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Director's Report to the National Advisory Council on Drug Abuse - February, 2007



Research Findings - Behavioral and Brain Development Research

Effects of Prenatal Methamphetamine Exposure, Polydrug Exposure, and Poverty on Intrauterine Growth

Methamphetamine use among pregnant women is an increasing problem in the United States. Effects of methamphetamine use during pregnancy on fetal growth have not been reported in large, prospective studies. Dr. Barry Lester and his colleagues at four clinical centers in California, Oklahoma, Hawaii and Iowa examined the neonatal growth effects of prenatal methamphetamine exposure. Of 13,808 subjects screened, 1,618 were eligible and consented, among which 84 were methamphetamine exposed, and 1,534 were unexposed. Both groups included prenatal alcohol, tobacco, or marijuana use, but excluded use of opiates, LSD, PCP or cocaine only. The methamphetamine exposed group was 3.5 times more likely to be small for gestational age than the unexposed group. Mothers who used tobacco during pregnancy were nearly two times more likely to have small-for-gestational-age infants. In addition, less maternal weight gain during pregnancy was more likely to result in a small-for-gestational-age infant. Birth weight in the methamphetamine exposed group was lower than the unexposed group. These findings suggest that prenatal methamphetamine use is associated with fetal growth restriction after adjusting for covariates. Continued follow-up will determine if these infants are at increased risk for growth and/or neurodevelopmental deficits in the future. Smith, L.M., LaGasse, L.L., Derauf, C., Grant, P., Shah, R., Arria, A., Huestis, M., Haning, W., Strauss, A., Della Grotta, S., Liu, J., and Lester, B.M. The Infant Development, Environment, and Lifestyle Study: Effects of Prenatal Methamphetamine Exposure, Polydrug Exposure, and Poverty on Interuterine Growth, Pediatrics, 118(3), pp. 1149-1156, 2006.

Neuroimaging of Frontal White Matter and Executive Functioning in Cocaine-Exposed Children

Researchers at the University of Florida have reported on the use of Diffusion Tensor Imaging (DTI) to assess frontal white matter development in prenatally cocaine-exposed and non-exposed children, and also have reported on associations between frontal white matter development and executive functioning in these children. DTI uses magnetic resonance imaging (MRI) to investigate white matter microstructure by measuring the movement, or diffusion, of water molecules in tissues. Using different DTI quantification indices, researchers study maturation of white matter tracts. Executive functioning is a concept that describes a diverse set of skills involved in goal-directed behavior such as problem solving, and includes skills such as attention control, inhibition abilities, and management of cognitive, emotional, and behavioral functions. Executive functioning was assessed using two frequently used instruments (the Stroop color and word test and the Trail Making Test). The sample for these analyses (tested and scanned in the age range 9.6 to 12.2 years) was drawn from an ongoing longitudinal study of development following prenatal cocaine exposure, and involved 28 cocaine-exposed children and 25 non-exposed children with similar sociodemographic characteristics. The investigators conclude that prenatal cocaine exposure, alone and in combination with exposure to other drugs, is associated with slightly poorer executive functioning and with subtle microstrucural characteristics that may suggest less mature development of frontal white matter pathways. They also state that the relative contribution of postnatal environmental factors (e.g., caregiving environment) on brain development and behavioral functioning in polydrug-exposed children awaits further research. Warner, T.D., Behnke, M., Eyler, F.D., et al. Diffusion Tensor Imaging of Frontal White Matter and Executive Functioning in Cocaine-Exposed Children. Pediatrics, 118, pp. 2014-2024, 2006.

Discrete Opioid Gene Expression Impairment in the Human Fetal Brain Associated with Maternal Marijuana Use

The most commonly used illicit drug by pregnant women is marijuana. In light of the strong interactions between the cannabinoid and Opioid systems, Dr. Yasmin Hurd and her colleagues investigated the effects of in utero marijuana exposure on expression levels of Opioid-related genes in the human fetal forebrain. The Opioid peptide precursors (preprodynorphin and preproenkephalin (PENK)) and receptor (mu, kappa and delta) mRNA expression were assessed in distinct brain regions in 42 midgestation fetuses from saline-induced voluntary abortions and the effects of prenatal cannabis exposure was analyzed while controlling for confounding variables such as maternal alcohol and cigarette use, fetal age, sex, growth measure and post-mortem interval. Prenatal cannabis exposure was found to be significantly correlated with increased mu receptor expression in the amygdala, reduced kappa receptor mRNA in mediodorsal thalamic nucleus and reduced preproenkephalin expression in the caudal putamen. Prenatal alcohol exposure was found to primarily influence kappa receptor mRNA, with reduced levels in the amygdala, claustrum, putamen and insula cortex. No significant effect of prenatal nicotine exposure was seen in the analyses performed. These results indicate that maternal cannabis and alcohol exposure during pregnancy differentially affect opioid-related genes in distinct brain circuits; alterations that may have long-term effects on cognitive and emotional behaviors. Wang, X., Dow-Edwards, D., Anderson, V., Minkoff, H., and Hurd, Y.L. Discrete Opioid Gene Expression Impairment in the Human Fetal Brain Associated with Maternal Marijuana Use. Pharmacogenomics Journal, 6(4), pp. 255-264, 2006.

Prenatal Cocaine Exposure and Risk for Developing Learning Disabilities

Dr. Emmalee Bandstra and her colleagues at the University of Miami examined prenatal cocaine exposure and risk for developing a learning disability (LD) or impaired intellectual functioning by age seven in a sample of 409 children (212 cocaine-exposed, 197 non-cocaine-exposed) born full term and enrolled prospectively at birth. LDs were categorized based on ability-achievement discrepancy scores. The cocaine-exposed children had 2.8 times greater risk of developing a LD by age seven than non-cocaine-exposed children. No differences were found in the estimate of relative risk for impaired intellectual functioning (IQ below 70) between children with and without prenatal cocaine exposure. Results remained stable with adjustment for multiple child and caregiver covariates including but not limited to maternal education, caregiver substance use, the home environment, and attendance in Head Start/prekindergarten suggesting that children with prenatal cocaine exposure are at increased risk for developing a learning disability by age seven when compared to their non-cocaine-exposed peers. Morrow, C.E., Culbertson, J.L., Accornero, V.H., Xue, L., Anthony, J.C., and Bandstra, E.S. Learning Disabilities and Intellectual Functioning in School-Aged Children with Prenatal Cocaine Exposure. Developmental Neuropsychology, 30(3), pp. 905-931, 2006.

Prenatal Smoking Exposure and Developmental Patterns of Conduct Problems in Boys

There are reports in the research literature of associations between prenatal smoking exposure and increased risk of conduct problems among offspring. This report examines associations of prenatal smoking exposure with oppositional defiant disorder (ODD) and attention-deficit/hyperactivity disorder (ADHD) in young boys (during first grade), and with developmental patterns of delinquent behavior during adolescence. Researchers from the University of Illinois at Chicago and from the University of Pittsburgh examined data from the Pittsburgh Youth Study, a prospective, population-based study of conduct problems in boys. In the analyses for this report, prenatal smoking exposure was examined relative to the presence of ODD and ADHD, singly and as comorbid conditions at age 7 years. Also investigated was the association of prenatal exposure with the timing of onset of both mild and more serious conduct problems, using in-depth measures of delinquency administered prospectively from early school age through age 19 years. Multiple potentially confounding factors were controlled in multivariate analyses. The investigators report that exposed boys were more likely to show evidence of ODD and comorbid ODD-ADHD, but not ADHD alone. They also report that exposed boys were more likely to have an earlier onset of significant delinquent behavior. The authors note that whether prenatal smoking plays an etiological role in, or is a marker for risk of antisocial behavior, it is clear that the offspring of prenatal smokers as a group are at increased risk for an early-starter pathway to antisocial behavior that is evident as early as first grade. Wakschlag, L.S., Pickett, K.E., Kasza, K.E., and Loeber, R. Is Prenatal Smoking Associated with a Developmental Pattern of Conduct Problems in Young Boys? Journal of the American Academy of Child and Adolescent Psychiatry, 45, pp. 461-467, 2006.

Prenatal Cannabis Exposure Increases Heroin Seeking with Allostatic Changes in Limbic Enkephalin Systems in Adulthood

Very little is known about the long-term consequences of prenatal cannabis exposure on behavior and neural systems. Dr Yasmin Hurd and her colleagues used an animal model to study the effects of prenatal exposure to _9-tetrahydrocannabinol (THC) on heroin self-administration behavior and opioid neural systems in adult male rats (postnatal day 62) that were exposed to THC from gestational day five to postnatal day two. They found that THC-exposed rats exhibited shorter latency to pressing a lever for heroin, responded more for low heroin doses, and had more readily sought heroin when stressed and during drug extinction. Neurobiologically, they found that THC exposure reduced preproenkephalin (PENK) mRNA expression in the nucleus accumbens during early development, but this was elevated in adulthood. PENK mRNA was also increased in the central and medial amygdala in adult THC-exposed animals. Finally, THC animals had reduced heroin-induced locomotor activity and nucleus accumbens _ opioid receptor coupling. This study demonstrates that the effects of prenatal THC exposure endure into adulthood and that these effects are evident on heroin-seeking behavior and in changes in mesocorticolimbic PENK systems relevant to drug motivation/reward and stress responses. Spano, M.S., Ellgren, M., Wang, X., and Hurd, Y.L. Prenatal Cannabis Exposure Increases Heroin Seeking with Allostatic Changes in Limbic Enkephalin Systems in Adulthood. Biological Psychiatry, July 27, 2006.

Intrauterine Growth Restriction and Prenatal Substance Exposure in Term Infants and Risk for Hypertension at Age Six

Researchers from the Maternal Lifestyle Study, a prospective longitudinal multi-site study of prenatal cocaine and opiate exposure, investigated the association between intrauterine growth restriction (IUGR) status at birth among full-term infants, exposure to substance use during pregnancy, and risk of hypertension at six years of age. Of the 1,388 infants (600 cocaine exposed, 781 non-exposed, and seven indeterminate, matched by gestational age, race, and sex), enrolled in this study, 950 children (415 exposed, 535 non-exposed) completed the age six assessment, 891 had blood pressure data and of these, 516 were born at full term. One hundred and forty-four (28%) of the 516 children had a diagnosis of IUGR at birth. At six years of age, 93 (19%) of 516 children had hypertension, defined as either systolic or diastolic blood pressure higher than the 95th percentile for sex, age, and height. Of 144 children with IUGR, 35 (24%) had hypertension as compared with 58 (16%) of 372 children without IUGR. The study did not find any association with cocaine, opiate, marijuana, tobacco, or alcohol use during pregnancy and hypertension at 6 years of age. Twenty percent of cocaine-exposed children had hypertension as compared with 16% of nonexposed children. Intrauterine growth restriction status at birth was significantly associated with hypertension adjusting for site; maternal race, education, and tobacco, marijuana, alcohol, and cocaine use during pregnancy; and child's current body mass index. In term infants, IUGR is linked to risk of hypertension in early childhood, which may be a marker for adult cardiovascular disease. Shankaran, S., Das, A., Bauer, C.R., Bada, H., Lester, B., Wright, L., Higgins, R., and Poole, K. Fetal Origin of Childhood Disease: Intrauterine Growth Restriction in Term Infants and Risk for Hypertension at Age Six. Archives of Pediatrics and Adolescent Medicine, 160(9), pp. 977-981, 2006.

Perinatal HIV Infection, In Utero Substance Exposure and Cognitive Development in Young Children

Researchers from the Women and Infants transmission study examined the effect of HIV in combination with other health and social factors including in utero exposure to drugs on the development of cognitive abilities of children perinatally exposed to HIV and substances of abuse. Serial cognitive assessments were performed for 117 children who were infected vertically and 422 children (50% African American, 32% Hispanic, and 12% Caucasian) who were exposed to but not infected with HIV. Forty-one percent of the children were exposed to cocaine, heroin, or methadone in utero as measured by self-report and/or urine screen and 63% were exposed to alcohol, tobacco, or marijuana as measured by self-report. Repeated-measures analyses were used to evaluate the neurocognitive development of these children between the ages of three and seven years. Children with HIV/no Class C conditions were more likely to experience exposure to hard drugs during pregnancy than were children without HIV. (Class C refers to the CDC categorization of clinical conditions or symptoms of HIV infection considered severe including recurrent serious bacterial infections and encephalopathy). Children with HIV infection and class C status scored significantly lower in all domains of cognitive development, across all time points, than did those who were HIV infected without an AIDS-defining illness and those who were HIV exposed but not infected adjusting for presence of hard and soft substance exposure and other maternal factors during pregnancy and delivery, social demographic variables, test administration variables, and maternal and child disease stages. There were no significant differences between the two latter groups in General Cognitive Index or specific domain scores. Rates of change in cognitive development were parallel among all three groups over a period of four years. Factors that were associated consistently and significantly with lower mean scores were HIV status, number of times an examination had been completed previously, primary language, maternal education, and gender. No factors were related to rate of change of any mean domain score. An early AIDS-defining illness increased the risk of chronic static encephalopathy during the preschool and early school age years. Children with HIV infection but no class C event performed as well as non-infected children in measures of general cognitive ability. No significantly different profiles of strengths and weaknesses for verbal, perceptual-performance, quantitative, or memory functioning were observed among children with or without HIV infection. The authors recommend that future research include various environmental stressors in these children's lives including current parental drug use. Smith, R., Malee, K., Leighty, R., Brouwers, P., Mellins, C., Hittelman, J., Chase, C., Blasini, I., and the Women and Infants Transmission Study Group. Effects of Perinatal HIV Infection and Associated Risk Factors on Cognitive Development among Young Children. Pediatrics, 117(3), pp. 851-862, 2006.

Prenatal Exposure to Cocaine and Childhood Exposure to Violence: Association with Friends' and Own Substance Use

Children exposed to substances of abuse in utero may also be at risk for environmental stressors during childhood that can influence their neurodevelopmental trajectories and risk for substance use. This study examined the association between exposure to violence during childhood and own and friends' substance use in a sample of children from a prospective longitudinal study of in-utero cocaine exposure (IUCE). One hundred and four children were assessed at age 8.5, 9.5, and 11 years with the Violence Exposure Scale for Children-Revised (VEX-R) and the Substance Exposure Assessment, a child-report measure of their own and their friends' ATOD use. The sample consisted of 90% African-American/ Caribbean children (mean age 8.5 years, SD 3 years), 53% males, and 49% with IUCE. Twenty-eight percent of the sample reported own use of any ATOD by age 11. The percentage of children who reported having substance-using friends was 12% at 8.5 years, 25% by 9.5 years, and 45% by 11 years. In multivariate survival analyses controlling for caregiver type, in-utero cocaine exposure category (heavy, light, and none), and child gender, children in the upper quartile of violence exposure at age 8.5 years were at significantly greater risk of having reported friends' use of ATOD by age 11 compared to those in the first through third quartiles. Quartiles of the violence exposure score, however, were not significantly associated with children's acknowledgment of their own use. Findings suggest an association between exposure to violence in childhood and report of peer ATOD use at school age. Campaigns to prevent ATOD use should address the impact of childhood exposure to violence. Joseph, N.P., Augstyn, M., Cabral, H., and Frank, D.A. Preadolescents' Report of Exposure to Violence: Association with Friends' and Own Substance Use. Journal of Adolescent Health, 38(6), pp. 669-674, 2006.

Maternal Cocaine Use and Caregiving Status: Group Differences in Caregiver and Infant Risk Variables

This study examined differences between cocaine and non-cocaine-using mothers, and between parental and non-parental caregivers of cocaine-exposed infants on caregiver childhood trauma, psychiatric symptoms, demographic, and perinatal risks. Participants included 115 cocaine and 105 non-cocaine mother-infant dyads recruited at delivery. Approximately 19% of cocaine mothers lost custody of their infants by one month of infant age compared to 0.02% of non-cocaine mothers. Mothers who used cocaine during pregnancy had higher demographic and obstetric risks and their infants had higher perinatal risks. Birth mothers who retained custody of their infants had higher demographic risks and perinatal risks, higher childhood trauma, and higher psychiatric symptoms compared to birth mothers who did not use cocaine and non-parental caregivers of cocaine-exposed infants. Results highlight the importance of addressing childhood trauma issues and current psychiatric symptoms in substance abuse treatment with women who engaged in substance use during pregnancy. Eiden, R.D., Foote, A., and Schuetze, P. Maternal Cocaine Use and Caregiving Status: Group Differences in Caregiver and Infant Risk Variables. Addictive Behaviors, July 10, 2006.

Gender, Substance Exposure, Lymphocyte Populations, Plasma HIV RNA Levels, and Disease Progression in a Cohort of HIV Exposed Children

Researchers from the Women and Infants Transmission study analyzed blood samples from antiretroviral therapy-treated, HIV-infected children (n = 158) and HIV-uninfected children (n = 1801) to examine gender and substance exposure differences in lymphocyte subsets and plasma RNA levels. In terms of immunologic parameters, for anti-retroviral therapy (ART) treated, HIV-infected children, maternal hard drug use during pregnancy showed a trend toward children having lower CD4+ cell counts (p= .06). Children whose mothers did not use hard drugs during pregnancy also had, on average, greater CD16+ CD56+ natural killer cell counts. In contrast, children exposed to hard drugs during pregnancy but not HIV infected had a higher CD4+ percentage. In terms of virologic parameters and mortality rates, ART-treated, HIV-infected children whose mothers used hard drugs during pregnancy had a higher mean log RNA level. Maternal alcohol use during pregnancy had no effect on CD4+ cell counts or percentages, however, ART-treated, HIV-infected children whose mothers did not use alcohol during pregnancy had on average higher absolute CD19+ cell counts and higher mean log RNA level. ART-treated, HIV-infected female children had lower plasma RNA levels than did their male counterparts, but lymphocyte differences were not noted. Despite their higher plasma RNA level, a greater proportion of male children survived through 8 years of age. There were no gender differences with respect to the age of diagnosis of HIV, time to antiretroviral therapy after diagnosis of HIV, or type of antiretroviral therapy. Lymphocyte differences were noted for uninfected children. Plasma RNA levels differed among antiretroviral therapy-treated, HIV-infected children according to gender, in a manner similar to that noted in previous pediatric and adult studies. Lymphocyte subsets varied according to gender in a cohort of HIV-exposed but uninfected children. Most importantly, overall mortality rates for this cohort differed according to gender. Foca, M., Moye, J., Chu, C., Matthews, Y., Rich, K., Handelsman, E., Luzuriaga, K., Paul, M., Diaz, C., and the Women and Infants Transmission Study. Gender Differences in Lympocyte Populations, Plasma HIV RNA Levels, and Disease Progression in a Cohort of Children Born to Women Infected with HIV. Pediatrics, 118(1) pp. 146-155, 2006.

Maternal Cocaine Use During Pregnancy and Caregiving Status: Group Differences in Caregiver and Infant Risk Variables

This study examined differences between caregiver childhood trauma, psychiatric symptoms, demographic variables, perinatal risks and infant birth outcomes between cocaine and non-cocaine-using mothers, and within the cocaine group, between parental and non-parental caregivers taking part in a longitudinal study on the long term effects of prenatal substance exposure. Two hundred and twenty mother-infant dyads including 115 cocaine exposed (93 parental care, 22 foster care) and 105 non-cocaine were recruited at delivery. Approximately 19% of cocaine mothers lost custody of their infants by 1 month of infant age compared to 0.02% of non-cocaine mothers. Mothers who used cocaine during pregnancy had higher demographic and obstetric risks and their infants had lower birth weights. Birth mothers who retained custody of their infants had higher demographic risks and perinatal risks, higher childhood trauma (childhood emotional abuse, sexual abuse, and emotional neglect), and higher psychiatric symptoms (PTSD, antisocial behavior, anger/hostility) compared to birth mothers who did not use cocaine and non-parental caregivers of cocaine-exposed infants. Mothers in the cocaine group who retained custody of their children used more cigarettes and alcohol postnatally compared to non-cocaine users. The results highlight the importance of addressing childhood trauma issues and current psychiatric symptoms in substance abuse treatment and parenting interventions for mothers who used substances during pregnancy. Treatment planning should include treatment for other substances of abuse including cigarettes. Eiden, R.D., Foote, A., and Schuetze, P. Maternal Cocaine Use and Caregiving Status: Group Differences in Caregiver and Infant Risk Variables. Addictive Behaviors, July 10, 2006.

A Framework to Monitor Environment-induced Major Genes for Developmental Trajectories: Implications for a Prenatal Cocaine Exposure Study

Whether there are specific genes involved in response to different environmental agents and how such genes regulate developmental trajectories during lifetime are of fundamental importance in health, clinical and pharmaceutical research. Drs. Fonda Eyler, Marylou Behnke and colleagues at the University of Florida developed a novel statistical model for monitoring environment-induced genes of major effects on longitudinal outcomes of a trait. This model is derived within the maximum likelihood framework, incorporated by mathematical aspects of growth and developmental processes. A typical structural model is implemented to approximate time-dependent covariance matrices for the longitudinal trait. This model allows for a number of biologically meaningful hypothesis tests regarding the effects of major genes on overall growth trajectories or particular stages of development. It can be used to test whether and how major genetic effects are expressed differently under altered environmental agents. In a well-designed case-control study, the model has been employed to detect cocaine-dependent genes that affect growth trajectories for head circumference during childhood. The detected gene triggers significant effects on growth curves in both cocaine-exposed (case) and unexposed groups (control), but with different extents. Significant genotype-environment interactions due to this so-called environment-sensitive gene are promising for further studies toward its genomic mapping using polymorphic molecular markers. Hou, W., Garvan, C.W., Littell, R.C., Behnke, M., Eyler, F.D., and Wu, R. A Framework to Monitor Environment-Induced Major Genes for Developmental Trajectories: Implication for a Prenatal Cocaine Exposure Study. Statistics in Medicine, 25, pp. 4020-4035, 2006.

Bootstrapping Conceptual Deduction Using Physical Connection: Rethinking Frontal Cortex

Infants as young as 9 months of age have the ability to deduce abstract rules, but only if the items to be conceptually related are presented physically connected. Adele Diamond at the University of British Columbia hypothesizes that the periarcuate region of the frontal lobe (and its human homologue) is the crucial region responsible for learning abstract rules in the absence of physical connections. This region of the brain may be too immature in infants under the age of 21 months and thus the reason that a physical connection between items is necessary in order for infants to grasp the conceptual relationship. Many young children with developmental delays have difficulty learning abstract principles which could be due to a biological abnormality in the periarcuate. Dr. Diamond proposes that children with learning delays and especially those with autism should be able to perceive a conceptual connection if the items are presented physically connected. Diamond, A. Bootstrapping Conceptual Deduction Using Physical Connection: Rethinking Frontal Cortex, Trends in Cognitive Sciences, 10(5), pp. 212-218, 2006.

Development of Cognitive Control and Executive Functions from 4 to 13 Years: Evidence from Manipulations of Memory, Inhibition, and Task Switching

This study describes the developmental progression and interactions over development of working memory, inhibition and cognitive flexibility (switching between tasks or rules) abilities. A battery of interrelated tasks that could be used across a wide age range and that could be independently and systematically varied in order to manipulate memory and cognitive control skills were administered to 325 participants (approximately 30 per age from 4 to 13 years and young adults). The results indicated that as long as the rules remained constant, the youngest children could hold information in mind and could inhibit a dominant response and could also combine working memory and inhibition skills. Cognitive flexibility, even with memory demands kept to a minimum, showed a longer developmental progress with 13- year-olds still not reaching adult levels. Davidson, M., Amso, D., Anderson, L., and Diamond, A. Development of Cognitive Control and Executive Functions from 4 to 13 Years: Evidence from Manipulations of Memory, Inhibition and Task Switching, Neuropsychologia, 44, pp. 2037-2078, 2006.

Functional Correlates of Verbal Memory Deficits Emerging During Nicotine Withdrawal in Abstinent Adolescent Cannabis Users

Cannabis is the most commonly used illicit substance in the adolescent population. Among those teenagers who use cannabis, many of them also smoke tobacco. Dr. Leslie Jacobsen and her colleagues examined the interacting effects of these drugs on verbal learning and memory in twenty adolescent users of tobacco and cannabis users compared to 25 adolescent tobacco users with a minimal use of cannabis. Functional magnetic resonance (fMRI) was conducted to examine whether the modulation of regional activation and functional connectivity was different in cannabis users who continued to smoke versus those experiencing nicotine withdrawal. The results indicated that delayed recall of verbal stimuli was impaired in abstinent cannabis users, but only if they were also going through nicotine withdrawal. The fMRI data indicated a different pattern of activation in those subjects who were abstinent from both marijuana and nicotine with the withdrawal of nicotine selectively increasing task-related activation of posterior regions and disrupting frontoparietal connectivity relative to comparison subjects. Dr. Jacobsen proposes the hypothesis that adolescent cannabis users who also smoke tobacco may be inclined to increase their use of tobacco in order to prevent the attendant decline in cognitive function during nicotine withdrawal. Jacobsen, L., Pugh, K., Constable, R., Westerrveld, M., and Mencl, E. Functional Correlates of Verbal Memory Deficits Emerging During Nicotine Withdrawal in Abstinent Adolescent Cannabis Users. Biological Psychiatry, 59(8) Supplement, pp. 1-10, 2006.

μ Opioid receptor A118G Polymorphism in Association with Striatal Opioid Neuropeptide Gene Expression in Heroin Abusers

μ Opioid receptors are critical for heroin dependence, and A118G SNP of the _ opioid receptor gene (OPRM1) has been linked with heroin abuse. In a sample of European Caucasians, Dr. Yasmin Hurd and colleagues found that approximately 90% of the carriers of the118G allele were heroin users. Postmortem brain analyses showed that preproenkephalin and preprodynorphin genes were downregulated in all heroin users, but that these the effects were exaggerated in 118G subjects and were most prominent for preproenkephalin in the shell of the nucleus accumbens. Reduced opioid neuropeptide transcription was accompanied by increased dynorphin and enkephalin peptide concentrations exclusively in 118G heroin subjects, suggesting that the peptide processing is associated with the OPRM1 genotype. Abnormal gene expression related to peptide convertase and ubiquitin/proteosome regulation was also evident in heroin users. Taken together, these data suggest that alterations in opioid neuropeptide systems might underlie the enhanced opiate abuse vulnerability apparent in 118G individuals. Drakenber, K., Nikjoshkov, A., Horvath, M.C., Fagergren, P., Gharibyan, A., Saarelainen, K., Rahman, S., Nylander, I., Bakalkin, G., Rajs, J., Keller, E., and Hurd, Y.L. μ Opioid receptor A118G Polymorphism in Association with Striatal Opioid Neuropeptide Gene Expression in Heroin Abusers. Proc Natl Acad Sci. 103(20), pp. 7883-7888, 2006.

C957T Polymorphism of the Dopamine D2 Receptor Gene Modulates the Effect of Nicotine on Working Memory Performance and Cortical Processing Efficiency

Nicotine has been shown to produce behavioral effects that vary across individuals in animals and humans, and recent work has shown that genetic variation at the dopamine D2 receptor (DRD2) predicts response to pharmacotherapy for tobacco dependence. To determine whether a polymorphism of the DRD2 gene, C957T, that alters DRD2 binding availability in humans modifies the effects of nicotine on verbal working memory performance and on processing efficiency of brain regions that support verbal working memory, Dr. Leslie Jacobsen and colleagues assessed working memory and brain function in 36 adult subjects, 15 of which carried the 957T allele while 21 were 957C homozygotes. Each participant was studied twice, once after placement of a placebo patch and once after placement of a nicotine patch. Brain function was assessed using functional magnetic resonance imaging while the subjects performed a verbal working memory task. They found that, in performing a task with high verbal working memory load, nicotine administration worsened the performance accuracy and reduced the processing efficiency of brain regions that support phonological rehearsal during verbal working memory in carriers of the 957T allele. These findings are consistent with the notion that genetic variation in the dopamine D2 receptor contributes to individual variation in a range of behavioral and brain responses to nicotine in humans. Jacobsen, L.K., Pugh, K.R., Menci, W.E., and Gelernter, J. C957T Polymorphism of the Dopamine D2 Receptor Gene Modulates the Effect of Nicotine on Working Memory Performance and Cortical Processing Efficiency, Psychopharmacology, 188(4), pp. 530-540, 2006.

Age of First Marijuana Use Associated with Marijuana Use Disorders in Southwest California Native Americans

In several national surveys a younger age of substance usage has been associated with a higher likelihood of the development of dependence. Some studies have suggested that age at first use is primarily an environmentally driven variable, whereas others suggest that it may be partially mediated by a general vulnerability to exhibit problem behaviors. Although Native Americans, overall, have the highest prevalence of substance dependence of any US ethnic group, the relationship of age of first marijuana use on the development of dependence in Native American populations is relatively unknown. In this study, Dr. Cindy Ehlers and her colleagues obtained demographic information and DSM-III-R diagnoses from 525 Southwest California Native American adults residing on contiguous reservations. Multinomial logistic regression was used to investigate the relationship between age of first use and marijuana use disorders. Early marijuana use was found to be strongly associated with abuse and dependence in this population, even in the presence of several other risk factors including externalizing diagnoses. These data suggest that effective environmental prevention efforts at reducing early marijuana use may be an important strategy to lower the prevalence of use disorders in this high risk population. Ehlers, C.L., Slutske, W.S., Gilder, D.A., and Lau, P. Age of First Marijuana Use and the Occurrence of Marijuana Use Disorders in Southwest California Indians. Pharmacology, Biochemistry and Behavior, doi:10.1016/j.pbb.2006.07.024.

Electrophysiological Responses to Affective Stimuli in Native Americans Experiencing Trauma With and Without PTSD

Native Americans are at high risk for exposure to violence and other traumatic events, yet few studies have investigated posttraumatic stress disorder (PTSD) or its neurobiological consequences in Native American communities. In the present study data on traumatic life events and symptoms emerging following those events and electroencephalogram (EEG) spectra and visual event-related potentials (ERPs) to happy, sad, and neutral faces were recorded from 146 Native Americans participants recruited from eight geographically contiguous reservations. Trauma rates in the sample were high: 99% had experienced at least one category of trauma with the mean number being five, 27% had experienced at least eight categories, and 13% met DSM-IV criteria for PTSD. Sixty-three percent of the sample met criteria for a lifetime diagnosis of alcohol dependence, however, the PTSD group did not differ from the larger sample on rates of alcohol dependence or any other diagnostic or demographic variables. An electrophysiological signature for PTSD was found that included increases in high-frequency gamma activity (20-40 Hz) in frontal leads, higher N1 amplitudes to sad stimuli in frontotemporal leads, and longer latency P3 components to happy stimuli in midline, central, and right frontal leads. These findings were observed in participants with PTSD, but not in a group with equivalently high trauma counts. These findings suggest that PTSD is associated with EEG hyperarousal, higher attentional levels to sad stimuli, and slower processing of happy stimuli. They also partially confirm ERP data reported in combat victims with PTSD suggesting that PTSD may induce neurobiological consequences that transcend type of eliciting trauma as well as ethnic and cultural factors. Ehlers, C.L., Hurst, S., Phillips, E., Gilder, D.A., Dixon, M., Gross, A., Lau, P., and Yehuda, R. Electrophysiological Responses to Affective Stimuli in Native Americans Experiencing Trauma With and Without PTSD. Annals of NY Academy of Science, 1071, pp. 125-136, 2006.

First Injection of Ketamine Among Young Injection Drug Users

Ketamine, a dissociative anesthetic, has emerged as an increasingly common drug among subgroups of young injection drug users (IDUs) in cities across the United States. In-depth qualitative interviews were conducted with 213 young IDUs aged 16-28 years recruited in New York, New Orleans, and Los Angeles between 2004 and 2006. While some initiated injection drug use with ketamine, the drug was more frequently injected by IDUs with extensive polydrug using histories. IDUs initiating with ketamine commonly self-injected via an intramuscular mode of administration. The injection group provided crucial knowledge and material resources that enabled the injection event to occur, including ketamine, syringes, and injection skills. Injection paraphernalia was commonly shared during the first injection of ketamine, particularly vials of pharmaceutically-packaged liquid ketamine. Injection events infrequently occurred in a rave or club and more typically in a private home, which challenges ketamine's designation as a 'club' drug. The first injection of ketamine was a noteworthy event since it introduced a novel drug or new mode of administration to be further explored by some, or exposed others to a drug to be avoided in the future. Risk reduction messages directed towards young IDUs should be expanded to include ketamine. Lankenau, S.E., Sanders, B., Bloom, J.J., Hathazi, D., Alarcon, E., Tortu, S., and Clatts, M.C. First Injection of Ketamine among Young Injection Drug Users (IDUs) in Three U.S. Cities. Drug and Alcohol Dependence, doi 10.1016/j.drugalcdep.2006.08.015.

Prevalence of Primary HIV-1 Drug Resistance among Recently Infected Adolescents

Dr. Craig Wilson and his colleagues in the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) examined the prevalence of primary human immunodeficiency type 1 (HIV-1) drug resistance among recently infected youth in the United States. Previous studies on HIV drug resistance have been conducted primarily with adult, male, Caucasian samples. Fifty-five HIV+ youth were recruited from 15 clinical sites across the U.S. and Puerto Rico. Participants included male (65%) and female (35%), African American (47%), Hispanic (24%), Caucasian (22%) youth with an average age of 19.3 years (SD 1.9 yrs). Risk factors for HIV acquisition reported among the youth included having sex under the influence of drugs or alcohol (36% male, 21% female) and exchanging sex for money or drugs (14% male and 5% female). Major mutations conferring HIV drug resistance were present in 10 participants (18%). Eight (15%) had nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations, with the majority (6) having the K103N mutation; 2 (4%) had nucleoside reverse-transcriptase inhibitor (NRTI) mutations; and 2 (4%) had protease inhibitor (PI) mutations. Phenotypic drug resistance was present in 12 (22%) subjects: 10 (18%) for NNRTIs, 2 (4%) for NRTIs, and 3 (5.5%) for PIs. There was a high prevalence of primary HIV-1 drug resistance, particularly to NNRTIs, in this group of recently infected youth. Vivani, R.M., Peralta, L., Aldrovandi, G., Kapogiannis, B.G., Mitchell, R., Spector, S.A. Wilson, C.M. and the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Prevalence of Primary HIV-1 Drug Resistance among Recently Infected Adolescents: A Multicenter Adolescent Medicine Trials Network for HIV/AIDS Interventions Study. Journal of Infectious Diseases, 194(11), pp. 1505-1509, 2006.


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