Association of cognitive function and liability to addiction with childhood herpesvirus infections: A prospective cohort study.

Liability to substance use disorder (SUD) is largely nonspecific to particular drugs and is related to behavior dysregulation, including reduced cognitive control. Recent data suggest that cognitive mechanisms may be influenced by exposure to neurotropic infections, such as human herpesviruses. In this study, serological evidence of exposure to human herpesvirus Herpes simplex virus Type 1 (HSV-1), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) as well as Toxoplasma gondii was determined in childhood (age ~11 years) in 395 sons and 174 daughters of fathers with or without SUD. Its relationships with a cognitive characteristic (IQ) in childhood and with risk for SUD in adulthood were examined using correlation, regression, survival, and path analyses. Exposure to HSV-1, EBV, and T. gondii in males and females, and CMV in males, was associated with lower IQ. Independent of that relationship, EBV in females and possibly in males, and CMV and possibly HSV-1 in females were associated with elevated risk for SUD. Therefore, childhood neurotropic infections may influence cognitive development and risk for behavior disorders such as SUD. The results may point to new avenues for alleviating cognitive impairment and SUD risk.

Risk and resistance perspectives in translation-oriented etiology research.

Risk for a disorder and the mechanisms that determine its elevation, risk factors, are the focus of medical research. Targeting risk factors should serve the goal of prevention and treatment intervention. Risk, however, is but one of the aspects of liability to a disorder, a latent trait that encompasses effects of all factors leading to or from the diagnostic threshold. The coequal but opposite aspect of liability is resistance to a disorder. The factors that increase resistance and thus enable prevention or recovery may differ from those that elevate risk. Accordingly, there are nontrivial differences between research perspectives that focus on risk and on resistance. This article shows how this distinction translates into goals and methods of research and practice, from the choice of potential mechanisms tested to the results sought in intervention. The resistance concept also differs from those of "resilience" and "protective factors," subsuming but not limited to them. The implications of the concept are discussed using substance use disorder as an example and substantiate the need for biomedical research and its translation to shift to the resistance perspective.

Common liability to addiction and "gateway hypothesis": theoretical, empirical and evolutionary perspective.

BACKGROUND: Two competing concepts address the development of involvement with psychoactive substances: the "gateway hypothesis" (GH) and common liability to addiction (CLA). METHOD: The literature on theoretical foundations and empirical findings related to both concepts is reviewed. RESULTS: The data suggest that drug use initiation sequencing, the core GH element, is variable and opportunistic rather than uniform and developmentally deterministic. The association between risks for use of different substances, if any, can be more readily explained by common underpinnings than by specific staging. In contrast, the CLA concept is grounded in genetic theory and supported by data identifying common sources of variation in the risk for specific addictions. This commonality has identifiable neurobiological substrate and plausible evolutionary explanations. CONCLUSIONS: Whereas the "gateway" hypothesis does not specify mechanistic connections between "stages", and does not extend to the risks for addictions, the concept of common liability to addictions incorporates sequencing of drug use initiation as well as extends to related addictions and their severity, provides a parsimonious explanation of substance use and addiction co-occurrence, and establishes a theoretical and empirical foundation to research in etiology, quantitative risk and severity measurement, as well as targeted non-drug-specific prevention and early intervention.

The AVPR1A gene and substance use disorders: association, replication, and functional evidence.

BACKGROUND: The liability to addiction has been shown to be highly genetically correlated across drug classes, suggesting nondrug-specific mechanisms. METHODS: In 757 subjects, we performed association analysis between 1536 single nucleotide polymorphisms (SNPs) in 106 candidate genes and a drug use disorder diagnosis (DUD). RESULTS: Associations (p ≤ .0008) were detected with three SNPs in the arginine vasopressin 1A receptor gene, AVPR1A, with a gene-wise p value of 3 × 10(-5). Bioinformatic evidence points to a role for rs11174811 (microRNA binding site disruption) in AVPR1A function. Based on literature implicating AVPR1A in social bonding, we tested spousal satisfaction as a mediator of the association of rs11174811 with the DUD. Spousal satisfaction was significantly associated with DUD in males (p < .0001). The functional AVPR1A SNP, rs11174811, was associated with spousal satisfaction in males (p = .007). Spousal satisfaction was a significant mediator of the relationship between rs11174811 and DUD. We also present replication of the association in males between rs11174811 and substance use in one clinically ascertained (n = 1399) and one epidemiologic sample (n = 2231). The direction of the association is consistent across the clinically-ascertained samples but reversed in the epidemiologic sample. Lastly, we found a significant impact of rs11174811 genotype on AVPR1A expression in a postmortem brain sample. CONCLUSIONS: The findings of this study call for expansion of research into the role of the arginine vasopressin and other neuropeptide system variation in DUD liability.

Measurement of the risk for substance use disorders: phenotypic and genetic analysis of an index of common liability.

The inability to quantify the risk for disorders, such as substance use disorders (SUD), hinders etiology research and development of targeted intervention. Based on the concept of common transmissible liability to SUD related to illicit drugs, a method enabling quantification of this latent trait has been developed, utilizing high-risk design and item response theory. This study examined properties of a SUD transmissible liability index (TLI) derived using this method. Sons of males with or without SUD were studied longitudinally from preadolescence to young adulthood. The properties of TLI, including its psychometric characteristics, longitudinal risk assessment and ethnic variation, were examined. A pilot twin study was conducted to analyze the composition of TLI's phenotypic variance. The data suggest that TLI has concurrent, incremental, predictive and discriminant validity, as well as ethnic differences. The data suggest a high heritability of the index in males. The results suggest applicability of the method for genetic and other etiology-related research, and for evaluation of individual risk.

Dopamine receptors in human lymphocytes: radioligand binding and quantitative RT-PCR assays.

Analysis of dopamine receptors (DR) in lymphocytes of the human peripheral blood mononuclear cell (PBMC) fraction is an attractive tool for evaluation of functional properties of dopaminergic function underlying variation in complex psychological/psychopathological traits. Receptor binding assays (RBAs) with selective radioligands, which are widely used in CNS studies, have not produced consistent results when applied to isolated PBMC. We tested the assay conditions that could be essential for detection of DR in human PBMC and their membrane preparations. Using [(3)H]SCH23390, a dopamine D1-like receptor antagonist, we demonstrated the presence of two binding sites in PBMC-derived membrane fraction. One of them is characterized by the K(d) value consistent with that reported for D5 dopamine receptors in human lymphocytes, whereas the other K(d) value possibly corresponds to serotonin receptor(s). Although D5 receptor binding sites in PBMC membranes could be characterized by binding assays, the low protein expression and the large volume of blood needed for membrane preparation render the binding method impracticable for individual phenotyping. In contrast, real-time RT-PCR may be used for this purpose, contingent on the relationship between DR expression in the brain and in lymphocytes. The expression of the DRD2-DRD5 genes, as detected by this method, varied widely among samples, whereas the DRD1 expression was not detected. The expression levels were comparable with those in the brain for DRD3 and DRD4, and were significantly lower for DRD2 and DRD5.

Physical maturation, peer environment, and the ontogenesis of substance use disorders.

The risk for substance use disorders (SUD) is transmissible between generations via both genetic and environmental mechanisms. One path that is hypothesized to mediate this transmission and include both types of mechanisms is through faster physiological maturation, leading to suboptimal self-regulation, affiliation with deviant peers, and higher risk for conduct disorder (CD). Extending prior research, this hypothesis was tested in a longitudinal study. A sample of 478 males whose fathers were affected with SUD or psychiatrically normal was assessed prospectively at ages from 9-13 to 17-20. The DSM-III-R diagnoses were obtained using standard methodology. Blood testosterone was assayed by radioimmunoassay, and Tanner staging was used to evaluate sexual maturation. Peer deviance was evaluated by the Peer Delinquency Scale. Correlation and path analysis, Cox proportional hazard regression, and growth curve modeling were used to determine the relationships between the variables. The data support the hypothesis that parental SUD liability influences the rate of physiological maturation in offspring, which in turn is related to affiliation with deviant peers and an elevated rate of the development of CD and SUD.

Social dominance mediates the association of testosterone and neurobehavioral disinhibition with risk for substance use disorder.

This investigation determined the influence of testosterone and neurobehavioral disinhibition (ND) on risk for substance use disorder (SUD). Testosterone level during puberty was hypothesized to promote social dominance associated with norm-violating behavior that, in turn, predisposes individuals to use of illicit drugs and, subsequently, SUD. Using a prospective paradigm, the authors recruited 179 boys (mean age=11.62 years, SD=0.88) and followed up when participants were ages 12-14, 16, 19, and 22. Results indicated that social dominance/norm-violating behavior (SD/NVB) at age 16 mediated the association between testosterone level (ages 12-14) and SUD (age 22). In addition, SD/NVB mediated the association between ND and SUD. These findings suggest that development of SUD is influenced by androgen-dependent and neurobehavioral processes via a social motivational style characterized by SD/NVB.

The MAOA promoter polymorphism, disruptive behavior disorders, and early onset substance use disorder: gene-environment interaction.

OBJECTIVES: Conduct, oppositional defiant, and attention deficit hyperactivity disorders, reflecting early antisociality and behavior dysregulation, are predictive of substance use disorders. Liabilities to these disorders share genetic and environmental variance. Parenting characteristics have been shown to influence development of antisociality, moderated by variation at the MAOA gene, which has also been associated with the risk for substance use disorders. To extend these findings, we tested the relationships between the MAOA promoter polymorphism (variable number tandem repeat), indices of child's perception of paternal and maternal parenting, and disruptive behavior disorders and substance use disorders. METHODS: A sample of 148 European-American males was assessed prospectively at ages from 10-12 to 18-19 years and genotyped for the monoamine oxidase A variable number tandem repeat. The Diagnostic and statistical manual of mental disorder-III-R diagnoses were obtained using standard methodology. Parenting was assessed using a scale summarizing the child's evaluation of the parenting style (parent's behavior toward him, parental emotional distance and involvement). Correlation, logistic regression, and Cox proportional hazard regression analysis was used to determine the relationships between the variables. RESULTS: The strength of association between parenting index and conduct and attention deficit hyperactivity disorders depended on the MAOA genotype. Unlike earlier findings, the parenting-risk relationships were observed in the 'high-' rather than 'low-activity' genotypes. The strength and direction of relationships depended on the parental sex. The MAOA polymorphism's association with the risk for substance use disorders was detected when parenting was controlled for. CONCLUSIONS: The results are consistent with the contribution of the MAOA gene, parenting style and their interactions to variation in the risk for early onset behavior disorders and liability to substance use disorders.

Haplotypes of the monoamine oxidase genes and the risk for substance use disorders.

Monoamine oxidase A (MAOA) locus is an attractive candidate for exploring genetic contribution to the variation in the risk for substance use disorders (SUD) because of its important role in the metabolism of neurotransmitters, including dopamine and serotonin. Prior findings have suggested an association of the MAOA gene with the risk for early onset SUD. To extend this research, we genotyped four MAOA markers (two VNTR polymorphisms and two SNPs) and built a cladogram reflecting the evolutionary history of MAOA haplotypes [Nguyen et al., under review]. The cladogram served as the framework for nested ANOVA and logit analyses of association between MAOA and indices of liability to SUD (diagnosis, age of onset, and a dimensional index of substance use related problems) in a sample of adult males of European ancestry. Whereas no association was found for the categorical diagnosis, a significant relationship was detected between the dimensional liability indices and MAOA haplotypes. Overall, our results, albeit not definitive, are consistent with the hypothesis that variants in MAOA account for a small portion of the variance of SUD risk, possibly mediated by liability to early onset behavioral problems.

Liability to substance use disorders: 2. A measurement approach.

Liabilities to complex disorders, discussed in the accompanying paper, present difficulties in measurement related to the arbitrariness of diagnostic threshold definitions and problems with discrimination between trait values, especially within the 'normal' individuals. The inability to quantitatively estimate the risk for a disorder, such as substance use disorders (SUD), is an obstacle for studying etiological (e.g. genetic) mechanisms and developing efficient prevention and treatment measures. Based on the concept of common liability to SUD, this paper delineates an application of the longitudinal family/high-risk design and item response theory to the development of a continuous index of liability. The method has been tested in both simulation study and empirical data. The approach described affords the opportunity to quantitatively estimate the risk for SUD at an early age and before any drug exposure. This method is also applicable to measuring liabilities to other complex disorders, especially those with relatively late onset.

Liability to substance use disorders: 1. Common mechanisms and manifestations.

Variation in the risk for and severity of substance use disorders (SUD) in the population is caused by multiple organismic (genetic, biochemical, psychological) and environmental factors. Whereas drug- or drug-class-specific liability mechanisms exist, a substantial proportion of variance in the risk is shared between specific liabilities, reflecting mechanisms that determine common liability to SUD. Data from epidemiologic, clinical, psychological, physiological, biochemical, and family and genetic studies reviewed in this paper indicate the existence of mechanisms and characteristics shared in common by liabilities to SUD related to different drugs. These mechanisms can be conceptualized as common liability to SUD, a latent trait accounting for a substantial portion of variation in SUD risk and severity and determined by all factors influencing the probability of SUD development. An accompanying paper describes an approach to the quantitative estimation of this trait.

Salivary cortisol, personality, and aggressive behavior in adolescent boys: a 5-year longitudinal study.

OBJECTIVE: The present investigation tested the hypothesis that low resting salivary cortisol concentration in preadolescent boys would be associated with aggressive behavior later in adolescence. Second, it tested whether personality traits would mediate this relation. METHOD: Resting salivary cortisol concentrations from 314 boys (10-12 years of age) were assayed. When the boys reached 15 to 17 years of age these concentrations were analyzed in the context of personality traits, measured with the Multidimensional Personality Questionnaire, and aggressive behavior, measured with the Youth Self-Report inventory. RESULTS: Low cortisol in preadolescence was associated with low harm avoidance, low self-control, and more aggressive behavior 5 years later, during middle adolescence. Cortisol was not related to negative emotionality or any of its factors (including trait aggression). Low self-control was identified as the primary personality mediator of the relation between low cortisol and later aggressive behavior. CONCLUSIONS: In adolescent boys, low resting cortisol concentrations appear predictive of clinically important personality factors. Increased aggressive behavior in adolescents with low resting cortisol may be more strongly associated with lack of self-control than with a specifically "aggressive personality."