Galina P. Kirillova

Origins and consequences of child neglect in substance abuse families.

The empirical literature pertaining to the prevalence, origins, and consequences of neglectful parenting as it relates to substance abuse is critically reviewed. Available evidence indicates that children who experience parental neglect, with or without parental alcohol or drug abuse, are at high risk for substance use disorder (SUD). The effects of parental substance abuse on substance abuse outcome of their children appear to be partly mediated by their neglectful parenting. The discussion concludes with presentation of a developmental multifactorial model in which neglect, in conjunction with other individual and environmental factors, can be integratively investigated to quantify the childs overall liability across successive stages of development as well as to map the trajectory toward good and poor outcomes.

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 responses in prepubertal boys: the effects of parental substance abuse and association with drug use behavior during adolescence

BACKGROUND The purpose of this investigation was three-fold. First, we extended our original observation of decreased cortisol reactivity to an anticipated stressor in sons of fathers with a substance use disorder (SUD). Second, we examined the hypothesis that salivary cortisol underresponsivity in these high-risk prepubertal boys is an adaptation to the stress associated with having a father with a current, rather than remitted, SUD. Third, we tested the hypothesis that prepubertal cortisol underreactivity might be associated with subsequent drug use behavior during adolescence. METHODS Preadolescent salivary cortisol responses were examined in the context of risk-group status, paternal substance abuse offsets, and subsequent adolescent drug use behavior. RESULTS The results confirmed a decreased salivary cortisol response to an anticipated stressor among sons of SUD fathers in our expanded sample. In addition, sons of fathers with a current SUD and boys whose fathers had a SUD offset from their 3rd to 6th birthdays had lower anticipatory stress cortisol levels compared with sons of control fathers. Finally, lower preadolescent anticipatory cortisol responses were associated with regular monthly cigarette smoking and regular monthly marijuana use during adolescence. CONCLUSIONS Hyporeactivity as an adaptation to chronic stress may be salient to the intergenerational transmission of substance abuse 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.

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 childs 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 childs evaluation of the parenting style (parents 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 polymorphisms 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.

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.

Antisociality, substance dependence, and the DRD5 gene : A preliminary study

A pilot population-based study of a microsatellite polymorphism at the DRD5 locus in adult European-Americans showed its association with childhood symptom counts for oppositional defiant disorder (ODD) in males and females and adult antisocial personality disorder (ASPD) in females. No association with childhood conduct disorder symptom count was observed. ODD mediated the genotype-ASPD relationship in females. Neither ODD nor ASPD significantly mediated the relationship between the genotype and the liability to substance dependence (SD). The data suggest involvement of the DRD5 locus in the variation and sexual dimorphism of SD liability and antisociality and in the developmental continuity of antisociality.

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.

Testosterone Levels and Sexual Maturation Predict Substance Use Disorders in Adolescent Boys: A Prospective Study

BACKGROUND This investigation determined whether testosterone level and sexual maturation in boys biased development of socially nonnormative behavior culminating in a substance use disorder (SUD). METHODS The subjects were 179 boys recruited in late childhood through a high-risk paradigm. Path analysis was used to evaluate the influence of testosterone level and sexual maturation in early adolescence (age 12-14) on attitudes toward antisociality, affiliation with deviant peers, and social potency in middle adolescence (age 16), illicit drug use by late adolescence (age 19), and SUD in young adulthood (age 22). RESULTS Testosterone level predicted social potency and approval of aggressive/antisocial behavior. Sexual maturation mediated the relation between testosterone level in early adolescence and later affiliation with deviant peers. Social potency, approval of aggressive/antisocial behavior, and deviant peer affiliations predicted illicit drug use by late adolescence that in turn predicted SUD in young adulthood. CONCLUSIONS This study demonstrated that pubertal processes in early adolescence influence the risk for SUD via effects on psychosocial functioning.

Prospective Study of the Association Between Abandoned Dwellings and Testosterone Level on the Development of Behaviors Leading to Cannabis Use Disorder in Boys

BACKGROUND The role of testosterone in the development of behaviors presaging cannabis use and subsequently cannabis use disorder was investigated in a prospective study of 208 boys. It was theorized that adverse neighborhood correlates with testosterone level that in turn potentiates behaviors predisposing to cannabis consumption and subsequently diagnosis of cannabis use disorder. METHODS Proportion of boarded-up dwellings in the 1990 census tract and testosterone level were recorded at baseline (ages 10-12), followed by assessments of assaultiveness and testosterone level (ages 12-14), social dominance/norm-violating behavior (SDNVB) (age 16), cannabis use (age 19), and cannabis use disorder (age 22). RESULTS Percent of vacant dwellings correlates with testosterone level that in turn predicts assaultive behavior sequentially leading to SDNVB, cannabis use, and cannabis use disorder. Externalizing behaviors and cannabis use disorder are not directly predicted by neighborhood quality. CONCLUSIONS Elevated testosterone level intermediates the association between neighborhood adversity and aggressive socially deviant behaviors presaging cannabis use and cannabis use disorder.