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Neuroimaging demonstrates that athletes of collision sports can suffer significant changes to their brain in the absence of concussion, attributable to head acceleration event (HAE) exposure. In a ...

The dopamine transporter gene,SLC6A3, has received substantial attention in genetic association studies of various phenotypes. Although some variable number tandem repeats (VNTRs) present inSLC6A3have been tested in genetic association studies, results have not been consistent. VNTRs inSLC6A3that have not been examined genetically were characterized. Tandem Repeat Annotation Library (TRAL) was used to characterize the VNTRs of 64 unrelated long-read haplotype-phasedSLC6A3sequences. Sequence similarity of each repeat unit of the five VNTRs is reported, along with the correlations of SNP-SNP, SNP-VNTR and VNTR-VNTR alleles across the gene. One of these VNTRs is a novel hyper-VNTR (hyVNTR) in intron 8 ofSLC6A3, which contains a range of 3.4-133.4 repeat copies and has a consensus sequence length of 38bp, with 82% G+C content. The 38-base repeat was predicted to form G-quadruplexesin silicoand was confirmed by circular dichroism spectroscopy. Additionally, this hyVNTR contains multiple putative binding sites for PRDM9, which, in combination with low levels of linkage disequilibrium around the hyVNTR, suggests it might be a recombination hotspot.Summary BlurbThis VNTR has a heterozygosity value of 0.93, forms G-tetrads, and is in low linkage disequilibrium with surrounding sequence, making it a new site for genetic analysis.

The most extensively studied influence on adolescent conduct problem behaviors is peers, and the literature points to genetics as one source of individual differences in peer influence. The purpose of this study was to test the hypothesis that an environmental sensitivity genetic index comprised of DRD4, 5-HTTLPR, and GABRA2 variation would moderate the association between peer and adolescent conduct problems. Latent growth modeling was applied to PROSPER project longitudinal data from adolescents and their peers. Results showed the hypothesis was supported; adolescents with more copies of putative sensitivity alleles were more strongly influenced by their peers. The interaction form was consistent with differential susceptibility in follow-up analyses. Strengths and weaknesses of genetic aggregates for sensitivity research are discussed.

The dopamine transporter gene,SLC6A3, has received substantial attention in genetic association studies of various phenotypes. Although some variable number tandem repeats (VNTRs) present inSLC6A3have been tested in genetic association studies, results have not been consistent. VNTRs inSLC6A3that have not been examined genetically were characterized. The Tandem Repeat Annotation Library was used to characterize the VNTRs of 64 unrelated long-read haplotype-phasedSLC6A3sequences. Sequence similarity of each repeat unit of the five VNTRs is reported, along with the correlations of SNP–SNP, SNP–VNTR, and VNTR–VNTR alleles across the gene. One of these VNTRs is a novel hyper-VNTR (hyVNTR) in intron 8 ofSLC6A3, which contains a range of 3.4–133.4 repeat copies and has a consensus sequence length of 38 bp, with 82% G+C content. The 38-base repeat was predicted to form G-quadruplexes in silico and was confirmed by circular dichroism spectroscopy. In addition, this hyVNTR contains multiple putative binding sites for PRDM9, which, in combination with low levels of linkage disequilibrium around the hyVNTR, suggests it might be a recombination hotspot.

This candidate gene study evaluated the relationship of a past history of concussion with single nucleotide polymorphisms (SNPs) in nine genes in a small cohort (N = 87) of a nationally ranked Division I football team. Genes and SNPs studied were selected based on their published connection to brain injury and brain development, as well as impulsivity. We used multinomial logistic regression analysis (MLRA) to quantify how well genotype predicted the number of previously diagnosed concussions (three categories: none, one, two or more), while covarying race and number of years participating in football. The rs4504469 SNP for KIAA0319 was the only locus that significantly predicted number of previously diagnosed concussions (p = 0.005, meeting Bonferroni correction for multiple comparisons). The KIAA0319 results raise the hypothesis that having the CT or TT genotype of KIAA0319 may be predictive of a lower incidence of previously diagnosed concussion. This finding raises a number of hypotheses for future pre-clinical research, particularly whether alterations in neural organization related to KIAA0319 rs4504469 lead to reduced susceptibility for lasting head trauma, or greater resilience in the face of repeated subconcussive injury.

Neuroimaging demonstrates that athletes of collision sports can suffer significant changes to their brain in the absence of concussion, attributable to head acceleration event (HAE) exposure. In a sample of 24 male Division I collegiate football players, we examine the relationships between tryptophan hydroxylase 2 (

Previous research has identified the importance of romantic partners—including spouses, significant others, and dating partners—for influencing the engagement in health-risking behaviors, such as alcohol misuse during emerging adulthood. Although genetic factors are known to play a role in the development of young adult alcohol misuse, little research has examined whether genetic factors affect young adults’ susceptibility to their romantic partners’ alcohol misusing behaviors. The current study tests whether a single nucleotide polymorphism in the GABRA2 gene (rs279845) moderates the relationship between romantic partner alcohol misuse and frequency of drunkenness in young adulthood. Results revealed differential risk associated with romantic partner alcohol misuse and young adult drunk behavior according to GABRA2 genotype, such that individuals with the TT genotype displayed an elevated risk for frequency of drunkenness when romantic partner alcohol misuse was also high (incidence rate ratio = 1.06, p ⩽ .05). The findings demonstrate the potential for genetic factors to moderate the influence of romantic partners’ alcohol misuse on drunk behavior during the transition to young adulthood.

Data from the in-school sample of the PROSPER preventive intervention dissemination trial were used to investigate associations between alcohol dehydrogenase genes and alcohol use across adolescence, and whether substance misuse interventions in the 6th and 7th grades (targeting parenting, family functioning, social norms, youth decision making, and peer group affiliations) modified associations between these genes and adolescent use. Primary analyses were run on a sample of 1,885 individuals and included three steps. First, we estimated unconditional growth curve models with separate slopes for alcohol use from 6th to 9th grade and from 9th to 12th grade, as well as the intercept at Grade 9. Second, we used intervention condition and three alcohol dehydrogenase genes, 1B (ADH1B), 1C (ADH1C), and 4 (ADH4) to predict variance in slopes and intercept. Third, we examined whether genetic influences on model slopes and intercepts were moderated by intervention condition. The results indicated that the increase in alcohol use was greater in early adolescence than in middle adolescence; two of the genes, ADH1B and ADH1C, significantly predicted early adolescent slope and Grade 9 intercept, and associations between ADH1C and both early adolescent slope and intercept were significantly different across control and intervention conditions.

Previous research has identified the importance of romantic partners—including spouses, significant others, and dating partners—for influencing the engagement in health-risking behaviors, such as alcohol misuse during emerging adulthood. Although genetic factors are known to play a role in the development of young adult alcohol misuse, little research has examined whether genetic factors affect young adults’ susceptibility to their romantic partners’ alcohol misusing behaviors. The current study tests whether a single nucleotide polymorphism in the GABRA2 gene (rs279845) moderates the relationship between romantic partner alcohol misuse and frequency of drunkenness in young adulthood. Results revealed differential risk associated with romantic partner alcohol misuse and young adult drunk behavior according to GABRA2 genotype, such that individuals with the TT genotype displayed an elevated risk for frequency of drunkenness when romantic partner alcohol misuse was also high (IRR = 1.06, p ≤ 0.05). The findings demonstrate the potential for genetic factors to moderate the influence of romantic partners’ alcohol misuse on drunk behavior during the transition to young adulthood.

Preventive intervention effects on adolescent alcohol misuse may differ based on genotypes in gene-by-intervention (G x I) interactions, and these G x I interactions may vary as a function of age. The current study uses a novel statistical method, time-varying effect modeling (TVEM), to test an age-varying interaction between a single nucleotide polymorphism in the GABRA2 gene (rs279845) and a preventive intervention in predicting alcohol misuse in a longitudinal study of adolescents (ages 11-20). The preventive intervention was PROSPER, a community-based system for delivery of family and school programs selected from a menu of evidence-based interventions. TVEM results revealed a significant age-varying GABRA2 x intervention interaction from ages 12 to 18, with the peak effect size seen around age 13 (IRR = 0.50). The intervention significantly reduced alcohol misuse for adolescents with the GABRA2 TT genotype from ages 12.5 to 17 but did not reduce alcohol use for adolescents with the GABRA2 A allele at any age. Differences in intervention effects by GABRA2 genotype were most pronounced from ages 13 to 16-a period when drinking is associated with increased risk for alcohol use disorder. Our findings provide additional evidence that intervention effects on adolescent alcohol misuse may differ by genotype, and provide novel evidence that the interaction between GABRA2 and intervention effects on alcohol use may vary with age. Implications for interventions targeting adolescent alcohol misuse are discussed.

This study addresses replication in candidate gene × environment interaction (cG×E) research by investigating if the key findings from Brody, Beach, Philibert, Chen, and Murry (2009) can be detected using data (N = 1,809) from the PROSPER substance use preventive intervention delivery system. Parallel to Brody et al., this study tested the hypotheses that substance misuse initiation would increase faster from age 11 to age 14 and be higher at age 14 among: (a) 5-HTTLPR short carrier adolescents versus long homozygotes, (b) control versus intervention adolescents, and (c) 5-HTTLPR short carriers in the control condition versus all other participants. The hypotheses were generally supported and results were consistent with Brody et al.'s cG×I finding. Results are discussed in light of replication issues in cG×E research and implications for intervention.

Objective To determine (1) whether delirium severity was associated with Apolipoprotein E (APOE) genotype status and occupational complexity, a measure of cognitive reserve, in individuals with delirium superimposed on dementia; and (2) whether decline in delirium severity was associated with these same factors over a post-acute care (PAC) stay. Methods Control group data (n = 142) from a completed randomized clinical trial were used to address the aims of the study. Delirium severity was calculated by combining items from the Confusion Assessment Method and the Montreal Cognitive Assessment. APOE e4 carriers versus non-carriers were considered. Occupational complexity, a measure of cognitive reserve, was derived from the Lifetime of Experiences Questionnaire. Covariates examined included age, gender, education, Clinical Dementia Rating Scale, and the Charlson comorbidity score. Data were nested (i.e., days nested within persons) and analyzed using multilevel models. Results The presence of an APOE e4 allele and higher Clinical Dementia Rating Scale were associated with greater delirium severity at baseline. The presence of an APOE e4 allele was also associated with greater delirium severity averaged across the PAC stay. Occupational complexity was not associated with baseline delirium severity or average daily delirium severity; however, individuals with low occupational complexity showed a significant decreased in delirium severity during the course of their PAC stay. Conclusions Individual differences, including genetic factors and level of cognitive reserve, contribute to the severity of delirium in older adults with dementia. Copyright © 2016 John Wiley & Sons, Ltd.

In the past 20 years, technological advances in genetics have made it relatively easy to add molecular genetic data collection to conventional datasets. This ease creates valuable opportunities for behavioral scientists to consider how genetic factors might influence individuals’ sensitivity to environmental experiences, including those that put individuals at developmental risk. Successfully incorporating molecular genetic approaches into conventional behavioral science designs is not without challenges. To help behavioral scientists understand and address these challenges, this chapter reviews critical issues involved in the data collection and analyses of molecular genetic data in a GxE context. More specifically, this chapter provides a brief summary of basic principles of molecular genetics, an overview of how to check the quality of genetic data prior to analysis, a brief review of the history of candidate gene-by-environment (cGxE) research and its associated criticisms, a framework for evaluating the quality of individual cGxE studies, and an explanation of current approaches used to combine multiple genetic variants to advance GxE research. We aim to provide information that will function as a starting point for behavioral scientists considering adding GxE approaches to their own research area.

Better integrating human developmental factors in genomic research is part of a set of next steps for testing gene-by-environment interaction hypotheses. This study adds to this work by extending prior research using time-varying effect modeling (TVEM) to evaluate the longitudinal associations between the PROSPER preventive intervention delivery system, a GABRA2 haplotype linked to alcohol use, and their interaction on adolescent delinquency. Logistic and Poisson analyses on eight waves of data spanning ages 11 to 19 (60% female, 90% Caucasian) showed the intervention reduced delinquency from ages 13 to 16. Moreover, interaction analysis revealed that the effect of the multicomponent intervention was significantly greater for T-allele carriers of the GABRA2 SNP rs279845, but only during the 13 to 16 age period. The results are discussed in terms of adolescent delinquency normativeness, implications for preventive intervention research, and the utility of incorporating development in GxE research.

INTRODUCTION Prevention intervention programs reduce substance use, including smoking, but not all individuals respond. We tested whether response to a substance use prevention/intervention program varies based upon a set of five markers (rs16969968, rs1948, rs578776, rs588765, and rs684513) within the cluster of nicotinic acetylcholine receptor subunit genes (CHRNA5/A3/B4). METHODS Participants (N = 424) were randomly assigned to either control condition, or a family-based intervention in grade 6 and a school-based drug preventive intervention in grade 7. Smoking in the past month was assessed in grades 9-12 using a four-point scale (0 = never smoked, 1 = smoked but not in last month, 2 = one or a few times, 3 = about once a week or more). RESULTS There was a main effect of both the intervention (b = -0.24, P < .05) and genotype at rs16969968 (b = 0.14, P < .05) on high school smoking. Using dummy coding to allow for nonlinear effects, individuals with the A/A genotype smoked more often than those with G/G (b = 0.33, P < .05). A genotype × intervention effect was found with reduced smoking among those with A/A and G/A genotypes to levels similar to those with the G/G genotype (G/G vs. A/A: b = -0.67, P < .05; A/G vs. A/A: b = -0.61, P < .05; G/G vs. A/G ns). Results were nonsignificant for the other four markers. CONCLUSIONS Preventive interventions can reduce the genetic risk for smoking from rs16969968.

An extensive record of research documents that interparental conflict markedly disrupts child and adolescent development (Buehler et al., 1997; Cummings & Davies, 1994; Emery, 1982). Recent research on risk mechanisms has provided important insight and revealed meaningful heterogeneity regarding child and adolescent adjustment problems associated with interparental conflict (e.g., Davies & Cummings, 1994; Davies & Sturge-Apple, 2007; Fosco, DeBoard, & Grych, 2007; Grych & Fincham, 1990; Grych, Jouriles, Swank, McDonald, & Norwood, 2000). Germane to this work is an emergent developmental theory that has shown much promise for explicating for whom parenting and parenting processes affect children. In the general sense, differential susceptibility theory (DST; Belsky & Pluess, 2009; Boyce & Ellis, 2005; Ellis, Boyce, Belsky, Bakermans-Kranenburg, & van IJzendoorn, 2011) posits heterogeneity in environmental sensitivity based on intrapersonal characteristics. More specifically, the perspective contends that child characteristics related to increased risk for maladjustment when exposed to harsh, unsupportive environments can also lead to exceptional positive adjustment when exposed to more supportive circumstances. Developed to complement DST, the vantage sensitivity perspective (Pluess & Belsky, 2013) emphasizes that some intrapersonal characteristics dispose greater sensitivity to specifically positive aspects of the environment relative to negative. These perspectives, as well as others (e.g., Davies, Martin, & Cicchetti, 2012), emphasize the importance of considering both positive and negative aspects of interparental relationships to understand their unique implications for adolescent maladjustment. In the current study, we applied DST and its vantage sensitivity complement to prevailing perspectives on interparental conflict that place adolescent evaluations as the key link between parental acrimony and adolescent maladjustment (Davies & Cummings, 1994; Grych & Fincham, 1990). Specifically, we examined whether variation in the dopamine receptor D4 (DRD4) gene is related to variation in sensitivity to both negative (conflict) as well as positive (positivity) dimensions of interparental relations. Below, we provide an overview of the research that links interparental conflict, adolescent evaluations, and adjustment. We then describe the implications of DST for this research.

We are grateful to the Journal of Marriage and Family for this forum in which to discuss important issues in candidate Gene× Environment (cGxE) family research and to Drs. Salvatore and Dick (2015) for sharing their expertise and their thoughtful and balanced commentary on our article (Schlomer, Fosco, Cleveland, Vandenbergh, & Feinberg, 2015). We found many points of agreement in their commentary and believe that differences in our views are a matter of degree and emphasis rather than contrast.We agree with Salvatore and Dick that a major challenge in cGxE research is "which gene." We differ, however, with the suggestion that considering the "usual suspects" is necessarily problematic. Although this strategy should not be exclusively pursued, there is now a decades-old literature on these usual-suspect markers (e.g., SLC6A4, DRD4, MAOA, CHRNA5), including genomic function, neurological/hormonal correlates, endophenotypes, psychological/behavioral outcomes, and environmental moderation. It is because these markers have been well characterized, at multiple analytic levels, that they have been incorporated into family/developmental research. Given adequate sophistication and care (see Cleveland et al., in press), research with these genes can provide valuable insights into gene-environment interplay.Salvatore and Dick note that genome-wide association studies (GWAS) have shown inconsistent associations with psychiatric phenotypes and suggest we should be no better at "guessing" sensitivity genes. Our own skepticism (Schlomer et al., 2014) has been somewhat abated, however, by the growing number of studies that have found cGxE patterns consistent with plasticity theories (i.e., differential susceptibility theory, diathesis-stress, vantage sensitivity), including compelling evidence from experimental studies (e.g., van IJzendoorn & Bakermans-Kranenburg, in press) and prevention/intervention studies that use random assignment (e.g., Brody Beach, Philibert, Chen, & Murry, 2009). Two additional experimental studies of DRD4 and alcohol use (Creswell et al., 2012; Larsen et al., 2010) have made a particularly strong case that some genes deserve the status of a usual suspect.GWAS and cGxE approaches have unique strengths, and neither should be dismissed on the basis of their limitations. GWAS analyses are greatly important for discovering gene-phenotype links. However, the inconsistency noted by Salvatore and Dick may be the result of the search for population-level main effects. Because they require large samples, GWAS findings likely reflect a gene's average effect over the wide range of environments from which the samples were drawn. However, if a genetic effect is larger in one environment and smaller in others, the overall main effect may be small and thus difficult to detect statistically. The solution to this problem has been to increase power through sample size. Interaction-based work underscores a reality that in many cases (based on the shape of the interaction and the distribution of the environments sampled) a null main effect may hide an interaction, as exemplified in our findings (Schlomer et al., 2015). Thus, in conventional GWAS a null main effect overlooks the possibility that an allelic association may be environmentally contingent. The remedy for inconsistent GWAS findings may include more than increasing sample size, such as considering conditional associations (i.e., moderation).MOVING FORWARD IN CGXE RESEARCHOur view of the future of cGxE research is optimistic, tempered by the need for careful and critical evaluation of this work. To assist in this process, we emphasize five domains in which cGxE research should be evaluated: Design, Measurement, Theory, Biological Role, and Population Structure.DesignThere are substantial benefits of applying randomized designs to cGxE research. In epidemiological studies, causality is difficult to determine because experience-outcome associations may equally reflect causal environmental influences or self-selection into those environmental experiences. …

Data drawn from the in-home subsample of the PROSPER intervention dissemination trial were used to investigate the moderation of intervention effects on underage alcohol use by maternal involvement and candidate genes. The primary gene examined was dopamine receptor D4 (DRD4). Variation in this gene and maternal involvement were hypothesized to moderate the influence of intervention status on alcohol use. The PROSPER data used were drawn from 28 communities randomly assigned to intervention or comparison conditions. Participating youth were assessed in five in-home interviews from sixth to ninth grades. A main effect of sixth-grade pretest maternal involvement on ninth-grade alcohol use was found. Neither intervention status nor DRD4 variation was unconditionally linked to ninth-grade drinking. However, moderation analyses revealed a significant three-way interaction among DRD4 status, maternal involvement, and intervention condition. Follow-up analyses revealed that prevention reduced drinking risk, but only for youth with at least one DRD4 seven-repeat allele who reported average or greater pretest levels of maternal involvement. To determine if this conditional pattern was limited to the DRD4 gene, we repeated analyses using the serotonin transporter linked polymorphic region site near the serotonin transporter gene. The results for this supplemental analysis revealed a significant three-way interaction similar but not identical to that found for DRD4.

This study investigated the oxytocin receptor (OXTR) gene’s moderation of associations between exposure to a substance misuse intervention, average peer substance use, and adolescents’ own alcohol use during the 9th-grade. OXTR genetic risk was measured using five single nucleotide polymorphisms (SNPs), and peer substance use was based on youths’ nominated closest friends’ own reports of alcohol, cigarette, and marijuana use, based on data from the PROSPER project. Regression models revealed several findings. First, low OXTR risk was linked to affiliating with friends who reported less substance use in the intervention condition but not the control condition. Second, affiliating with high substance-using friends predicted youth alcohol risk regardless of OXTR risk or intervention condition. Third, although high OXTR risk youth in the intervention condition who associated with low substance-using friends reported somewhat higher alcohol use than comparable youth in the control group, the absolute level of alcohol use among these youth was still among the lowest in the sample.

Studies of nicotine consumption in rodents often intend to investigate nicotine's post-absorptive effects, yet little is known about the pre-absorptive sensory experience of nicotine drinking, including gustatory, trigeminal, and olfactory influences. We conditioned taste aversion (CTA) to nicotine in males of 3 inbred mouse strains: C57BL/6J, DBA/2J, and 129X1/SvJ by repeatedly pairing 150 μg/ml nicotine drinking with lithium chloride injections. Generalization to a variety of bitter, sour, sweet, salty, and irritant solutions and to nicotine odor was then examined. Nicotine CTA generalized to the bitter stimulus quinine hydrochloride and the chemosensory irritant spilanthol in all strains. It also showed strain specificity, generalizing to hydrogen peroxide (an activator of TRPA1) in C57BL/6J mice and to the olfactory cue of nicotine in DBA/2J mice. These behavioral assays demonstrate that the sensory properties of nicotine are complex and include multiple gustatory, irritant, and olfactory components. How these qualities combine at the level of perception remains to be assessed, but sensory factors clearly exert an important influence on nicotine ingestion and their contribution to net intake of nicotine should not be neglected in animal or human studies.

Trade-offs occur when two traits have opposing fitness effects such that positive selection on one trait is constrained by the negative fitness consequences of the other trait. To understand why trade-off may arise we need to study the genetic and non-genetic factors that influence associated traits because these may respond differently to selective pressure. Research into trade-offs has largely focused on the genetic basis of associated traits, yet both maternal effects and epigenetic effects have recently been shown to affect life history traits that play a role in trade-offs. In this study, we analyze genetic, epigenetic and life-history predictors of one of the most important trade-offs, that between offspring number and offspring mortality. Using a large-scale 3-generational intercross between two divergent mouse lines C57BL/6J and DBA/2J, we show that litter size differences between these lines, although significant, are surprisingly not the most important predictors of mortality. Offspring genotype, maternal effects and their interactions are the most influential factors determining mortality. We found significant paternal effects suggesting an important influence of paternal care or potentially the role of imprinted genes. Perhaps contrary to expectations our results further show that the trade-off between offspring number and mortality is not just a simple function of the two factors yielding, on average, an ‘optimal’ litter size at weaning. Indeed if one focused on litter size and mortality alone, the slope of relationship is the same for the two lines, yet they differ in the number of young at weaning. Our study reveals that a perceived trade-off between two traits is governed by a more complex set of interactions between genetic and non-genetic effects.

Nicotine, the primary psychoactive compound in tobacco, is responsible for the addictive effects of smoking; however, there is a paucity of information indicating whether the presence of other biological chemicals in tobacco alters nicotine's rewarding effects. It has been suggested that the addictive effects of smoking may be due, in part, to the inhibition of the pair of monoamine oxidase enzymes responsible for a significant fraction of monoamine metabolism, Monoamine Oxidase A and B (MAO-A and MAO-B). This paper reviews the current, limited literature examining the role of MAO inhibition on the rewarding effects of nicotine (e.g., self-administration) in rodents. Overall, studies with rats and mice do suggest that MAO plays a role in nicotine reward. However, results are mixed regarding the MAO subtype responsible for the rewarding effects of nicotine, most likely due to methodological variation across the limited number of studies. Important individual difference factors such as age, sex and genetics are discussed, along with relevant brain and neurotransmitter systems. Future research is needed that builds on the available literature to map out the relationship between MAO inhibition and nicotine reward. These data will enhance our understanding of the neuropharmacological effects of smoking and the value of implementing MAO inhibitors as pharmacotherapies for smoking cessation.

Background and aims: Genes associated with longevity have been identified using both single gene and genome-wide approaches in a variety of species. The aim of this study was to identify quantitative trait loci (QTLs) that influence longevity in male and female mice from twenty-three C57BL/6J by DBA/2J (BXD) recombinant inbred (RI) strains. Methods: Approximately 12 animals of each sex for each RI strain were maintained under standard conditions until natural death or moribundity criteria were met. Results: A number of life span-relevant loci previously reported on chromosomes (Chrs) 7,8, 10 and 11 were confirmed. In addition, 5 previously unre-ported QTLs for mouse life span on Chrs 1,2,6,11, and X were identified as significant and 3 QTLs on Chrs 5, 8, and 16 were suggestive. Conclusions: Several QTLs were coincident in males and females although the modest correlation between male and female median lifespans and the identification of sex specific QTLs provide evidence that the genetic architecture underlying longevity in the sexes may differ substantially. The identification of multiple QTLs for longevity will provide valuable resources for both reductionist and integrationist research into mechanisms of life span determination.

A quantitative trait locus (QTL) approach was used to define the genetic architecture underlying variation in systolic blood pressure (SBP) and heart rate (HR), measured indirectly on seven occasions by the tail cuff procedure. The tests were conducted in 395 F2adult mice (197 males, 198 females) derived from a cross of the C57BL/6J (B6) and DBA/2J (D2) strains and in 22 BXD recombinant-inbred (RI) strains. Interval mapping of F2data for the first 5 days of measurement nominated one statistically significant and one suggestive QTL for SBP on chromosomes (Chr) 4 and 14, respectively, and two statistically significant QTL for HR on Chr 1 (which was specific to female mice) and Chr 5. New suggestive QTL emerged for SBP on Chr 3 (female-specific) and 8 and for HR on Chr 11 for measurements recorded several weeks after mice had undergone stressful blood sampling procedures. The two statistically significant HR QTL were confirmed by analyses of BXD RI strain means. Male and female F2mice did not differ in SBP or HR but RI strain analyses showed pronounced strain-by-sex interactions and a negative genetic correlation between the two measures in both sexes. Evidence for a role for mitochondrial DNA was found for both HR and SBP. QTL for HR and SBP may differ in males and females and may be sensitive to different environmental contexts.

Purpose The present study examined the extent of genetic and environmental influences on individual differences in children’s conversational language use. Method Behavioral genetic analyses focused on conversational measures and 2 standardized tests from 380 twins ( M = 7.13 years) during the 2nd year of the Western Reserve Reading Project (S. A. Petrill, K. Deater-Deckard, L. A. Thompson, L. S. DeThorne, & C. Schatschneider, 2006) Multivariate analyses using latent factors were conducted to examine the extent of genetic overlap and specificity between conversational and formalized language. Results Multivariate analyses revealed a heritability of .70 for the conversational language factor and .45 for the formal language factor, with a significant genetic correlation of .37 between the two factors. Specific genetic effects were also significant for the conversational factor. Conclusions The current study indicated that over half of the variance in children’s conversational language skills can be accounted for by genetic effects with no evidence of significant shared environmental influence. This finding casts an alternative lens on past studies that have attributed differences in children’s spontaneous language use to differences in environmental language exposure. In addition, multivariate results generally support the context-dependent construction of language knowledge, as suggested by the theory of activity and situated cognition (J. S. Brown, A. Collins, & P. Duguid, 1989; T. A. Ukrainetz, 1998), but also indicate some degree of overlap between language use in conversational and formalized assessment contexts.

Cigarette smoking, like many addictive behaviors, has a genetic component, and the dopamine D2-like receptor genes (DRD2, DRD3 and DRD4) are candidates for contributing to these behaviors. Phenotypic information concerning smoking-related behaviors from a nationally representative sample of research volunteers was analyzed for association with polymorphisms in these genes. Genotype status at the DRD2 intron 2 simple tandem repeat was related to cigarettes per day (P = 0.035) and heaviness of smoking index (P = 0.049). The presence of the glycine allele at the S9G polymorphism of the DRD3 gene was associated with frequency/quantity measures of smoking [log-transformed time to first cigarette (P = 0.031) and heaviness of smoking index (P = 0.035)]. There was a trend for DRD4 long alleles of the variable number of tandem repeats polymorphism to be associated with reduced severity of three withdrawal symptoms [desire/craving (P = 0.054); anger/irritability (P = 0.10); and trouble sleeping (P = 0.068)]. Interactions between genotypes at all three genes were associated with nervousness (P = 0.020) and trouble sleeping (P = 0.015). An interaction between DRD2 and DRD3 was found for trouble concentrating (P = 0.020). These relationships present possible dopamine-related responses to nicotine that warrant further study.

Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by involuntary motor and phonic tics. The pattern of inheritance and associated genetic abnormality has yet to be fully characterized. A dopaminergic abnormality in this disorder is supported by response to specific therapies, nuclear imaging, and postmortem studies. In this protocol, dopaminergic polymorphisms were examined for associations with TS and attention-deficit hyperactivity disorder (ADHD). Polymorphisms investigated included the dopamine transporter (DAT1 DdeI and DAT1 VNTR), dopamine receptor (D4 Upstream Repeat and D4 VNTR), dopamine converting enzyme (dopamine β-hydroxylase), and the acid phosphatase locus 1 (ACP1) gene. DNA was obtained from 266 TS individuals ± ADHD and 236 controls that were ethnicity-matched. A significant association, using a genotype-based association analysis, was identified for the TS-total and TS-only versus control groups for the DAT1 DdeI polymorphism (AG vs. AA, P = 0.004 and P = 0.01, respectively). Population structure, estimated by the genotyping of 27 informative SNP markers, identified 3 subgroups. A statistical re-evaluation of the DAT1 DdeI polymorphism following population stratification confirmed the association for the TS-total and TS-only groups, but the degree of significance was reduced (P = 0.017 and P = 0.016, respectively). This study has identified a significant association between the presence of TS and a DAT polymorphism. Since abnormalities of the dopamine transporter have been hypothesized in the pathophysiology of TS, it is possible that this could be a functional allele associated with clinical expression. © 2006 Wiley-Liss, Inc.

Although peer pressure can influence adolescents’ alcohol use, individual susceptibility to these pressures varies across individuals. The dopamine receptor D4 gene (DRD4) is a potential candidate gene that may influence adolescents’ susceptibility to their peer environment due to the role dopamine plays in reward sensation during social interaction. We hypothesized that DRD4 genotype status would moderate the impact of 7th-grade antisocial peer pressure on 12th-grade lifetime alcohol use (n = 414; 58.7 % female; 92.8 % White). The results revealed significant main effects for antisocial peer pressure, but no main effects for DRD4 genotype on lifetime alcohol use. Adolescent DRD4 genotype moderated the association between peer pressure and lifetime alcohol use. For individuals who carried at least one copy of the DRD4 7-repeat allele (7+), antisocial peer pressure was associated with increased lifetime alcohol use. These findings indicate that genetic sensitivity to peer pressure confers increased alcohol use in late adolescence.

Several studies have established that child interparental conflict evaluations link parent relationship functioning and adolescent adjustment. Using differential susceptibility theory and its vantage sensitivity complement as their framework, the authors examined differences between adolescents who vary in the DRD4 7 repeat genotype (i.e. 7+ vs. 7−) in how both interparental conflict and positivity affect adolescents’ evaluations of interparental conflict (i.e., threat appraisals) and how these evaluations affect internalizing problems. Results from longitudinal multiple-group path models using PROSPER data (N = 452) supported the hypothesis that threat appraisals for 7+ adolescents would be more affected by perceptions of interparental positivity compared to 7− adolescents; however, threat appraisals for 7+ adolescents were also less affected by interparental conflict. Among 7− adolescents, interparental conflict perceptions were associated with higher threat appraisals, and no association was found for perceptions of positivity. For adolescents of both genotypes, higher threat was associated with greater internalizing problems.

The main goal of the study was to explore the genetic architecture underlying muscle weight in old mice. Weight of soleus, tibialis anterior (TA), extensor digitorum longus (EDL), and gastrocnemius muscles was measured in the C57BL/6J (B6) and DBA/2J (D2) strains and derivative generations: a panel of the BXD recombinant inbred (RI) strains and a B6D2 F(2) intercross at the age of 800 days. The between-strain difference in muscle weight (B6 > D2) ranged between 16% and 38%. Linkage analysis identified suggestive quantitative trait loci (QTL) on Chromosomes (Chr) 2, 6, 7, 8, 19, and X that influenced muscle weight in the 800-day-old group. Comparison of weights at 200, 500, and 800 days revealed a variable effect of age among the four muscles. Linkage analysis in the B6D2 F(2) population combined across the three different age groups identified muscle-, sex-, and age-specific QTL on Chr 1, 2, 3, 5, 6, 8, 9, 11, 13, 17, X, and Y. Genetic factors that influence the rate of weight change (within-strain weight difference at two ages) over the lifespan of BXD RIs were mapped to the markers D2Mit369 and D3Mit130 at the genome-wide p < 0.05 for TA muscle in males (between 200 and 800 days) and females (between 500 and 800 days), respectively. Analysis of all age groups supported previous findings that the genetic effects may be muscle-, age-, and sex-specific.

We examined the genetic and environmental contribution to the stability and instability of reading outcomes in early elementary school using a sample of 283 twin pairs drawn from the Western Reserve Reading Project. Twins were assessed across two measurement occasions. In Wave 1, children were either in kindergarten or first grade. Wave 2 assessments were conducted one year later. Results suggested substantial genetic stability across measurement occasions. Additionally, shared environmental influences also accounted for stability, particularly for variables more closely tied to direct instruction such as phonological awareness, letter knowledge, and word knowledge. There was also evidence for independent genetic and shared environmental effects, suggesting that new sources of variance may emerge as the demands of school change and children begin to acquire early reading skills.

The wild type human dopamine transporter (DAT) and five DAT mutants were transfected into COS-7 cells and their ability to uptake dopamine or to bind cocaine was examine three days later. In each mutant, a single charged amino acid, located in areas that initial hydrophobic analysis had indicated were DAT transmembrane domains was substituted by alanine. Mutants used in this study were lysines 257 and 525 (termed K257A and K525A), arginines 283 and 521 (termed R283A and R521A), and glutamate 491 (termed E491A). Dopamine affinity was significantly enhanced in the K257A and R283A mutants, and the IC(50) for displacement of the radioactive cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (CFT) by cocaine was significantly elevated in the E491A mutant. All mutants displayed a reduction or complete loss of the maximal velocity (V(m)) of dopamine transport.

C57BL/6J (B6) and DBA/2J (D2) strains and two derivative populations, BXD recombinant inbred strains (BXD RIs) and B6D2F2, were used to explore genetic basis for variation in muscle weight at 500 days of age. In parallel with findings in 200-day-old mice (Lionikas A, Blizard DA, Vandenbergh DJ, Glover MG, Stout JT, Vogler GP, McClearn GE, and Larsson L. Physiol Genomics 16: 141–152, 2003), weight of slow-twitch soleus, mixed gastrocnemius, and fast-twitch tibialis anterior (TA) and extensor digitorum longus (EDL) muscles was 13–22% greater ( P < 0.001) in B6 than in D2. Distribution of BXD RI strain means indicated that genetic influence on muscle weight (strain effect P < 0.001, all muscles) was of polygenic origin, and effect of genetic factors differed between males and females (strain-by-sex interaction: P < 0.01 for soleus, EDL; P < 0.05 for TA, gastrocnemius). Linkage analyses in B6D2F2population identified QTL affecting muscle weight on Chr 1, 2, 6, and 9. Pleiotropic influences were observed for QTL on Chr 1 (soleus, TA), 2 (TA, EDL, gastrocnemius), and 9 (soleus, TA, EDL) and were not related to muscle type (fast/slow-twitch) or function (flexor/extensor). Effect of QTL on Chr 9 on soleus muscle was male specific. QTL on Chr 2 and 6 were previously observed at 200 days of age, whereas QTL on Chr 1 and 9 are novel muscle weight QTL. In summary, muscle weight in B6/D2 lineage is affected by a polygenic system that has variable influences at different ages, between males and females, and across muscles in a manner independent of muscle type.

The aim of the study was to explore the genetic architecture influencing weight of fast- and slow-twitch skeletal muscles. The weights of the slow-twitch soleus, the mixed gastrocnemius, the fast-twitch tibialis anterior (TA), and extensor digitorum longus (EDL) muscles were 11–34% greater ( P < 0.001) in 200-day-old C57BL/6J (B6) than in DBA/2J (D2) mice. Male muscles were 13–28% larger than female ( P < 1 × 10−5, no strain by sex interaction). The sex-related difference in muscle weight, however, varied significantly among the 23 derivative BXD recombinant inbred (RI) strains (strain by sex interaction for soleus, P < 0.01; TA, P < 1 × 10−4; EDL, not significant; and gastrocnemius, P < 0.001). Quantitative trait loci (QTL) affecting muscle weight were mapped in an F2 intercross of B6 and D2 mice (B6D2F2) and BXD RIs. A total of 10 autosomal, muscle-specific, but not muscle-type-specific, QTL, explaining a total of 5.4, 7.7, 22.9, and 8.6% of phenotypic variance for soleus, TA, EDL, and gastrocnemius muscles, respectively, were found across chromosomes 1 (Chr 1), 2, 3 (female-specific), 5 (two), 6, 7, 8, and 9 in B6D2F2 mice. The QTL on Chr 8 for EDL and the female-specific QTL on Chr 3 for gastrocnemius muscles were statistically significant, but the remaining QTL were at the suggestive level of statistical significance. Ten QTL on Chr 1, 2, 4, 5, 7, 8, 14, 17 (two), and 19 were identified in BXD RIs. Half of the QTL in BXD RIs had pleiotropic effects and were at the suggestive level of significance (except for the significant QTL for gastrocnemius muscle on Chr 17). The B6D2F2 nominated QTL on Chr 8 for EDL weight was validated in BXD RIs ( P < 0.03). Support intervals for the QTL on Chr 1 and 5 overlapped between B6D2F2 and BXD RIs. An epistatic interaction between markers on Chr 1 and 17 affected gastrocnemius weight in BXD RIs. The interaction was not, however, validated in the B6D2F2 population. Our results indicate that the differences in muscle weight in the B6 and D2 segregating populations were the outcome of a polygenic system, with each factor contributing a small amount to the phenotypic variance and the genetic architecture affecting muscle weight was muscle specific, but not muscle-type specific, and in some instances sex specific.

Participation in genetic studies is often limited by a volunteer's reluctance to donate blood samples. We wished to determine if alternate, less painful, methods to venipuncture could be used to collect cells to provide DNA for genotyping, and whether the cells could be grown in culture for extraction of DNA. Volunteers in the study were comprised of two groups. Nine individuals from a university campus were recruited to provide samples for initial experiments. A second group of 710 twins and singletons from North Carolina and of African-American descent were a part of an ongoing study of age-related traits and participated in collection of buccal swabs via the mail. A protocol was generated that maximizes the recovery of DNA from buccal swabs, which are easier to handle than saline rinses. The DNA recovered is stable over several years, allowing genotype tests at a future date. Attempts to encourage growth of buccal epithelial cells recovered from swabs in tissue culture proved unsuccessful. Buccal swabs work well for the collection of DNA, especially from nonclinic-based volunteers, and can be sent via the mail to the laboratory for DNA extraction. Thus, an inexpensive and efficient method exists for genetic studies of population-based samples.

Maternal cigarette smoking is a risk factor for adolescent smoking. One possible explanation for increased smoking by human adolescents after maternal nicotine exposure is that exposure increases nicotine preference. However, it is difficult to separate the biological and social causes of smoking behavior in humans. This experiment examined the relationship between maternal nicotine exposure and nicotine preference in periadolescent offspring using a mouse model of oral nicotine consumption. Pregnant females were provided saccharin-flavored water containing 50 microg/ml nicotine (n = 4) or no nicotine (n = 5) from the ninth day of gestation through weaning on postnatal day (PD) 21. Offspring from these females were tested for nicotine preference during periadolescence (PDs 35-42) by providing access to both saccharin-only and nicotine solutions (50 microg/ml) 24 hr a day in the home cage in a two-bottle choice test. Male mice exposed maternally to nicotine (n = 9) exhibited an increased nicotine preference in adolescence compared to non-nicotine exposed controls (n = 12). Maternal nicotine exposure did not alter nicotine preference by periadolescent female mice. Nicotine consumption was confirmed by serum cotinine measurement. These data are consistent with human epidemiological reports that maternal nicotine exposure is associated with increased risk of cigarette smoking. Differential outcomes for males and females suggest that different processes underlie sex differences in nicotine consumption following maternal nicotine exposure.

The genetics underlying variation in health‐related musculoskeletal phenotypes can be investigated in a mouse model. Quantitative trait loci (QTLs) affecting musculoskeletal traits in the LG/J and SM/J strain lineage remain to be refined and corroborated. The aim of this study was to map muscle and bone traits in males ( n = 506) of the 50th filial generation of advanced intercross lines (LG/SM AIL) derived from the two strains. Genetic contribution to variation in all musculoskeletal traits was confirmed; the SNP heritability of muscle mass ranged between 0.46 and 0.56; and the SNP heritability of tibia length was 0.40. We used two analytical software, GEMMA and QTLRel, to map the underlying QTLs. GEMMA required substantially less computation and recovered all the QTLs identified by QTLRel. Seven significant QTLs were identified for muscle weight (Chr 1, 7, 11, 12, 13, 15, and 16), and two for tibia length, (Chr 1 and 13). Each QTL explained 4–5% of phenotypic variation. One muscle and both bone loci replicated previous findings; the remaining six were novel. Positional candidates for the replicated QTLs were prioritized based on in silico analyses and gene expression in muscle tissue. In summary, we replicated existing QTLs and identified novel QTLs affecting muscle weight, and replicated bone length QTLs in LG/SM AIL males. Heritability estimates substantially exceed the cumulative effect of the QTLs, hence a richer genetic architecture contributing to muscle and bone variability could be uncovered with a larger sample size.

To study the possibility that increasing striatal activity of aromatic L-amino acid decarboxylase (AADC; EC 4.1.1.28) can increase dopamine production in dopamine denervated striatum in response to L-3,4-dihydroxy-phenylalanine (L-DOPA) administration, we grafted Cos cells stably expressing the human AADC gene (Cos-haadc cells) into 6-hydroxydopamine denervated rat striatum. Before grafting, the catalytic activity of the enzyme was assessed in vitro via the generation of 14CO2 from L-[14C]DOPA. The Km value for L-DOPA in intact and disrupted cells was 0.60 and 0.56 mM, respectively. The cofactor, pyridoxal 5-phosphate, enhanced enzymatic activity with maximal effect at 0.1 mM. The pH optimum for enzyme activity was 6.8. Grafting Cos-haadc cells into denervated rat striatum enhanced striatal dopamine levels measured after systemic administration of L-DOPA. When measured 2 h after L-DOPA administration, the mean dopamine level in the striata of Cos-haadc-grafted animals was 2 micrograms/g of tissue, representing 31% of normal striatal dopamine concentration. The mean dopamine concentration in the striata grafted with untransfected Cos cells (Cos-ut cells) was 1 microgram/g. At 6-8 h after L-DOPA administration, striatal dopamine content in the Cos-haadc-grafted animals was 0.67 microgram/g of tissue weight, representing 9% of intact striatum dopamine content. By contrast, the average dopamine content in the Cos-ut-grafted animals was undetectable. These findings demonstrate that enhancing striatal AADC activity can improve dopamine bioformation in response to systemically administered L-DOPA.

In the Smokers and Nonsmokers Study, the authors investigated the feasibility of using random digit dialing telephone interviews to locate adults in the continental United States who were willing to provide DNA from buccal swabs through the mail. Interviews with 3,383 adults regarding their smoking-related behaviors (response rate = 70%) were conducted in 1999-2000; swab returns continued into early 2001. Overall, 57% of interviewees agreed to receive mailed information explaining the study. Better-educated persons (odds ratio (OR) = 1.3, 95% confidence interval (CI): 1.1, 1.6), younger persons (OR = 0.988, 95% CI: 0.983, 0.992), persons with symptoms of depression (OR = 1.8, 95% CI: 1.4, 2.4), and current smokers (OR = 2.25, 95% CI: 1.8, 2.8) were likelier to agree to receive a mailing. Approximately 26% of interviewees (45% of those receiving kits) returned buccal swabs, and 18% were successfully genotyped. Older (OR = 1.02, 95% CI: 1.01, 1.03), better-educated (OR = 1.4, 95% CI: 1.1, 1.7), and White (OR = 1.8, 95% CI: 1.4, 2.5) participants were more likely to return DNA samples, but current smokers (OR = 0.6, 95% CI: 0.5, 0.8) were less likely to do so. Participants were randomly assigned to one of two forms of participation: the "registry" group (names were kept on file) or the "made-anonymous" group (names were unassociated with samples). The two groups were equally likely to return kits, but registry respondents were more likely to nominate siblings for participation in the study (OR = 1.6, 95% CI: 1.2, 2.1). The participants in this study were similar demographically to the national population. The authors conclude that random digit dialing surveys coupled with mail collection of DNA may constitute a practical method of obtaining DNA samples for biobehavioral research.

Aggression-related problems such as assault and homicide among adolescents and young adults exact considerable social and economic costs. Although progress has been made, additional research is needed to help combat this persistent problem. Several lines of research indicate that parental hostility is an especially potent predictor of adolescent aggression, although most longitudinal research has focused on clarifying the direction of effects. In this study, we used longitudinal data from the PROSPER project (N = 580; 54.8 % female), a primarily rural Caucasian preventative intervention sample, to examine developmental change in early- to mid-adolescent aggressive behavior problems (age 11–16 years). In addition, we examined maternal hostility as a predictor of developmental change in aggression and the PROSPER preventative intervention, designed to reduce substance use and aggression, as a potential influence on this association. Lastly, several studies indicate that variation in the DRD4 7-repeat gene moderates both parenting and intervention influences on externalizing behavior. Accordingly, we examined the potential moderating role of DRD4. As hypothesized, there was a significant maternal hostility by intervention interaction indicating that the intervention reduced the negative impact of maternal hostility on adolescent change in aggressive behavior problems. DRD4 7-repeat status (7+ vs. 7−) further conditioned this association whereby control group 7+ adolescents with hostile mothers showed increasing aggressive behavior problems. In contrast, aggression decreased for 7+ adolescents with similarly hostile mothers in the intervention. Implications for prevention are discussed as well as current perspectives in candidate gene-by-environment interaction research.

Laboratory mice preferentially rear their offspring in communal nests (CN), with all mothers contributing to maternal care and feeding of all the pups. Previous studies using primarily outbred mice have shown that offspring reared under CN conditions may display increased preweaning growth rates and differences in adult behavior and neurobiology compared with mice reared under single-nesting (SN; one dam with her litter) conditions. Here we compared pup mortality; weaning and adult body weights; adult behavior; and gene expression in the hippocampus and frontal cortex between C57BL/6J, DBA/2J and 129x1/SvJ mice reared by using CN (3 dams and their litters sharing a single nest) or SN. Male and female pups of all 3 strains reared in CN cages showed higher body weight at weaning than did SN pups of the same strain, with no significant difference in pup mortality between groups. Adult male offspring reared in CN showed no differences in any behavioral test when compared with SN offspring. Combining CN dams and litters after parturition revealed greater cortical brain-derived neurotropic factor expression in adult male C57BL/6J offspring and cortical glucocorticoid receptor expression in adult male C57BL/6J and 129x1/SvJ offspring as compared with SN offspring of the same strain. Communal rearing can enhance juvenile growth rates but does not change adult behavior in inbred mouse strains, although potential effects on adult neurophysiology are possible.

Introduction Smoking has well-recognized endocrine disrupting effects in humans that have been linked specifically to nicotine in animal models. Nicotine's perinatal effects on genital development in mice, which is interpreted as a measure of endocrine disrupting activity, were evaluated in this report. Methods Pregnant C57B/6J dams were administered 50 μg/ml nicotine in drinking water from gestational day 9 until pups were weaned. Their pups’ anogenital distances and weights were measured at birth and at weaning. A subset of the pups was weighed again in adulthood. Results Female and male mice had significantly reduced anogenital distance at birth; however, by 34 days of age, differences in anogenital distance were no longer apparent, while body weight, which had been equal at birth and weaning, was significantly reduced in mice exposed to perinatal nicotine. Discussion Perinatal nicotine exposure significantly delayed genital development and altered adolescent body weight in this model.

Substance abuse is a complex behavior that is caused by both environmental and genetic factors. Work to understand the genetic factors has focused on genes related to dopamine activity because of its critical role in rewarding and reinforcing behaviors. The DRD3 and other dopamine receptor subtypes are expressed in many areas of the limbic system, and have been the objects of study for their possible roles in several neuropsychiatric disorders. Interest in variants of the D4 gene was heightened by reports that some alleles were more frequent in individuals who score high on Novelty Seeking, an aspect of personality that may be related to drug seeking behavior. We now show that the long form of the DRD4 gene is more frequent in individuals with high quantity/frequency of drug use compared to controls (χ2 = 5.7, df = 1, P = 0.017, odds ratio = 1.89, CI = 1.1–3.2). There is no difference in DRD3 allele frequencies in these samples, and there is no interaction of DRD4 alleles with those of the catecholamine-o-methyl- transferase gene (COMT) that we previously identified to be more frequent in substance abusers than controls [Vandenbergh, et al.: 1997: Am. J. Med. Gen. 74:439–442]. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:678–683, 2000. Published 2000 Wiley-Liss, Inc.

[125I]RTI-55 is a cocaine analog with high affinity for dopamine (DA) and serotonin (5-HT) transporters. Quantitative ligand binding studies revealed a novel high affinity [125I]RTI-55 binding site assayed under 5-HT transporter (SERT) conditions which has low affinity for almost all classic biogenic amine transporter ligands, including high affinity 5-HT transporter inhibitors such as paroxetine, but which retains high affinity for cocaine analogs. This site, termed SERTsite2 for its detection under 5-HT transporter conditions (not for an association with the SERT) occurs in monkey caudate, human caudate, and guinea pig caudate membranes, but not in rat caudate membranes. SERTsite2 is distinguished from the DA transporter (DAT) and SERT by several criteria, including a distinct ligand-selectivity profile, the inability to detect SERTsite2 in cells stably expressing the cloned human DAT, and insensitivity to irreversible ligands which inhibit [125I]RTI-55 binding to the DAT and SERT. Perhaps the most striking finding about SERTsite2 is that a wide range of representative antidepressant agents have very low affinity for SERTsite2. The affinity of cocaine for this site is not very different from the concentration cocaine achieves in the brain at pharmacological doses. Viewed collectively with the observation that ligands with high affinity for SERTsite2 are mostly cocaine analogs, these data lead us to speculate that actions of cocaine which differ from those of classic biogenic amine uptake inhibitors may be mediated in part via SERTsite2. Synapse 28:322–338, 1998. Published 1998 Wiley-Liss, Inc.

Repeated doses of cocaine or amphetamine lead to long-lasting behavioral manifestations that include enhanced responses termed sensitization. Although biochemical mechanisms that underlie these manifestations currently remain largely unknown, new protein synthesis has been implicated in several of these neuroadaptive processes. To seek candidate biochemical mechanisms for these drug-induced neuroplastic behavioral responses, we have used an approach termed subtracted differential display (SDD) to identify genes whose expression is regulated by these psychostimulants. rGβ1is one of the SDD products that encodes a rat G-protein β subunit. rGβ1expression is upregulated by cocaine or amphetamine treatments in neurons of the nucleus accumbens shell region, a major center for psychostimulant effects in locomotor control and behavioral reward. Antisense oligonucleotide treatments that attenuate rGβ1expression in regions including the nucleus accumbens abolish the development of behavioral sensitization when they are administrated during the repeated cocaine exposures that establish sensitization. These treatments fail to alter acute behavioral responses to cocaine, and they do not block the expression of cocaine sensitization when it is established before oligonucleotide administrations. Full, regulated rGβ1expression is a biochemical component essential to the establishment of a key consequence of repeated cocaine administrations, sensitization.

Allelic variants at the catechol-O-methyltransferase (COMT) locus are candidates to contribute to genetic components of interindividual differences in vulnerability to substance abuse. COMT plays a prominent role in dopaminergic circuits important for drug reward, and COMT alleles encode enzymes whose activities vary from three- to four-fold. We compared COMT allele frequencies in control research volunteers reporting insignificant lifetime use of addictive substances with those in volunteers reporting substantial polysubstance use. Homozygosity for the high-activity COMT allele was found in 18% of controls, 31% of volunteers with high lifetime substance use, and 39% meeting DSMIII-R substance abuse criteria [odds ratio (relative risks) 2.0 (control vs. use; 95% confidence interval 1.2-3.5; P < 0.013) and 2.8 (control vs. DSM; 1.3-6.1; P < 0.008)]. Individuals with the high-activity COMT variant may have greater genetic vulnerability to drug abuse.