addition, opioid dependence was associated with rs6419156 located close to the protein phosphatase 3 catalytic subunit alpha isoform (PPP3CA) gene. The aim of the present study was to examine the associations between opioid dependence with rs2738888 and rs6419156 in an independent sample. The selected polymorphisms were genotyped in a sample of 392 individuals (69.9% male) diagnosed as alcohol- and/or opioid-dependent. A control group (n = 257; 67.7% male) was derived from the Polish National Health Survey (N = 14,350). The frequency of rs2738888 C allele was higher in controls than in opioid-dependent cases (OR = 0.65, p = .045). Phenotypic-oriented analyses performed within opioid-dependent individuals revealed the association between lifetime suicide attempt and rs2738888. The C allele of rs2738888 had a protective effect on lifetime suicide attempt in opioid-dependent patients (OR = 0.25, p = .003). Rs6419156 was not associated with substance dependence in the examined sample. The DISC1 may play an important role in vulnerability to opioid dependence. In addition, DISC1 may also be a genetic risk factor for suicide attempt in opioid-dependent individuals.

Cis-Regulatory Variants Affect CHRNA5 mRNA Expression in Populations of African and European Ancestry

Variants within the gene cluster encoding α3, α5, and β4 nicotinic receptor subunits are major risk factors for substance dependence. The strongest impact on risk is associated with variation in the CHRNA5 gene, where at least two mechanisms are at work: amino acid variation and altered mRNA expression levels. The risk allele of the non-synonymous variant (rs16969968; D398N) primarily occurs on the haplotype containing the low mRNA expression allele. In populations of European ancestry, there are approximately 50 highly correlated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and the adjacent PSMA4 gene region that are associated with CHRNA5 mRNA levels. It is not clear which of these variants contribute to the changes in CHRNA5 transcript level. Because populations of African ancestry have reduced linkage disequilibrium among variants spanning this gene cluster, eQTL mapping in subjects of African ancestry could potentially aid in defining the functional variants that affect CHRNA5 mRNA levels. We performed quantitative allele specific gene expression using frontal cortices derived from 49 subjects of African ancestry and 111 subjects of European ancestry. This method measures allele-specific transcript levels in the same individual, which eliminates other biological variation that occurs when comparing expression levels between different samples. This analysis confirmed that substance dependence associated variants have a direct cis-regulatory effect on CHRNA5 transcript levels in human frontal cortices of African and European ancestry and identified 10 highly correlated variants, located in a 9 kb region, that are potential functional variants modifying CHRNA5 mRNA expression levels.

The Relationship Between Impulsivity for Reward and Learning From Reward

Event Abstract Back to Event The Relationship Between Impulsivity for Reward and Learning From Reward Antoinette Poulton1, Kaitlyn Harrington1, Caitlyn Mackenzie1 and Robert Hester1* 1 University of Melbourne, Melbourne School of Psychological Sciences, Australia Background: Although relatively large numbers of Australians are drug users, few individuals transition from low-level occasional use to substance dependence. The specific factors influencing this transition remain unclear. Substance dependent individuals tend to be swayed by the immediate rewards of drug taking, but are often insensitive to the delayed negative consequences of their behaviour. Dependence is consequently associated with impulsivity for reward and atypical learning from feedback. Animal and human studies of drug naïve populations demonstrate impulsivity for reward might precede drug-related problems. Research also suggests dependent individuals are more likely to learn from rewarding (relative to punishing) feedback, which may explain why they fail to modify their behaviour in response to negative outcomes, and may constitute a further pre-existing risk factor for substance dependence. Although impulsivity for reward and preferential learning from rewarding feedback are both underpinned by a compromised dopaminergic system, few studies have examined the relationship between these two mechanisms. Method: Ninety-eight healthy individuals (52 female, M = 23.53, SD = 6.07) undertook 1) An inhibitory control task that quantified ability to inhibit responses in the presence of immediate reward, and 2) A spatial associative learning task that measured capacity to learn from positive and negative feedback (monetary reward and punishment). Results: 1) Compared to the neutral condition, inhibitory control was significantly reduced in the presence of immediate reward, 2) Compared to the punishing feedback condition, recall was significantly better following rewarding feedback, and 3) A reduced ability to inhibit responses in the presence of immediate reward was significantly associated with a preference for learning from rewarding, relative to punishing, feedback. Discussion: Results suggest individual differences in inhibitory control are related to individual differences in learning from feedback in the healthy population. The interplay of these processes may provide evidence explaining why some individuals transition to substance dependence. While our data support an overall relationship, there was a subgroup that was both highly impulsive for, and sensitive to learning from, reward. It is possible these two mechanisms serve as dual pre-existing cognitive markers for vulnerability to the transition from substance use to dependence. Keywords: substance dependence, Inhibitory Control, associative learning, Impulsivity and self-control, Reward sensitivity Conference: ACNS-2013 Australasian Cognitive Neuroscience Society Conference, Clayton, Melbourne, Australia, 28 Nov - 1 Dec, 2013. Presentation Type: Poster Topic: Other Citation: Poulton A, Harrington K, Mackenzie C and Hester R (2013). The Relationship Between Impulsivity for Reward and Learning From Reward. Conference Abstract: ACNS-2013 Australasian Cognitive Neuroscience Society Conference. doi: 10.3389/conf.fnhum.2013.212.00049 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 15 Oct 2013; Published Online: 25 Nov 2013. * Correspondence: Dr. Robert Hester, University of Melbourne, Melbourne School of Psychological Sciences, Melbourne, Victoria, 3010, Australia, hesterr@unimelb.edu.au Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Antoinette Poulton Kaitlyn Harrington Caitlyn Mackenzie Robert Hester Google Antoinette Poulton Kaitlyn Harrington Caitlyn Mackenzie Robert Hester Google Scholar Antoinette Poulton Kaitlyn Harrington Caitlyn Mackenzie Robert Hester PubMed Antoinette Poulton Kaitlyn Harrington Caitlyn Mackenzie Robert Hester Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

GABRA2 Genotype, Impulsivity, and Body Mass

The goal of this study was to test a hypothesis associating impulsivity with an elevated body mass index (BMI). To this end, we examined associations of BMI with putative genetic, neurophysiological, psychiatric, and psychological indicators of impulsivity in 78 women and 74 men formerly dependent on alcohol or drugs. A second analysis was designed to test the replicability of the genetic findings in an independent sample of 109 women and 111 men with a similar history of substance dependence. The results of the first analysis showed that BMI was positively correlated with Total and Nonplanning Scale Scores on the Barratt Impulsiveness Scale and the number of childhood symptoms of Attention-Deficit/Hyperactivity Disorder in women. It was also positively correlated, in women, with a GABRA2 variant previously implicated as a risk factor for substance dependence and an objective electroencephalographic feature previously associated with GABRA2 and relapse risk. The second analysis confirmed that the correlation between BMI and the substance-dependence-associated GABRA2 genotype was reliable and sex-specific. We conclude that an elevated BMI is associated with genetic, neurophysiological, psychiatric, and psychological indicators of impulsivity. The sex difference may be explained by greater opportunities to eat and overeat, a preference for higher calorie foods, a longer duration of alcohol/drug abstinence, or previous pregnancies in women.

Adverse childhood events as risk factors for substance dependence: Partial mediation by mood and anxiety disorders

Aims Adverse childhood events (ACEs) are associated with negative health outcomes. We examined ACEs as risk factors for substance dependence (SD) and the mediating effects of mood and anxiety disorders on the relations between ACEs and SD risk. Design We compared early life experiences in 2061 individuals with a lifetime diagnosis of alcohol, cocaine, or opioid dependence and 449 controls. Measurements Diagnostic and ACE data were obtained using the Semi-Structured Assessment for Drug Dependence and Alcoholism. Findings Childhood abuse or exposure to violent crime was positively related to the number of lifetime mood and anxiety disorders and to SD risk. Mood and anxiety disorders had their first onset a mean of nearly 3 years before the first SD diagnosis and partially mediated the effect of ACEs on SD risk. Conclusion ACEs appear to contribute additively to the risk of SD, with mood and anxiety disorders in the causal path for a portion of this risk. The identification and effective treatment of mood and anxiety disorders associated with ACEs could reduce the risk of developing SD.

Incentive‐elicited striatal activation in adolescent children of alcoholics

Deficient recruitment of motivational circuitry by non-drug rewards has been postulated as a pre-morbid risk factor for substance dependence (SD). We tested whether parental alcoholism, which confers risk of SD, is correlated with altered recruitment of ventral striatum (VS) by non-drug rewards in adolescence. During functional magnetic resonance imaging, adolescent children of alcoholics (COA; age 12-16 years) with no psychiatric disorders (including substance abuse) and similarly aged children with no risk factors responded to targets to win or avoid losing $0, $0.20, $1, $5 or a variable amount (ranging from $0.20 to $5). In general, brain activation by either reward anticipation or outcome notification did not differ between COA and age/gender-matched controls. Cue-elicited reward anticipation activated portions of VS in both COA and controls. In nucleus accumbens (NAcc), signal change increased with anticipated reward magnitude (with intermediate recruitment by variable incentives) but not with loss magnitudes. Reward deliveries activated the NAcc and mesofrontal cortex in both COA and controls. Losses activated anterior insula bilaterally in both groups, with more extensive right anterior insula activation by losses in controls. NAcc signal change during anticipation of maximum rewards (relative to non-reward) correlated positively with both Brief Sensation-Seeking Scale scores and with self-reported excitement in response to maximum reward cues (relative to cues for non-reward). Among adolescents with no psychiatric disorders, incentive-elicited VS activation may relate more to individual differences in sensation-seeking personality than to presence of parental alcoholism alone. Future research could focus on adolescents with behavior disorders or additional risk factors.

Genetics of two mu opioid receptor gene (OPRM1) exon I polymorphisms: population studies, and allele frequencies in alcohol- and drug-dependent subjects.

The gene encoding the mu opioid receptor, OPRM1, contains at least two polymorphisms affecting protein sequence in exon 1, Ala6Val and Asp40Asn. In previous studies, each variant has been reported to be associated with some form of drug dependence. Although past reports have not been consistent, they have also not considered comparable populations. The goals of the present study were to delineate allele and haplotype frequencies of these variants in a range of populations, and in drug- or alcohol-dependent subjects deriving from some of those populations. We developed new PCR-RFLP methods to detect both of these polymorphisms and studied them in control and substance-dependent populations of African American (AA), European American (EA) and Hispanic origin, and in a series of populations differing in geographic origin (Japanese, Ethiopians, Bedouins, and Ashkenazi Jews), 891 subjects overall. We designed primers flanking the DNA segment containing both polymorphisms, each primer creating a different artificial restriction site, such that a single PCR reaction can be completed, then divided, and the PCR product digested with either of two enzymes to reveal both polymorphisms. We found that allele frequencies for both polymorphic systems were significantly different between AA and EA subjects, and there was significant heterogeneity among the more extensive set of populations. Furthermore, there were no significant differences in allele frequency by diagnosis; that is, neither polymorphism appears to be a direct risk factor for substance dependence. Finally, we demonstrated linkage disequilibrium between the two exon 1 markers, and a previously described short tandem repeat (STR) marker.