Director's Report to Council - Research Findings Excerpts

May, 2006

Basic Neurosciences Research

Pregnancy & Cigarette Smoking

Children of women who smoked during pregnancy are at increased risk of dependence when smoking is initiated during adolescence. Studies conducted in experimental animals demonstrate that gestational nicotine exposure attenuated dopamine release induced by nicotine delivered during adolescence. In a recent study, NIDA supported researchers report that exposing pregnant rats to nicotine for a period equivalent to the three trimesters of human brain development period reduced nicotine cholinergic receptor (nAChR) expression in dopaminergic regions during adolescence. This reduction reflects lower nAChR subunits transcript levels and fewer neurons in the VTA, as well as other undefined mechanisms. These data indicate that gestational nicotine exposure affected the developmental regulation of nAChR expression and these effects can endure at least into adolescence. These findings are important from a public health perspective because the down-regulation of nAChR expression during brain development may result in heightened vulnerability to dependence on cigarette smoking that affects adolescent offspring of women who smoked tobacco during pregnancy. Chen, H., Parker, S.L., Matta, S.G., and Sharp, B.M. Gestational Nicotine Exposure Reduces Nicotinic Cholinergic Receptor (nAChR) Expression in Dopaminergic Brain Regions of Adolescent Rats. European Journal of Neuroscience, 22, pp. 380-388, 2005.

Estradiol Selectively Reduces the Stimulated Release of GABA in Rat Striatum

NIDA-supported research has shown that females (rats and humans) appear to be more sensitive to the effects of psychostimulants than males. Research conducted in Dr. Jill Becker's laboratory suggests that the naturally occurring higher concentrations of estrogen in females relative to males may be related to this observation. Becker and her colleagues ovariectomized female rats, replaced the estradiol in some of them, and monitored the efflux of GABA, taurine, and glutamate in the striatum after local application of 75 mM K+. They found that GABA and taurine were both enhanced in the striatum after the K+ challenge, but that the increase in GABA was much less in rats that also were given estradiol; glutamate did not change after challenge in either group. As GABA is the predominant inhibitory transmitter in the brain, this finding may be important for our understanding of how estradiol can alter neurotransmission and how that may be related to the differential effects of stimulants on males and females. Hu, M., Watson, C.J., Kennedy, R.T. and Becker, J.B. Estradiol Attenuates the K+ -induced Increase in Extracellular GABA in Rat Striatum. Synapse, 59, pp. 122-124, 2006.

Estrogen Neuroprotection from HIV Protein-Induced Oxidative Stress

Estrogen replacement therapy in older women is associated with improvement of symptoms of dementia and Parkinson's Disease, so it is believed that estradiol may have neuroprotective qualities in some circumstances. Although the mechanisms of such neuroprotection are unknown, it is possible that estradiol acts as a free-radical scavenger to reduce oxidative stress. Some HIV infected patients experience similar neurological problems, likely involving glutamate and/or oxidative stress-mediated neurotoxicity that may be caused in part by extracellular HIV proteins gp120 and Tat. This study used human neuronal cells grown in culture to test whether estrogen could reverse damage by tat and gp120, as well as the free-radical generator SIN-1. Both tat and gp120, alone and combined, increased oxidative stress as measured by a fluorescent indicator. This increase was greatly diminished in the presence of estradiol but not progesterone or estradiol plus a selective antagonist. When exposed to tat or gp120, synaptosomes made from rat striatal tissue showed reduced dopamine uptake, and this effect was blocked by preincubation with estradiol. Reduced dopamine transporter activity in the striatum is a component of HIV-associated neuropathology; so together these findings suggest that estradiol may be a useful strategy for neuroprotection in the context of HIV-associated neurological disease. Wallace, D.R., Dodson, S., Nath, A. and Booze, R.M. Estrogen Attenuates gp120- and Tat(1-72)-Induced Oxidative Stress and Prevents Loss of Dopamine Transporter Function. Synapse, 59, pp. 51-60, 2006.

Basic Behavioral Research

An Animal Model of Disruption of Maternal Behavior and Intergenerational Effects of Cocaine Treatment

Pregnant women who use cocaine are more likely to abuse or neglect their children and to exhibit deficits in bonding and interacting with their infants. In addition, numerous studies have shown an intergenerational transfer of childhood maltreatment: daughters with a history of abuse or neglect are more likely to exhibit these same behaviors in rearing their own offspring. Dr. Josephine Johns and her colleagues have developed a rat model to investigate the causal factors involved in disruption of maternal behavior and intergenerational transfer. During gestation, they treated rat dams with cocaine, or with saline, or merely handled them as a control condition. Then, after the litters were culled to form comparable sized groups, the dams reared either their natural or cross-fostered litters such that some pups that were not themselves exposed to cocaine were reared by cocaine exposed dams and vice versa. Measures of maternal behavior were then collected on postpartum days 1, 5, 10, and 15. Subsequently, first generation daughters from these various litters were bred with no cocaine exposure, and their maternal behavior towards their natural litters was also studied. The authors found: 1) Dams treated with cocaine, regardless of whether they reared exposed or unexposed pups, showed disruption of the onset of maternal behavior, with a diminishing effect over the postpartum period; 2) Pups prenatally exposed to cocaine were treated differently by all dams, regardless of their own treatment condition. Overall, the dams had a tendency to spend less time caring for these pups, consistent with other animal studies suggesting that drug-exposed rat pups have attributes that may make them vulnerable to neglect; 3) Intergenerational deficits in maternal behavior were apparent in the first generation daughters. This effect largely resulted from prenatal exposure to cocaine, but it was also influenced by the treatment of the dams that had reared them. Johns, J.M., Elliott, D.L., Hofler, V.E., Joyner, P.W., McMurray, M.S., Jarrett, T.M., Haslup, A.M., Middleton, C.L., Elliott, J.C. and Walker, C.H. Cocaine Treatment and Prenatal Environment Interact to Disrupt Intergenerational Maternal Behavior in Rats. Behavioral Neuroscience, 119, pp. 1605-1618, 2005.

Psychological Processes Underlying Risky Decisions

Poor self- control or disinhibition is a characteristic feature of young adults with drug addiction. NIDA researcher Julie Stout and her colleagues recently applied mathematical decision models with a simulated gambling task (SGT) to investigate the processes underlying decision making in 66 drug abusers and 58 control participants. The mathematical model enabled these investigators to separately examine the effects of wins and losses on the SGT. The investigators also assessed impulsivity, social deviance and harm avoidance. The results of the study showed that drug abusers differed from controls in SGT performance and in the processes underlying performance. The results showed also that individual differences, such as personality and drug abuse characteristics, are related to SGT performance. For the men, for example, drug group participants performed more poorly than did controls. Moreover, male drug abusers were more influenced by rewards than by punishments, consistent with other studies that have found drug abusers are hypersensitive to rewards and relatively insensitive to future consequences. In contrast to the findings from men, the performance of women was not straightforward. Control women performed at chance level, which is unusual for a control group on this task. By contrast, performance of the drug-abusing women fell below that of control men, but was slightly better than that of the drug-abusing men. Overall the findings suggest a difference between men and women in their approach to the SGT. Thus, generalizations from studies that have focused on male participants may not be germane to understanding cognitive aspects of drug abuse in women. Finally, individual differences in the decision processes used in performing the SGT task are related not only to drug abuse but also to personality factors. Stout, J.C., Rock, S.L., Campbell, M.C., Busemeyer, J.R. and Finn, P.R. Psychological Processes Underlying Risky Decisions in Drug Abusers. Psychology of Addictive Behaviors, 19, pp. 148-157, 2005.

Potentiation of Cocaine-Primed Reinstatement of Drug Seeking in Female Rats During Estrus

Researchers at the Medical University of South Carolina previously reported that cue-induced reinstatement of cocaine-seeking was greater in male than in female rats at the highest (1.0 mg/kg) and lowest training dose (0.25 mg/kg), but did not differ at the intermediate training doses (0.4, 0.5, 0.6 mg/kg). At the lowest training dose, females in estrus failed to exhibit reinstatement. (Fuchs, R.A., Evans, A., Mehta, R.H., Case, J. M., and See, R.E. Influence of Sex and Estrous Cyclicity on Conditioned Cue-induced Reinstatement of Cocaine-seeking Behavior in Rats. Psychopharmacology, 179, pp.662-672, 2005.) In a follow up study, the researchers sought to determine whether sex and estrous cycle phase play a role in cocaine-primed reinstatement. Following the acquisition of cocaine self-administration (0.5 mg/kg per infusion) and subsequent extinction, reinstatement was assessed with a priming infusion of i.p. cocaine (0, 5.0 or 10.0 mg/kg) in males and in females tested in either the diestrus, proestrus, or estrus phase. Both males and females exhibited a dose-related increase in reinstatement. The effects, however, were opposite those previously observed under conditioned cue-reinstatement. At the 10.0 mg/kg priming dose, females in estrus were more susceptible to reinstatement than both males and non-estrus females (that did not differ). These sex differences in cocaine-induced versus conditioned cue-induced reinstatement could have implications for sex differences in relapse in humans, suggesting perhaps that the factors leading to relapse may differ in males and females. The neuroendocrine basis for the sex differences observed in the present study is unknown, although prior work has shown that dopamine transmission in the prefrontal cortex is associated with cocaine-primed reinstatement, whereas dopamine transmission in the basolateral amygdala is associated with conditioned cue-reinstatement. Further investigation into sex differences and hormonal factors involved in these brain regions and the relationship to reinstatement is warranted. Kippen, T.E., Fuchs, R.A., Mehta, R.H., Case, J.M., Parker, M.P., Bimonte-Nelson, H.A. and See, R.E. Potentiation of Cocaine-primed Reinstatement of Drug Seeking in Female Rats During Estrus. Psychopharmacology, 182, pp. 245-252, 2005.

Exogenous Estrogen Enhances Reinstatement of Cocaine-Seeking Behavior in Ovariectomized Female Rats

In recent studies from the Medical University of South Carolina, reinstatement of cocaine-seeking behavior was found to be affected by phase of the estrous cycle. In a separate investigation by researchers at the University of Minnesota, the role of estrogen as a modulator of reinstatement of cocaine-seeking behavior has been explicitly examined by comparing reinstatement in ovariectomized female rats administered estrogen replacement (OVX+EST), OVX females administered vehicle (OVX+VEH), and sham-operated females administered vehicle (SH+VEH). In the first of two experiments, in the OVX+EST females EST was administered long-term, during training of self-administration, maintenance, extinction and reinstatement. Results indicated that cocaine-primed reinstatement of responding was greater in the OVX+EST and the SH+VEH females than in the OVX+VEH females, indicating that estrogen mediates cocaine-primed reinstatement of responding. In order to distinguish between estrogen's effects on motivation versus learning, in the second experiment, EST was administered short-term, over 3 days prior to and during the reinstatement phase in OVX+EST. As in the first experiments, greater reinstatement occurred in the OVX+EST females compared to OVX+VEH controls. Comparison of OVX+EST rats in the two experiments (i.e., those receiving long versus short-term EST), however, revealed no differences in reinstatement, suggesting to the authors that estrogen's enhancing effects on reinstatement reflects a direct effect of estrogen's enhancement of motivation for cocaine as opposed to an effect of estrogen on associative learning. Larson, E.B., Roth, M.E., Anker, J.J. and Carroll, M.E. Effect of Short- vs. Long-term Estrogen on Reinstatement of Cocaine-seeking Behavior in Female Rats. Pharmacology, Biochemistry and Behavior, 82, pp. 98-108, 2005.

Nicotine Reward More Influenced by Dose Instructions in Female than Male Smokers

Studies on smoking behavior have shown that females are more sensitive to the non-pharmacological cues associated with nicotine and less sensitive to nicotine dose compared to males. These findings suggest that different interventions may be effective in smoking cessation strategies for men and women. Ken Perkins and his colleagues investigated the effects of accurate or inaccurate instructions about nicotine content on smoking reward. The investigators report that accurate instructions increased smoking reward more in women than in men. In a follow-up study, these investigators enrolled 60 subjects who smoked more than 10 cigarettes per day for at least one year to assess the influence of dose instruction versus no instruction on male and female smokers. Subjects were abstinent overnight and were randomly assigned to one of four conditions on the study day. Subjects smoked either a normal cigarette with 0.6mg nicotine (nic) or a de-nicotinized brand with <0.05 mg. Half of each group was given instructions and half were not. After two puffs, they completed the Rose Sensory Questionnaire to assess smoking reward, and the Diener and Emmons Mood Scale. Craving was also measured and smoking behavior was quantified by number of puffs and latency to first puff during a 30-min ad lib smoking period. Data analysis revealed the following: For women, nic increased reward only in the presence of dose instructions, whereas for men, nic increased reward only in the absence of dose instructions. Nic increased positive affect overall. Craving decreased from baseline to post-puffs, but this decrease was greater for men than for women. Also, for men but not women, nic decreased craving in the presence, but not the absence, of instructions (opposite from the observation for smoking reward). In the 30-min ad lib smoking period, nic decreased the latency to the first puff for women, only in the presence of dose instruction; this effect was not seen in men. These observations add to a rapidly accumulating body of evidence that women's smoking behavior is guided by a different set of influences from those that are important for men. Perkins, K.A., Doyle, T., Ciccocioppo, M. Conklin, C., Sayette, M. and Caggiula, A. Sex Differences in the Influence of Nicotine Dose Instructions on the Reinforcing and Self-reported Rewarding Effects of Smoking. Psychopharmacology, 184, pp. 600-607, 2006.

Sibutramine Decreases the Appetitive and Consummatory Aspects of Feeding in Baboons

This study examined how sibutramine (0.06-4.0 mg/kg, i.m.), a clinically effective weight-loss medication that increases extracellular serotonin and norepinephrine levels, affected the appetitive and consummatory aspects of feeding of nonhuman primates (baboons) with task-dependent 24-hour access to food. Sibutramine effects were compared to those of dexfenfluramine (2.0-6.0 mg/kg, p.o.), which primarily increases extracellular serotonin levels. The baboons had to complete a two-response sequence to obtain food: responding on one lever during a 30-min appetitive phase was required before animals could start a consumption phase, where responding on a second lever led to food delivery. Responding during the appetitive phase resulted in presentations of food-related light stimuli only. Both males and females ate significantly less when treated with dexfenfluramine, but not sibutramine. Animals also ate fewer meals when treated with dexfenfluramine, but not with sibutramine. Although sibutramine had no effect on number of light presentations and did not alter performance during the appetitive phase, it did reduce consummatory behavior. Sibutramine increased the latency to the first meal of the session in females, but not males. By contrast, dexfenfluramine increased the latency to the first meal of the session, and decreased both appetitive and consummatory behavior in males and females. The presence of sibutramine's gender-specific effects suggests that sex may play a role in determining its effects on feeding behavior. The behavioral mechanism by which sibutramine decreases food intake appears distinct from anorectic drugs such as dexfenfluramine. That is, sibutramine has its anorectic effect by reducing consummatory behavior (eating), whereas dexfenfluramine reduces both consummatory and appetitive behavior (food seeking). Applied to drug abuse, this behavioral paradigm might be useful for understanding appetitive drug seeking and consummatory drug taking. Foltin, R.W. Effects of Sibutramine on the Appetitive and Consummatory Aspects of Feeding in Non-human Primates. Physiology and Behavior, 87, pp. 280-286, 2006.

Differential Responsivity to Non-Drug Reinforcers Predicts Vulnerability for Relapse in Female Rats

Previous studies have demonstrated that rats that freely explore novel environments, rats that have high activity levels, rats that are impulsive and rats that have a preference for highly palatable tastes readily acquire drug self-administration. Recently, Marilyn Carroll and colleagues examined the maintenance of i.v. cocaine intake and subsequent drug-primed relapse after an extended period of abstinence. In this study, female rats were allowed six hours per day access to running wheels for 21 days and then divided into groups that had high wheel running rates (H) or low rates (L) on the basis of a median split (mean revolutions/day). Patterns of wheel running over the 21 days increased in animals that were subsequently assigned to an H group, while steady rates were observed in the L group. Also, the investigators found that H rats took significantly more cocaine (0.4 mg/kg/infusion) over 14 days on a fixed ratio reinforcement schedule, than their low wheel running counterparts. Following self-administration tests, rats were withdrawn from cocaine by replacing saline in the infusion cannulae for 22 days. In response to a priming dose of cocaine on Day 23, both groups showed drug seeking by increasing their responses on the lever previously associated with drug, but the H group had a 7-fold increase over their prior response rates during extinction, as compared to a 3-fold increase by L animals. These differences cannot be accounted for by responses during extinction because both groups showed similar response rates during this phase. These findings support previous observations suggesting that inherent differences in an individual's behavior for non-drug reinforcers predict the propensity to engage in drug taking and drug seeking. Still to be determined is whether the increased vulnerability seen in maintenance and reinstatement reflects inherent differences in the sensitivity of motivational systems or more rapid neuroadaptations to cocaine exposure. However, as non-drug rewards and drugs of abuse activate similar neurobiological substrates, and H animals showed an escalating pattern of running wheel behavior, these animals may experience deprivation of hedonic effects produced by running. The authors suggest that they may show higher rates of drug intake and relapse in order to compensate for this loss. Larson, E.B. and Carroll, M.E. Wheel Running as a Predictor of Cocaine Self-administration and Reinstatement in Female Rats. Pharmacology Biochemistry and Behavior, 82, pp. 590-600, 2005.

Behavioral and Brain Development Research

Methamphetamine and Other Substance Use during Pregnancy: Preliminary Estimates from the Infant Development, Environment, and Lifestyle (IDEAL) Study

Methamphetamine use is a continuing problem in several regions of the United States yet few studies have focused on prenatal methamphetamine exposure. Dr. Barry Lester and his colleagues are conducting a study to estimate the prevalence and correlates of alcohol, tobacco, and other substance use-including methamphetamine-during pregnancy in four areas of the country (Los Angeles, CA; De Moines, IA; Tulsa, OK; and Honolulu, HI). The sample consists of the first 1632 eligible mothers who consented to participate in a large-scale multi-site study focused on prenatal methamphetamine exposure. This unselected screening sample includes both users and nonusers of alcohol, tobacco, methamphetamine, and other drugs. Substance use was determined by maternal self-report and/or GC/MS confirmation of a positive meconium screen. Overall, 5.2% of women used methamphetamine at some point during their pregnancy. One quarter of the sample smoked tobacco, 22.8% drank alcohol, 6.0% used marijuana, and 1.3% used barbiturates prenatally. Less than 1% of the sample used heroin, benzodiazapenes, and hallucinogens. Multivariate modeling results showed that tobacco smokers and illicit drug users were more likely to be single and less educated, have attended less than 11 prenatal visits, and utilize public financial assistance. IDEAL is the first large-scale investigation to report the prevalence of methamphetamine use during pregnancy in areas of the United States where methamphetamine is a notable concern. Given that this research extends and confirms previous findings showing that high-risk groups of pregnant women can be identified on the basis of basic demographic characteristics, targeted interventions are greatly needed to reduce serious adverse outcomes associated with prenatal alcohol and tobacco use. Arria, A.M., Derauf, C., Lagasse, L.L., Grant, P., Shah, R., Smith, L., Haning, W., Huestis, M., Strauss, A., Grotta, S. D., Liu, J. and Lester, B. Methamphetamine and Other Substance Use during Pregnancy: Preliminary Estimates from the Infant Development, Environment, and Lifestyle (IDEAL) Study. Maternal Child Health Journal, pp. 10, pp. 293-302, 2006.

Cocaine Exposure During Pregnancy and Neonatal Outcomes

Data in this report are for newborns in the Maternal Lifestyle Study, a multi-site longitudinal investigation of health and development following prenatal drug exposure. Associations between cocaine exposure in utero and newborn conditions were examined. One of the strengths of this study is its large sample size; these analyses were carried out for 717 cocaine-exposed infants and 7442 infants not exposed to cocaine. Cocaine-exposed infants were about 1.2 weeks younger, weighed 536 grams less, measured 2.6 cm shorter, and had head circumference 1.5 cm smaller than nonexposed infants. Results did not confirm previous reports in the literature of abnormal anatomic outcomes. Central and autonomic nervous system symptoms were more frequent in the exposed group (i.e., jittery/tremors, high-pitched cry, excessive suck, hyperalertness, and autonomic instability); they were usually transient. No differences were detected in organ systems by ultrasound examination. Exposed infants had more infections, including hepatitis, syphilis, and HIV. Exposed infants were also less often breastfed, had more child protective services referrals, and were more often not living with their biological mother. Bauer, C.R., Langer, J.C., Shankaran, S., et al. Acute Neonatal Effects of Cocaine Exposure During Pregnancy. Archives of Pediatrics and Adolescent Medicine, 159, pp. 824-834, 2005.

Anthropometric and Dysmorphologic Assessments in 6-Year-Old Children Prenatally-Exposed to Cocaine

Anthropometric and dysmorphologic assessments were carried out for 154 6-year-old children prenatally-exposed to cocaine (PCE) and 131 high-risk controls of similar race and social class. Dose-response relationships were observed for adjusted mean height z scores and for weight-for-height z scores, with higher cocaine exposure associated with lower height and lower weight for height. Severity of marijuana use also predicted lower height for age but greater weight for height. Higher average alcohol exposure throughout pregnancy and 3rd trimester predicted lower head circumference and weight z scores, respectively. After controlling for covariates, higher average prenatal cigarette exposure predicted higher incidence of cranial facial abnormalities. First trimester alcohol exposure predicted greater rates of ear abnormalities and third trimester marijuana exposure predicted greater rates of chest and head shape abnormalities. There was not an increased rate of minor anomalies among the PCE cohort, nor was a consistent phenotype identified, leading the authors to conclude that prenatal cocaine exposure is negatively related to specific growth outcomes, including standardized height and weight-for-height, but is not associated with a systematic pattern of structural abnormalities. The dysmorphologic examination utilized a standardized checklist of presence or absence of 271 common dysmorphic characteristics. The authors discuss limitations of the study in detail, such as implications for generalizability as a result of exclusion of children with birth defects (including suspected or diagnosed fetal alcohol syndrome) prior to recruitment. Minnes, S., Robin, N.H., Alt, A.A., et al. Dysmorphic and Anthropometric Outcomes in 6-Year-Old Prenatally Cocaine-Exposed Children. Neurotoxicology and Teratology, 28, pp. 28-38, 2006.

Prenatal Exposure to Substances of Abuse in Children Residing in Russian Orphanages

Over 600,000 children reside in institutional care in Russia, most of them in baby homes and orphanages. The actual prevalence of fetal alcohol spectrum disorders (FASD) and exposure to drugs of abuse among these children is unknown. In this study, a team of researchers from Boston and the Murmansk Region of Russia, led by Dr. Laurie Miller from Tufts-New England Medical Center conducted a systematic survey of phenotypic features associated with prenatal alcohol exposure among institutionalized Russian children and related these findings to their growth, development, medical, and social histories. Phenotypic screening was conducted for all 234 children residing in three baby homes in the Murmansk region of Russia (mean age 21+12.6 months). These baby homes care not only for orphaned children but also abandoned and relinquished children and children whose parents' rights were terminated. Phenotypic expression scores were devised based on facial dysmorphology and other readily observable physical findings. Growth measurements from birth, time of placement in the baby home, and at present were analyzed. In addition, the charts of 64% of the children were randomly selected for retrospective review. Information collected included maternal, medical, developmental, and social histories. Thirteen percent of children had facial phenotype scores highly compatible with prenatal alcohol exposure and 45% had intermediate facial phenotype scores. These scores correlated with maternal gravidity and age. At least 40% of mothers in whom history was available ingested alcohol during pregnancy; some also used illicit drugs and tobacco. Z scores for growth measurements corresponded to phenotypic score, as did the degree of developmental delay. Children with no or mild delay had significantly lower phenotypic scores than those with moderate or severe delay (p = 0.04); more than 70% of children with high phenotypic scores were moderately or severely delayed. More than half of residents of the baby homes in Murmansk, Russia, have intermediate (45%) or high (13%) phenotypic expression scores suggesting prenatal exposure to alcohol. Despite good physical care, stable daily routine, availability of well-trained specialists, and access to medical care, these vulnerable children show significant growth and developmental delays compared with their institutionalized peers. Miller, L.C., Chan, W., Litvinova, A., Rubin, A., Comfort, K., Tirella, L., Cermak, S., Morse, B., Kovalev, I., and Boston-Murmansk Orphanage Research Team. Fetal Alcohol Spectrum Disorders in Children Residing in Russian Orphanages: A Phenotypic Survey. Alcohol: Clinical and Experimental Research, 30 (3), pp. 531-538, 2006.

Caregiver Substance Abuse Associated with Violence Exposure among Young Urban Children

Dr. Delaney-Black and her colleagues at Wayne State University examined the relative importance of caregiver substance abuse as a correlate of child-reported exposure to violence in this study of 407 female African-American primary caregivers and their children 6 to 7 years of age. The association between child report of violence and exposure to substance abuse by others (both within and outside the home) was considered after controlling for variance accounted for by child characteristics, caregiver characteristics, home environment, and neighborhood environment (including neighborhood crime). Caregiver alcohol abuse, children's witnessing of drug use in the home, and children's witnessing of drug deals all explained significant additional variance in violence exposure. These findings suggest that for early elementary-age children, meaningful prevention of violence exposure may be possible via addressing their exposure to substance abuse in their home and community. Ondersma, S.J., Delaney-Black, V., Covington, C.Y., Nordstrom, B. and Sokol, R.J. The Association between Caregiver Substance Abuse and Self-Reported Violence Exposure among Young Urban Children. Journal of Traumatic Stress, 19 (1), pp. 107-118, 2006.

Maternal Acceptance Moderates Relationship between Community Violence Exposure and Child Functioning

Children in the United States are exposed to considerable community violence that has been linked to child functioning, however, not all those exposed experience negative outcomes. Dr. Delaney-Black and her colleagues examined the potential buffering or moderating role of maternal acceptance in the relationship between child-reported community violence exposure (reports of witnessing and being a victim of community violence) and internalizing and externalizing problems. In a sample of 268 urban African American first graders community violence exposure was significantly related to symptoms of post-traumatic stress, but did not correlate with either internalizing or externalizing problems for all children, after control for demographics, maternal mental health, and general life stress. However, children's perceptions of maternal acceptance moderated the relationship between violence exposure and internalizing and externalizing problems that included being withdrawn, anxious-depressed, and demonstrating delinquent behavior. Children with the lowest levels of self-reported maternal acceptance were most impacted by community violence. In this sample of urban first graders, low levels of maternal acceptance placed children at greater risk for adverse outcomes associated with community violence exposure compared to moderate and high levels of maternal acceptance. Bailey, B.N., Hannigan, J.H., Delaney-Black, V., Covington, C.Y., Covington, C.Y. and Sokol, R.J. The Role of Maternal Acceptance in the Relation between Community Violence Exposure and Child Functioning. Journal of Abnormal Child Psychology, 34, pp. 57-70, 2006.

Maternal Behavior among Drug Using Mothers

In this report, Dr. Rina Eiden and her colleagues examined the association between maternal cocaine use and maternal behavior in an infant feeding context. The investigators also tested a conceptual model predicting maternal insensitivity during mother-infant interactions. The analyses involved 130 mother-infant dyads (68 cocaine-exposed and 62 noncocaine-exposed) recruited after birth and assessed at 4-8 weeks of infant age. Results indicated that when the effects of prenatal cocaine use were examined in the context of polydrug use, maternal psychopathology, maternal childhood history, and infant birth weight, only postnatal cocaine use and maternal depression/anxiety were unique predictors of maternal insensitivity during the mother-infant interactions. Eiden, R.D., Stevens, A., Schuetze, P. and Dombkowski, L.E. A Conceptual Model for Maternal Behavior Among Polydrug Cocaine-Using Mothers: The Role of Postnatal Cocaine Use and Maternal Depression. Psychology of Addictive Behaviors, 20, pp. 1-10, 2006.

Gender Differences in the Prediction of Condom Use Among Incarcerated Juvenile Offenders

Dr. Angela Robertson and her colleagues at Mississippi State University examined the predictive value of the Information-Motivation-Behavioral Skills (IMB) model of HIV prevention for sexually active juvenile offenders at risk for substance abuse and explored gender differences in IMB model constructs for condom-protected vaginal intercourse. Self-report measures of HIV/AIDS knowledge, pro-condom peer influence, risk perception, condom attitudes, condom use self-efficacy, frequency of vaginal intercourse, and frequency of condom-protected vaginal intercourse were collected from predominantly African-American detainees 13-18 years of age. Analysis consisted of structural equation models for the combined sample (N = 523) and for separate gender groups (328 males and 195 females). In the combined model, condom use was significantly predicted by male gender, peer influence, positive condom attitudes, and condom self-efficacy. In separate gender analyses, condom use among adolescent males was predicted by peer influence (modestly) and by positive condom attitudes, whereas condom use among females was predicted by peer influence, self-efficacy, and condom attitudes. Compared with males, females reported significantly greater knowledge, less peer influence, higher perceived risk for infection, more positive condom attitudes, and more self-efficacy, but they reported less condom use. The authors conclude that females may find it difficult to use condoms consistently despite their awareness of their efficacy. Power imbalances or other dynamics operating in their relationships with males need further exploration. Gender differences in the relationship between condom self-efficacy and condom use were masked in the analysis of the total sample, indicating the value of testing theories of HIV prevention separately by gender. Robertson, A.A., Stein, J.A., and Baird-Thomas, C. Gender Differences in the Prediction of Condom Use among Incarcerated Juvenile Offenders: Testing the Information-Motivation-Behavior Skills (IMB) Model. Journal of Adolescent Health, 38 (1), pp. 18-25, 2006.

Clinical Neuroscience Research

Ambiguity in Groups of Emotional Faces Recruits Ventromedial Prefrontal Cortex

Paulus and colleagues at the University of California, San Diego, used fMRI in a social neuroscience study of affective appraisal of the mood of a group of people. Affective neuroimaging research often uses individual faces as stimuli when exploring the neural circuitry involved in social appraisal, but single face paradigms may not generalize to settings where multiple faces are simultaneously processed. In this study groups of multiple matrices of affective faces were briefly presented during fMRI scans. Subjects were asked to decide whether there were more angry or happy faces (emotional decision) or whether there were more male or female faces (gender decision). In each condition, the array contained either an equal (ambiguous trials) or an unequal (unambiguous trials) distribution of one affect or gender. Ambiguous trials relative to unambiguous trials activated regions implicated in conflict monitoring and cognitive control, including the dorsal anterior cingulate cortex (ACC), dorsolateral PFC, and posterior parietal cortex. The ventromedial PFC (including the ventral ACC) was activated specifically by ambiguous affective decisions compared with ambiguous gender decisions. This supports the dissociation of the ACC into dorsal cognitive and ventral affective divisions, and suggests that the ventromedial PFC may play a critical role in appraising affective tone in a complex display of multiple human faces. This study forms the foundation for investigating whether drug abusers show impairment in brain systems involved in affective appraisal of groups. Since many treatment approaches involve group therapy, such a dysfunction could have substantial implications for treatment development. Simmons, A., Stein, M.B., Matthews, S.C., Feinstein, J.S. and Paulus, M.P. Affective Ambiguity for a Group Recruits Ventromedial Prefrontal Cortex. Neuroimage, 29(2), pp. 655-661, 2006.

Increased White Matter Hyperintensities in Male Methamphetamine Abusers

Renshaw and colleagues at McLean Hospital used structural MRI to assess the prevalence, severity, and location of white matter signal hyperintensities (WMH) in methamphetamine (MA) abusers. Axial T-2 weighted images and fluid attenuated inversion recovery axial images were obtained using a 3T MR scanner from 33 MA abusers and 32 age- and gender-matched healthy comparison subjects. The severity of WMH was assessed separately for deep and periventricular WMH. Ordinal logistic regression models were used to assess the odds ratio for WMH. MA abusers had greater severity of WMH than the healthy comparison subjects (odds ratio: 7.06, 8.46, and 4.56 for all, deep, and periventricular WMH, respectively). Severity of deep WMH correlated with total cumulative dose of MA (p = 0.027). These differences were mainly due to increased WMH in male MA abusers. There was greater severity of WMH in male than female MA abusers (odds ratio = 10.00). Male MA abusers had greater severity of WMH than male comparison subjects (odds ratio = 18.86), but there was no significant difference in WMH severity between female MA abusers and female comparison subjects. Increased WMH in MA abusers may be related to MA-induced cerebral perfusion deficits. The lower severity of WMH in female MA abusers may be due to estrogen's protective effect against ischemic or neurotoxic effects of MA. Bae, S.C., Lyoo, I.K., Sung, Y.H., Yoo, J., Chung, A., Yoon, S.J., Kim, D.J., Hwang, J., Kim, S.J. and Renshaw, P.F. Increased White Matter Hyperintensities in Male Methamphetamine Abusers. Drug and Alcohol Dependence, 81(1), pp. 83-88, 2006.

Sex, Stress, and Fear: Gender and Individual Differences in Conditioned Learning

LaBar and colleagues at Duke University investigated the relationship among sex, stress hormones, and fear conditioning in humans in order to elucidate factors that contribute to individual variation in emotional learning. Forty-five healthy adults (22 females) underwent differential delay conditioning, using fear-relevant conditioned stimuli and a shock unconditioned stimulus. Salivary cortisol samples were taken at baseline and after acquisition training and a 24-h-delayed retention test. Acquisition of conditioning significantly correlated with postacquisition cortisol levels in males, but not in females. This sex-specific relationship was found despite similar overall levels of conditioning, unconditioned responding, and cortisol. There was no effect of postacquisition cortisol on consolidation of fear learning in either sex. These findings have implications for the understanding of individual differences in fear acquisition and risk factors for stress-elicited relapse in substance abusers. Zorawski, M., Cook, C.A., Kuhn, C.M. and LaBar, K.S. Sex, Stress, and Fear: Individual Differences in Conditioned Learning. Cognitive Affective & Behavioral Neuroscience, 5(2), pp. 191-201, 2005.

Gender and Functional Asymmetry of Ventromedial Prefrontal Cortex

Bechara and colleagues at the University of Iowa investigated whether gender plays a role in the development of defects in social conduct, emotional functioning and decision-making, following unilateral VMPC damage. A previous lesion study found that the more right-sided sector of the ventromedial prefrontal cortices (VMPCs) was critical for social/emotional functioning and decision-making than the left side. However, all but one of the subjects in that study were men, and the one woman did not fit the pattern very well. The study sample consisted of same-sex pairs of men or women patients who had comparable unilateral VMPC damage in either the left or right hemisphere. Two male pairs and one female pair were formed, and authors included two additional women with unilateral right VMPC damage (8 patients in all). The domains of measurement covered social conduct, emotional processing and personality, and decision-making. A systematic effect of gender was found on the pattern of left-right asymmetry in VMPC. Men had severe function defects following unilateral right VMPC damage, but not following left-sided damage. In contrast, functional defects were only found in women with unilateral left VMPC damage, whereas with right-sided damage the defects were mild or absent. The findings suggest that asymmetric, gender-related differences exist in the neurobiology of left and right VMPC sectors and as a result men and women may use different strategies to solve similar problems that parallel differences in information processing between hemispheres. Such differences could reflect. Tranel, D., Damasio, H., Denburg, N.L. and Bechara, A. Does Gender Play a Role in Functional Asymmetry of Ventromedial Prefrontal Cortex? Brain, 128(12), pp. 2872-2881, 2005.

COMT SNPs and Haplotypes Differentially Associated with European and African American, Male and Female Smokers

Li and colleagues studied 5 SNPs and associated haplotypes in over 600 nuclear families. Results showed the Val/Met polymorphism (rs4680) was associated with three different (but related) measures of smoking. Haplotype analysis revealed one SNP trio was a protective factor for European Americans; another three-SNP haplotype was protective for African Americans while a third was high-risk. However, further analysis showed the protective factors were only for the African American females and the European American males. Both SNPs and haplotypes had different frequencies in the two ethnic groups. These data suggest that COMT variants are related to nicotine dependence but that the effects are both sex and ethnic specific. Other studies have shown the val/met polymorphism to be related to low extraversion and high neuroticism usually in females. Beuten, J., Payne, T.J., Ma, J.Z. and Li, M.D. Significant Association of Catechol-O-Methyltransferase (COMT) Haplotypes with Nicotine Dependence in Male and Female Smokers of Two Ethnic Populations Neuropsychopharmacology, 31, pp. 675-684, 2006.

Sex Differences in Smoking Initiation and Consumption and in Linkage Analysis

Madden and her colleagues queried their sample of Australian twins with regard to smoking onset and continuation as a "smoker" in both males and females. Results demonstrated the presence of sex differences in the magnitude of genetic and genetic and environmental influences. Heritability was higher for men; shared environment was important only for women in a group where self-described non-smokers were excluded. For smoking initiation, the strongest linkage peak was at 20p13; for cigarette consumption where non-smokers were included, the highest peak was at 11q23 with secondary peaks at4q35 and 6p34. The peaks were similar but not the same when non-smokers were excluded. Also males tended to have the stronger peaks. These results support some recent studies and add to the growing list of possible susceptibility genes for smoking. Morley, K.I., Medland, S.E., Ferreira, M.A., Lynsky, M.T., Montgomery, G.W., Heath, A.C., Madden, P.A. and Martin, N.G. A Possible Smoking Susceptibility Locus on Chromosome 11p12: Evidence from Sex-Limitation Linkage Analyses in a Sample of Australian Twin Families. Behavior Genetics, 36(1), pp. 87-99.

Low Socialization Is Correlated with Increased Activity in the Medial Prefrontal Cortex in Cocaine-Dependent Women

Rajita Sinha, T. R. Kosten and C.S. Li assessed antisocial personality using the California Psychological Inventory socialization scale and compared it to brain activation during a script-guided induction of stress. Three (right inferior frontal cortex, right anterior cingulate and medial prefrontal cortex (MDFC)) of eight brain regions which showed greater activation during stress imagery than at baseline and which were within the corticolimbic circuitry were correlated with the socialization score separately for males and females. The scores were all correlated but only the MPFC in females was (negatively) significant. A low socialization score means a lower arousal to stress and has been previously related to physiological measurements such as skin conductance and heart rate. In other words, females seemed to be underaroused during stress imagery (a suggestion of antisocial pathology) which is shown to be related to increased brain activity in the MDFC. Li, C.S., Kosten, T.R. and Sinha, R. Antisocial Personality and Stress-Induced Brain Activation in Cocaine-Dependent Patients. Neuroreport, 17(3), pp. 243-247, 2006.

The Alpha-4 Subunit of the Nicotinic Acetylcholine Receptor Is Ethnically-Specific and Gender-Specific Associated with Nicotine Dependence

M.D. Li and associates assessed over 2,000 European or African American subjects from over 600 families. Two (different) single nucleotide polymorphisms are associated with measures of smoking in each of the two ethnic origin groups. After correction, one SNP and a haplotype remained significant in African American females. There were no associations with the beta-2 subunit of the receptor. These data suggest that there is involvement of the alpha 4 subunit of the nicotinic acetylcholine receptor in nicotine addiction. Li, M.D., Beuten, J., Ma, J.Z., Payne, T.J., Lou, X.Y.., Garcia, V., Duenes, A.S., Crews, K.M. and Elston, R.C. Ethnic- and Gender-Specific Association of the Nicotinic Acetylcholine Receptor Alpha4 Subunit Gene (CHRNA4) with Nicotine Dependence. Human Molecular Genetics, 14(9), pp. 1211-1219, 2005.

Epidemiology and Etiology Research

Cigarette Smoking in Two American Indian Reservation Populations

This study describes the prevalence and correlates of cigarette smoking in two American Indian reservation populations using multinomial logistic regression on data from a population-based, cross-sectional study of Southwest and Northern Plains American Indians aged 15-54. 19% of Southwest men, 10% of Southwest women, 49% of Northern Plains men and 51% of Northern Plains women were current smokers. Male gender and younger age were associated with higher odds of smoking in the Southwest tribe, whereas current or former marriage and less time spent on a reservation were associated with higher odds of smoking in the Northern Plains population. Alcohol consumption was strongly associated with higher odds of smoking in both groups. Nez Henderson, P., Jacobsen, C., Beals, J. and the AI-SUPERPFP Team. Correlates of Cigarette Smoking Among Selected Southwest and Northern Plains Tribal Groups: The AI-SUPERPFP Study. Am J Public Health, 95, pp. 867-872, May 2005.

Exposure to Trauma among Two American Indian Tribes

This study examined the prevalence of trauma in 2 large American Indian communities in an attempt to describe demographic correlates and to compare findings with a representative sample of the US population. The researchers determined differences in exposure to each of 16 types of trauma among 3084 tribal members aged 15 to 57 years through structured interviews. The researchers compared prevalence rates of trauma, by gender, across the 2 tribes and with a sample of the US general population. The researchers used logistic regression analyses to examine the relationships of demographic correlates to trauma exposure. Lifetime exposure rates to at least 1 trauma (62.4%-67.2% among male participants, 66.2%-69.8% among female participants) fell at the upper limits of the range reported by other researchers. Unlike the US general population, female and male American Indians exhibited equivalent levels of overall trauma exposure. Members of both tribes more often witnessed traumatic events, experienced traumas to loved ones, and were victims of physical attacks than their counterparts in the overall US population. Many American Indians live in adverse environments that place them at high risk for exposure to trauma and harmful health sequelae. Manson, S., Beals, J., Klein, S., Croy, C., and Croy, C. Social Epidemiology of Trauma Among 2 American Indian Reservation Populations. Am J Public Health, 95(5), pp. 851-859, 2005.

Psychosocial Adjustment among Drug Using Suburban Adolescents

Despite ongoing concern about substance use during adolescence, very little is known about alcohol and drug use among teens living in affluent social settings. In this longitudinal study, cluster analysis was used to characterize patterns of substance use and change in other dimensions of psychosocial adjustment within a cohort of 292 high school students (54% girls) living in an affluent, suburban community. When compared with a cluster of students reporting minimal use, clusters reporting escalating, declining, and persistently high use consistently demonstrated relatively poorer psychosocial adjustment. Moreover, other dimensions of psychosocial adjustment remained relatively stable despite changes in substance use, and there were relations involving substance use and other aspects of psychosocial adjustment that may be specific to this social setting. McMahon, T. and Luthar, S. Patterns and Correlates of Substance Use Among Affluent, Suburban High School Students. J Clin Child Adolesc Psychol, 35(1), pp. 72-89, 2006.

Late Onset Antisocial Behavior and Risk for SUD

This study compared late onset antisocial behavior with the more commonly recognized two courses, persisting (beginning by early adolescence and continuing through late adolescence) and desisting (stopping by mid-adolescence) antisocial behavior, in terms of risk for later substance dependence and background risk factors (gender, IQ, socioeconomic status, parental antisocial behavior, and parental divorce). A population-based sample of 500 twins from the Minnesota Twin Family Study, evaluated at ages 17 and 20, was used. The results indicated that youths with late onsets were similar to those with persisting antisocial behavior and that both groups were at higher risk of later nicotine, alcohol, and cannabis dependence than controls; both also had similarly high levels of background risk factors. The late-onset group included a significant overrepresentation of females, whereas the persisting and desisting groups included more males. The authors conclude that late-onset antisocial behavior has many of the same negative correlates of persisting antisocial behavior but includes significantly more females. Clinical implications include the need to recognize this pathway, particularly for vulnerable young women, even though they do not meet criteria for the diagnosis of antisocial personality disorder, for both etiologic studies and preventive interventions. Marmorstein, N. and Iacono, W. Longitudinal Follow-Up of Adolescents with Late-Onset Antisocial Behavior: A Pathological Yet Overlooked Group. J Am Acad Child Adolesc Psychiatry, 44(12), pp. 1284-1291, 2005.

Social Competence among Children of Alcoholics

In the current study, the authors tested the hypothesis that children of alcoholic parents (COAs) show deficits in social competence that begin in early childhood and escalate through middle adolescence. A community sample of families with high levels of alcohol use disorder and control families was used (n=110 COAs and 263 controls). Teachers, parents, and children reported on the social competence of COAs and matched controls assessed from ages 6 to 15. Hierarchical linear growth models revealed different patterns of change in social competence across development as a function of the reporter of various indicators of competence. Moreover, female COAs showed deficits in social competence in early childhood that receded in adolescence and that varied across subtypes of parent alcoholism. Implications of these findings for understanding the development of social competence in children, and at-risk children in particular, are discussed. Hussong, A., Zucker, R., Wong, M., Fitzgerald, H., and Puttler, L. Social Competence in Children of Alcoholic Parents Over Time. Dev Psychol, 41(5), pp. 747-759, 2005.

Behavior Problems among Maltreated Children

Maltreated children are at increased risk for behavior problems. This study examines a model in which shame mediates the potential relation between maltreatment and anger, and anger mediates the potential relation between shame and behavior problems. Participants were 177 children (ages 3 to 7 years) and their mothers, 90 of whom had histories of perpetrating neglect and/or physical abuse. Physical abuse, but not neglect, was related to increased shame during an evaluative task; shame was related to increased anger; and anger to teacher ratings of total behavior problems and externalizing problems. Age moderated the relation between physical abuse and adjustment, as abuse was related to more total problems only among the younger children. Anger was a significant mediator of shame and both behavior problems and externalizing problems. Shame, anger, age, and type of maltreatment appear to be important factors in explaining variance in behavioral adjustment following a history of maltreatment. Bennett, D., Sullivan, M., and Lewis, M. Young Children's Adjustment as a Function of Maltreatment, Shame, and Anger. Child Maltreat, 10(4), pp. 311-323, 2005.

Predictors of Early Initiation of Vaginal and Oral Sex among Urban Young Adults in Baltimore, Maryland

Over the past three decades, most research on adolescent sexual behavior has focused on vaginal intercourse and related behaviors, including contraception and unintended pregnancy. In this study, researchers describe the prevalence and correlates of vaginal, oral, and anal sex in an epidemiologically defined population in Baltimore, Maryland. Young adults (ages 18-24), who had been enrolled in a behavioral intervention trial during elementary school, were interviewed by telephone between 1998 and 2002 to assess their sexual behavior. Of 1679 respondents interviewed, 70.8% were Black and 55% were women. Overall, 93% of the young adults reported vaginal intercourse, 78% reported receiving oral sex, 57% reported performing oral sex, and 10% reported receptive anal intercourse. Among men, 27% reported insertive anal intercourse. Blacks initiated vaginal intercourse at an earlier age than Whites; White women performed oral sex earlier than Black women. Significant interactions were observed between age of first vaginal partner and both gender and race/ethnicity. Blacks with older partners initiated sex at an earlier age than both Blacks with a partner the same age or younger and Whites. A relationship between older female sex partners and earlier vaginal sex initiation among men was observed. These findings indicate that older sex partners play an important role in sexual initiation among young adults. In light of the rates of oral and anal sex, sexual education and intervention programs should address the risk for unintended consequences of these behaviors. Ompad, D., Strathdee, S., Celentano, D. and Latkin, C. Predictors of Early Initiation of Vaginal and Oral Sex Among Urban Young Adults in Baltimore, Maryland. Arch Sex Behav, 35(1), pp. 53-65, 2006.

The Impact of Emotional Distress on HIV Risk Reduction among Women

This study evaluated whether 333 seronegative African American female drug users (aged 18-59 years) participating in an HIV intervention and with higher levels of emotional distress, specifically symptoms of depression and anxiety, reduced HIV risk behaviors to a lesser extent than those with lower levels of emotional distress. Participants were recruited between June 1998 and January 2001 from inner-city Atlanta (Georgia, U.S.) neighborhoods and were randomly assigned to one of two enhanced gender-specific and culturally specific HIV intervention conditions or to the NIDA standard condition. Participants were interviewed at baseline, post-intervention and at 6-month follow-up with a structured questionnaire including information on sociodemographics, sexual and drug-using behavior, and psychosocial characteristics. Despite a significant decline in symptoms of emotional distress during the study period, the women in this sample reported high levels of depressive and anxiety symptoms at baseline and 6-month follow-up. Higher levels of emotional distress were positively associated with post-intervention sexual and drug-taking risk. Women in both enhanced intervention conditions reduced their sexual and drug-taking risks more than women in the standard intervention. Those in the motivation intervention arm experienced a greater reduction in depressive symptoms, accompanied by a greater reduction in sexual risk behavior. Findings suggest the need for effective interventions and mental health resources among subgroups of high-risk women who may be most resistant to behavioral change. Sterk, C., Theall, K. and Elifson, K. The Impact of Emotional Distress on HIV Risk Reduction Among Women. Subst Use Misuse, 41(2), pp. 157-173, 2006.

Drug Treatment Disparities among Hispanic Drug-Using Women in Puerto Rico and New York City

This paper reports findings on 334 out-of-treatment drug users in Puerto Rico and 617 in New York City, at the 6-month follow-up interview of a longitudinal survey. Main outcomes were health care and drug treatment utilization since baseline, assessed by asking participants if they had received physical or mental health services (including HIV medications), and if they had been in methadone maintenance, inpatient or outpatient drug treatment, or drug treatment while incarcerated. Chi-square tests were used to evaluate associations between gender and other correlates. Logistic regression was used to calculate the contribution of each variable in predicting use of drug treatment. The analysis suggests that women in both sites were likely to suffer from disparities in health care and drug treatment utilization when compared with men, although women in New York utilized more drug treatment resources and were more embedded in the immediate family than their female peers in Puerto Rico. Further research to specify the impact of contextual factors at the organizational and community levels, among members of the same ethnic group residing in different sites, may prove valuable in identifying the health needs and factors that impede or facilitate drug-using women in obtaining the most appropriate treatment. Findings from these studies can help in developing appropriate public health policy and science-based drug treatment programs to eliminate such disparities as those identified in this study. Robles, R., Matos, T., Deren, S., Colon, H., Sahai, H., Marrero, C., Reyes, J., Andia, J., and Shepard, E. Drug Treatment Disparities among Hispanic Drug-Using Women in Puerto Rico and New York City. Health Policy, 75(2), pp. 159-169, 2006.

Physical Victimization Related to Alcohol and Cigarette Use

This study examined associations between two forms of peer victimization, physical and relational, and externalizing behaviors including drug use, aggression, and delinquent behaviors among a sample of 276 predominantly African American eighth graders attending middle school in an urban public school system. Regression analyses indicated that physical victimization was significantly related to cigarette and alcohol use but not to advanced alcohol and marijuana use; relational victimization contributed uniquely to all categories of drug use after controlling for physical victimization. Physical victimization was also significantly related to physical and relational aggression and delinquent behaviors, and relational victimization made a unique contribution in the concurrent prediction of these behaviors. Physical victimization was more strongly related to both categories of alcohol use, aggression, and to delinquent behaviors among boys than among girls. In contrast, relational victimization was more strongly related to physical aggression and marijuana use among girls than among boys, but more strongly related to relational aggression among boys than among girls. These findings provide information about the generalizability of prior research and have important implications for intervention efforts. This research was supported by Cooperative Agreement U81/CCU309966 from the Centers for Disease Control and Prevention (CDC). Sullivan, T., Farrell, A., and Kliewer, W. Peer Victimization in Early Adolescence: Association Between Physical and Relational Victimization and Drug Use, Aggression, and Delinquent Behaviors Among Urban Middle School Students. Dev. Psychopathol., 18(1), pp. 119-137, 2006.

Psychiatric and Drug Use Disorders in Children of Antisocial Parents

The authors examined the prevalence of common externalizing and internalizing disorders in the pre-adolescent and late adolescent offspring of antisocial parents. Lifetime diagnoses for a sample of 11-year-old twins (958 males, 1042 females) and a sample of 17-year-old twins (1332 males, 1434 females) from the Minnesota Twin Family Study, as well as their parents, were obtained through in-person interviews. Odds ratios were calculated for the effect of the parent's diagnosis on the child's diagnosis, controlling for the effect of the co-parent's diagnosis. For the 11 year olds, antisocial behavior in either parent was associated with increased odds of a variety of externalizing disorders. For the 17 year olds, parental antisociality was associated with increased risk for a range of externalizing and internalizing disorders, including paternal antisociality with abuse and dependence on nicotine, alcohol, and drugs. This study extends the previous literature by using a population-based sample and looking at gender of both parents and offspring, finding that each parent has an effect net any effects of the co-parent. Herndon, R., and Iacono, W. Psychiatric Disorder in the Children of Antisocial Parents. Psychol Med, 35(12), pp. 1815-1824, 2005.

HIV, HBV, and HCV Infections among Drug-Involved, Inner-City, Street Sex Workers in Miami, Florida

This study describes the rates of HIV, HBV, and HCV seropositivity among drug-involved, female street sex workers in low-income, inner-city sections of Miami, Florida; further, their sociodemographic characteristics, drug use, and sexual risk behaviors were assessed; and predictors of infection were reported. A sample of 586 sex workers was recruited through targeted sampling methods, interviewed, and counseled and tested for the presence of antibody to HIV, HBV, and HCV. Respondents' median age was 38 years, median time in sex work was 14 years, all were heavily involved in the use of alcohol and drugs, and 42% were homeless. More than half (51.0%) had engaged in unprotected vaginal sex in the past month. Prevalences were HIV, 22.4%; HBV, 53.4%; HCV, 29.7%. A multidimensional public health program must address not only issues related to unsafe sex, but also the problems of drug abuse, homelessness, and other lifestyle factors that contribute to risk behaviors. Inciardi, J., Surratt, H.L., and Kurtz, S.P. HIV, HBV, and HCV Infections Among Drug-Involved, Inner-City, Street Sex Workers in Miami, Florida. AIDS Behav, 10(2), pp. 139-147, 2006.

Sex, Touch, and HIV Risk Among Ecstasy Users

This study examined HIV risk among heavy and non-heavy ecstasy users, focusing specifically on touch and sexual behavior as part of the ecstasy experience. Structured interviews were conducted with 268 young adult (age 18-25) ecstasy users in Atlanta, Georgia. Heavy ecstasy users were more likely to have been tested for HIV than non-heavy users (79 vs. 68%). However, they also were more likely to perceive no chance of contracting HIV (36 vs. 26%). Touch, both sensual and sexual, was a significant part of the ecstasy experience. In addition, ecstasy use seemed to increase the sexual desire, however, not the ability to achieve an orgasm. Heavy users reported more sexual risk-taking than their non-heavy using counterparts. Results suggest that the setting of ecstasy use also may influence involvement in risk behaviors. Future longitudinal studies are needed on the relationship between ecstasy use, touch, sexual arousal and ability, and risk behavior. Theall, K.P., Elifson, K.W. and Sterk, C.E. Sex, Touch, and HIV Risk Among Ecstasy Users. AIDS Behav, 10(2), pp. 169-178, 2006.

Needle-Sharing among Young IV Drug Users and Their Social Network Members: The Influence of the Injection Partner's Characteristics on HIV Risk Behavior

Injection drug use is a risk factor for HIV among adolescents and young adults, yet the interpersonal dynamics of needle-sharing among young injectors remain poorly understood. Research has focused on identifying the characteristics of injecting drug users (IDUs) that increase their risk of needle-sharing. Most studies have not taken into consideration IDUs' decisions to share needles with certain partners but not with other partners. This study examined partner characteristics associated with needle-sharing among 96 male and 77 female young adult IDUs who had shared needles previously. Men were most likely to share needles with partners who gave them emotional support, partners who they injected or who injected them, and partners with whom they had had sex. Women were most likely to share needles with partners who they injected or who injected them, partners with whom they had discussed HIV risk, and partners with whom they had had sex. Results indicate that needle-sharing occurs within the context of mutual injection rituals and close emotional and sexual relationships. These findings point to the need for targeted interventions to help young IDUs avoid needle-sharing with intimate partners. Unger, J.B., Kipke, M.D., De Rosa, C.J., Hyde, J., Ritt-Olson, A., and Montgomery, S. Needle-Sharing Among Young IV Drug Users and Their Social Network Members: The Influence of the Injection Partner's Characteristics on HIV Risk Behavior. Addict Behav, 31(9), pp. 1607-1618, 2006.

Alcohol and Other Drug Use in the US and Australia

Although youth drug and alcohol harm minimization policies in Australia are often contrasted with the abstinence and zero tolerance policies adopted in the United States, there has been little research directly comparing youth substance use behaviour in the two countries. Three state representative samples in Victoria, Australia (n = 7898) and in the US states of Oregon (n = 15,224) and Maine (n = 16,245) completed a common cross-sectional student survey. Rates of alcohol use (lifetime alcohol use, recent use in the past 30 days), alcohol use exceeding recommended consumption limits (binge drinking: five or more drinks in a session), other licit drug use (tobacco use), and norm-violating substance use (substance use at school, use in the past 30 days of marijuana or other illicit drug use) were compared for males and females at ages 12-17. Rates were lower (odds ratios 0.5-0.8) for youth in Maine and Oregon compared to Victoria for lifetime and recent alcohol use, binge drinking and daily cigarette smoking. However, rates of recent marijuana use and recent use of other illicit drugs were higher in Maine and Oregon, as were reports of being drunk or high at school. In contradiction of harm minimization objectives, Victoria, relative to the US states of Oregon and Maine, demonstrated higher rates of alcohol use exceeding recommended consumption limits and daily tobacco use. However, findings suggested that aspects of norm-violating substance use (substance use at school, marijuana use and other illicit drug use) were higher in the US states compared to Victoria. Toumbourou, J., Beyers, J., Catalano, R., Hawkins, J., Arthur, M., Evans-Whipp, T., Bond, L., and Patton, G. Youth Alcohol and Other Drug Use in the United States and Australia: A Cross-National Comparison of Three State-Wide Samples. Drug Alcohol Rev, 24(6), pp. 515-523, 2005.

For Females, Marriage at Any Age is Protective from Alcohol Use

Previous research shows that marriage leads to reductions in alcohol use, especially for women. Because marriage prior to age 20 (early marriage) is a marker for deviance, the protective effects of marriage may not extend to those who marry in adolescence. This study compared the effects of marriage in adolescence versus young adulthood on alcohol consumption, negative alcohol-related consequences and heavy episodic drinking at age 29. They analyzed data from 1,138 women in a longitudinal cohort followed from ages 18 to 29. The original sample was recruited from 30 California and Oregon middle schools and first surveyed at age 13. Women who had not married, had married early or had married between ages 20 and 29 did not differ on alcohol use at age 18. Women who married as young adults were less likely than singles to engage in any alcohol use, heavy episodic drinking or experience negative consequences and reported less alcohol use at age 29. Women who married in adolescence reported fewer negative consequences at age 29 than did singles and (if they had not divorced) were less likely to engage in heavy episodic drinking or experience any negative consequences, reported fewer consequences and consumed less alcohol. The protective effects of marriage in young adulthood were observed whether or not women divorced. Parenthood and college attendance before age 23 did not explain the marriage effect. Results support role theory, which posits that individuals who marry are socialized into conventional adult roles that discourage deviant behavior. Bogart, L., Collins, R., Ellickson, P., Martino, S., and Klein, D. Effects of Early and Later Marriage on Women's Alcohol Use in Young Adulthood: A Prospective Analysis. J Stud Alcohol, 66(6), pp. 729-737, 2005.

Personality Traits and Externalizing Disorders in Adolescence

The authors examined personality profiles among children who differed in their co-morbidity of externalizing disorders: attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD). 11- and 17-year-old male and female twins from a community sample of 2876 twin pairs in the Minnesota Twin Family Study were categorized as ADHD only, CD only, co-morbid CD-ADHD, and controls (no ADHD or CD) based on threshold and subthreshold CD and ADHD diagnoses assessed with structured interviews. Multivariate analyses were used to identify patterns of personality that differentiate these four diagnostic groups. The authors found that the co-morbid group had a pattern of personality marked by higher Negative Emotionality and lower Constraint than the other diagnostic groups. This pattern was evidenced across gender and age cohort. They concluded that an extreme personality profile may represent a liability toward the occurrence of ADHD and CD with more extreme profiles contributing to the occurrence of both disorders among boys and girls. The significance of this study lies in prediction and understanding of risk based on childhood psychiatric diagnosis and personality traits, given the findings from other groups that co morbid ADHD and CD represent a particularly strong risk group for substance use disorders. Significance is further strengthened by the use of a large, population-based sample and the extension of findings across ages and gender. Cukrowicz, K., Taylor, J., Schatschneider, C., and Iacono, W. Personality Differences in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder, Conduct Disorder, and Controls. J Child Psychol Psychiatry, 47(2), pp. 151-159, 2006.

Measuring Violence Risk and Outcomes among Mexican American Adolescent Females

Central to the development of culturally competent violence prevention programs for Hispanic youth is the development of psychometrically sound violence risk and outcome measures for this population. A study was conducted to determine the psychometric properties of two commonly used violence measures, in this case for Mexican American adolescent females. The Conflict Tactics Scales (CTS2) and the Past Feelings and Acts of Violence Scale (PFAV) were analyzed to examine their interitem reliability, criterion validity, and discriminant validity. A sample of 150 low-risk and 150 high-risk adolescent females was studied. Discriminant validity was indicated by the perpetrator negotiation scale and by the victim psychological aggression and sexual coercion scales of the CTS2 and the PFAV. Analysis indicates that the CTS2 scales and the PFAV demonstrate adequate reliability, whereas strong criterion validity was evidenced by eight of the CTS2 scales and the PFAV. Cervantes, R., Duenas, N., Valdez, A., and Kaplan, C. Measuring Violence Risk and Outcomes among Mexican American Adolescent Females. J. Interpers. Violence, 21(1), pp. 24-41, 2006.

Assessing Parenting Behaviors Among Mothers with a History of Maltreatment

Parenting assessments (the Parent-Child Conflict Tactics Scale, CTSPC; and a mother-child observation) were examined for their ability to identify mothers with a history of physically abusing or neglecting their child. Participants were mothers of 139 children (age 3 to 6 years; 58 with a history of maltreatment). Mothers with a history of maltreatment reported higher scores on the Neglect, Nonviolent Discipline, and Psychological Aggression subscales of the CTSPC. These group differences, however, were limited to mothers who acknowledged a history of maltreatment, as mothers who concealed their maltreatment history rated themselves similar to controls. Observation of parental behaviors during a brief, non-stressful task did not discriminate mothers who maltreated from mothers who did not maltreat. The findings suggest that parental report using the CTSPC may be useful in assessing parenting behaviors among mothers with a history of maltreatment, although socially desirable responding is a significant problem. Bennett, D., Sullivan, M., and Lewis, M. Relations of Parental Report and Observation of Parenting to Maltreatment History. Child Maltreat, 11(1), pp. 63-75, 2006.

Prevention Research

Definition and Outcome of the ATHENA Program to Prevent Disordered Eating and Body-Shaping Drug Use in Female Athletes

This study examined the outcomes of the Athlete Targeting Healthy Exercise and Nutrition Alternatives (ATHENA) intervention in female high school athletes. The ATHENA program is based on the Athletes Training and Learning to Avoid Steroids (ATLAS) curriculum, a sport team-centered drug-use prevention program for male high school athletes, which has been shown to reduce alcohol and illicit drug use. Just as anabolic steroid use is associated with male athletes, female sport participants may be at a greater risk for disordered eating and body-shaping drug use. Extending sport team-centered programs to young women athletes required defining and ranking factors related to developing those harmful behaviors. Survey results from a cross-sectional cohort of female middle and high school student athletes were used to identify and prioritize potential curriculum components, including mood and self-esteem, norms of behavior, perceptions of healthy body weight, effects of media depictions of women, and societal pressures to be thin. The derived sport team-centered program was prospectively assessed among a second group of female student athletes from 18 high schools, randomized to receive the intervention or the usual care control condition. The ATHENA intervention is a scripted, coach-facilitated, peer-led 8-session program, which was incorporated into a team's usual training activities. The ATHENA program significantly altered the targeted risk factors and reduced ongoing and new use of diet pills and body-shaping substances (amphetamines, anabolic steroids, and sport supplements). These findings illustrate the utility of a structured process to define curriculum content, and the program's positive results also confirm the sport team's potential as a vehicle to effectively deter health-harming behaviors. Elliot, D., Moe, E., Goldberg, L., Defrancesco, C., Durham, M., and Hix-Small, H. Definition and Outcome of a Curriculum to Prevent Disordered Eating and Body-Shaping Drug Use. J Sch Health, 76(2), pp. 67-73, 2006.

Intervention Outcomes for Girls Referred From Juvenile Justice: Effects on Delinquency

An increasing number of girls are entering the juvenile justice system. However, intervention programs for delinquent girls have not been examined empirically. The authors examined the 12-month outcomes of a randomized intervention trial for girls with chronic delinquency (N = 81). Girls were randomly assigned into an experimental condition (Multidimensional Treatment Foster Care; MTFC) or a control condition (group care; GC). Analysis of covariance indicated that MTFC youth had a significantly greater reduction in the number of days spent in locked settings and in caregiver-reported delinquency and had 42% fewer criminal referrals than GC youth (a trend) at the 12-month follow-up. Implications for reducing girls' chronic delinquency are discussed. Leve, L., Chamberlain, P., and Reid, J. Intervention Outcomes for Girls Referred From Juvenile Justice: Effects on Delinquency. J Consult Clin Psychol, 73(6), pp. 1181-1185, 2005.

Ethnic and Gender-specific Substance Use Patterns in Adolescence

This article documents the prevalence of self-reported substance use among White and American Indian adolescents enrolled in seventh grade (ages 12 through 13) in 1997 in a Northern Plains state. Data were collected by self-administered questionnaire preceding adolescents' participation in a randomized field trial of Project Alert, a seventh and eighth grade substance use prevention curriculum. Rates of lifetime and past-month use of cigarettes and marijuana were higher among American Indians than among Whites of the same gender. American Indian girls exceeded American Indian boys as well as White girls and White boys on lifetime and past-month use of cigarettes and marijuana as well as alcohol and inhalants; differences on cigarette and inhalant use reached statistical significance. These findings add to the sparse literature on substance use among adolescents as young as 12 through 13 years old and underscore the importance of examining gender-specific substance use patterns early in adolescence. Spear, S., Longshore, D., McCaffrey, D., and Ellickson, P. Prevalence of Substance Use Among White and American Indian Young Adolescents in a Northern Plains State. J Psychoactive Drugs, 37(1), pp. 1-6, 2005.

Externalizing Behavior & Gender Predict Drug Initiation Trajectories

The purpose of the current study was to investigate the influence of externalizing behaviors on substance initiation trajectories among rural adolescents over a 42-month period. Data were obtained from 198 rural adolescents who were participating in a longitudinal study. At the baseline assessment, subjects were on average 12.3 years old. Controlling for gender, higher baseline levels of externalizing were associated with a greater number of substances initiated over time. The initiation trajectory was curvilinear. Girls, compared with boys, reported a lower number of substances initiated at baseline, a greater linear growth trajectory, and a deceleration of growth over time. Lillehoj, C., Trudeau, L., Spoth, R., and Madon, S. Externalizing Behaviors as Predictors of Substance Initiation Trajectories Among Rural Adolescents. J Adolesc Health, 37(6), pp. 493-501, 2005.

Female Caregivers' Experiences with Intimate Partner Violence Are Related to Child Functioning

This study examined the relationship between women's experiences with intimate partner violence and their reports of child behavior problems. Data were from the National Survey of Child and Adolescent Well-Being, a national probability study of children who were the subjects of child abuse and neglect investigations. The sample consisted of 2020 female caregivers of children between the ages of 4 and 14 years who were interviewed about demographic characteristics, child behavior problems, female caregiver mental health, parenting behaviors, experiences with intimate partner violence, and community characteristics. Information on child abuse and neglect was obtained in interviews with child protective services workers. Multiple-regression analyses were used to investigate the association between caregiver victimization and child behavior problems while controlling for the effects of child, family, and environmental characteristics. The potential moderating effects of caregiver depression and parenting practices on the relation between intimate partner violence and child behavior problems were examined also. Severe intimate partner violence was associated with both externalizing and internalizing behavior problems when other risk factors were controlled. Use of corporal punishment and psychological aggression were significant moderators, but maternal depression did not moderate the relation between intimate partner violence and behavior problems. This study adds to the evidence that maternal caregivers' experiences with intimate partner violence are related to child functioning. The findings suggest that systematic efforts are needed to ensure that mental health needs are identified and addressed appropriately in children exposed to this violence. Hazen, A., Connelly, C., Kelleher, K., Barth, R., and Landsverk, J. Female Caregivers' Experiences With Intimate Partner Violence and Behavior Problems in Children Investigated as Victims of Maltreatment. Pediatrics, 117(1), pp. 99-109, 2006.

Measuring Adolescents' Smoking Expectancies

Outcome expectancies have been related to smoking behavior among adults, but less attention has been given to expectancies about smoking among adolescents at differing levels of smoking experience. The present study reports the psychometric properties and predictive validity of a brief expectancy scale across two samples of adolescents. Sample 1 (N = 349) consisted of high school students (54% female) who were regular smokers enrolled in a cessation program. Sample 2 (N = 273) consisted of 8th- and 10th-grade early experimenters (54% female) involved in a natural history study of smoking trajectories. In both samples, a principal component analysis of a 13-item expectancy scale yielded four factors (taste, weight control, boredom relief, and negative affect management), each with high internal consistency (coefficient alphas >.77) and accounting for 73% and 80% of the total variance for each sample, respectively. Expectancies were significantly higher among current smokers than among early initiators. In Sample 1, boredom relief and weight management expectancies predicted smoking status 6 months later. In Sample 2, students whose smoking increased over 18 months had higher overall expectancies at baseline compared with those who tried smoking and did not escalate. These findings support the predictive validity of expectancies in predicting escalation and cessation. Wahl, S., Turner, L., Mermelstein, R., and Flay, B. Adolescents' Smoking Expectancies: Psychometric Properties and Prediction of Behavior Change. Nicotine Tob Res, 7(4), pp. 613-623, 2005.

Psychometric Examination of English and Spanish Versions of Scales

The psychometric properties of the Revised Conflict Tactics Scales (CTS2) are examined for English-speaking (n = 211) and Spanish-speaking (n = 194) Latino women. Internal consistency of total scale scores is satisfactory (Cronbach's alpha of .70 to .84). However, subscale alphas range from .46 to .80. Confirmatory factor analysis supported five factors of negotiation, minor and severe psychological aggression, and minor and severe physical assault. In unconstrained two-group models, loadings are of similar magnitude across language of administration, with the exception of the Physical Assault scales. Unconstrained and constrained model comparisons show scale structure varied by language group for physical assault. Although results of this study show some comparability for English-speaking and Spanish-speaking Latinas, simply combining results across language groups may obscure important differences in rates of endorsement and patterns of responses reflecting cultural, educational, and economic differences. Connelly, C., Newton, R., and Aarons, G. A Psychometric Examination of English and Spanish Versions of the Revised Conflict Tactics Scales. J Interpers Violence, 20(12), pp. 1560-1579, 2005.

Measurement Properties of the Communities That Care Youth Survey Across Demographic Groups

revention science has produced information about risk and protective factors that predict adolescent use and related problem behaviors. This paper investigates the Communities That Care Youth survey that measures multiple risk and protective factors. Using a sample of 172,628 students who participated in surveys administered in seven states in 1998, analyses were conducted to test the factor structure of these risk and protective factors and to test the equivalence of the factor models across five racial/ethnic groups (African Americans, Asians or Pacific Islanders, Caucasians, Hispanic Americans, and Native Americans), four grade levels (6th, 8th, 10th and 12th), and both gender groups. Results support the construct validity of the survey's risk and protective factor scales and indicate that the measures are equally reliable across males and females and five racial/ethnic groups. Implications of these findings for science-based prevention planning are discussed. Glaser, R.R., Van Horn, M.L., Arthur, M.W., Hawkins, J.D., and Catalano, R.F. Measurement Properties of the Communities That Care Youth Survey Across Demographic Groups. J Quantitative Crim, 21(1), pp. 73-101, 2005.

Research on Behavioral & Combined Treatments for Drug Abuse

Cardiovascular Risk Behavior among Sedentary Female Smokers and Smoking Cessation Outcomes

Researchers from the Harvard School of Dental Medicine conducted this study to determine if female sedentary smokers with additional cardiovascular disease (CVD) health risk behaviors, like diet and alcohol use, predict abstinence from tobacco use. This study was part of a randomized controlled trial testing the effectiveness of exercise and nicotine gum in smoking cessation. Included in the analysis were 148 participates. This study suggested that high alcohol consumption alone and accumulation of two added risk behaviors predicted poorer smoking cessation outcome in a quit attempt. Dietary behavior alone was not related to cessation outcome. However, the high-fat diet interacted with depression, suggesting that depressed women engaging in high-fat diet are significantly more likely to relapse in their quit attempt compared to other subgroups. The authors conclude that non-moderate alcohol use alone and accumulation of multiple CVD risk behaviors seem to be associated with lower success in smoking cessation. Korhonen, T., Kinnunen, T., Quiles, Z., Leeman, R.F., Terwal, D.M. and Garvey, A.J. Tobacco Induced Diseases, 3, pp. 7-26, 2005.

Comprehensive Treatment Including Provision of Housing Reduced Drug Use for Homeless, Dually-Diagnosed Cocaine Abusers

Drs. Jesse Milby and Joseph Schumacher and colleagues at the University of Alabama delivered a cognitive behaviorally-based day treatment and work therapy platform to 196 homeless cocaine abusers, along with one of 3 randomly-assigned housing conditions: 1) provision of housing contingent upon abstinence from drugs; 2) provision of housing without an abstinence contingency; and 3) no provision of housing. Treatment occurred in phases, beginning with a skills-based day treatment and free housing for those receiving housing (months 1 - 2), followed by work therapy, group treatment, and low-cost rent for those receiving housing (months 3 - 6), and finally less intensive support group meetings (months 7 - 12). Participants who were provided housing had significantly better abstinence rates and retention rates than did those who were not provided housing, and there were few significant differences in outcomes between the two housing groups. However, among participants who were engaged into the day-treatment phase, those with abstinent-contingent housing had better abstinence than the other groups. Also, all housing recipients were successful in earning and paying rent during the work therapy phase of treatment. Sex/gender did not appear to moderate the relationships between interventions and outcomes. This study contributes to a line of related research highlight the value of housing in recovery, and suggests several methods for successfully integrating provisions of housing and work skills into substance abuse treatment. Milby, J.B., Schumacher, J.E., Wallace, D., Freedman, M.J. and Vuchinich, R.E. To House or Not to House: The Effects of Providing Housing to Homeless Substance Abusers in Treatment. American Journal of Public Health, 95, pp. 1259-1265, 2005.

Research on Pharmacotherapies for Drug Abuse

Gender Effects Following Repeated Administration of Cocaine and Alcohol in Humans

Use of cocaine, alcohol, and the two drugs simultaneously is common and the risk of morbidity and mortality associated with these drugs is widely reported. This double-blind, placebo-controlled, randomized study examined gender differences in response to administration of these drugs alone and in combination. Current users of cocaine and alcohol (n = 17) who met diagnostic criteria (DSM-IV) for cocaine dependence and alcohol abuse or dependence (not physiologically dependent on alcohol) and who were not seeking treatment for substance use disorders gave voluntary, written, informed consent to participate in three drug administration sessions:1) four doses of intranasal cocaine (1 mg/kg every 30 min) with oral alcohol (1 g/kg following the initial cocaine dose and a second drink at +60 min (120 mg/kg) calculated to maintain a plasma alcohol concentration of approximately 100 mg/dL; 2) four doses of cocaine and alcohol placebo; 3) cocaine placebo and alcohol. Pharmacokinetics were obtained by serial blood sampling, physiological measurements (heart rate and blood pressure) were obtained with automated equipment, and subjective effects were assessed using visual analog scales over 480 min. Responses to cocaine, alcohol, and cocaine-alcohol were equivalent by gender for most measurements. Women had higher heart rates following alcohol administration (p =.02). Women consistently reported higher ratings for "Feel Good" a measure of overall mental/physical well-being, for all study conditions, reaching statistical significance for cocaine (p = .05) and approaching significance for alcohol administration (p = .1). Women showed equivalent responses to drug administration with the exception of perception of well-being, which was significantly increased for women. These findings may have implications for differential risk for acute and chronic toxicity in women. McCance-Katz, E.F., Hart, C.L., Boyarsky, B., Kosten, T. and Jatlow, P. Gender effects following repeated administration of cocaine and alcohol in humans. Subst Use Misuse, 40(4), pp. 511-528, 2005.

Early Impact of Methadone Induction for Heroin Dependence: Differential Effects of Two Dose Sequences in a Randomized Controlled Study

The pharmacodynamic and pharmacokinetic effects of 2 methadone (METH) induction dose sequences were evaluated in this 15-day outpatient experimental protocol. Heroin-dependent, non-treatment-seeking volunteers were randomly assigned (stratified for gender, race, and route of heroin use) to 2 groups. In 1 sequence, METH doses ascended (28, 56, then 84 mg/day; stepwise, n = 18), whereas in the other sequence doses escalated, then tapered (28-84 mg on Days 1-6 to 56 mg/day; rapid, n = 16). A contingency-management intervention was common to both groups. Drug use and heroin craving and opioid withdrawal symptoms decreased, whereas agonist symptoms and positive mood increased overall across days for both groups. Plasma concentrations and the acute reinforcing effects of METH paralleled each dose sequence. Stepwise relative to rapid METH induction significantly decreased heroin craving and opioid withdrawal symptoms and increased agonist symptoms and positive mood but did not significantly improve drug use or retention. Although these specific dosing procedures would not necessarily be used in clinical settings, they provide a procedural template that might be applied safely and effectively with a broader range of treatment-seeking individuals. Greenwald, M.K. Early Impact of Methadone Induction for Heroin Dependence: Differential Effects of Two Dose Sequences in a Randomized Controlled Study. Exp. Clin. Psychopharmacol., 14, pp. 52-67, 2006.

Effects of Topiramate in Combination with Intravenous Nicotine in Overnight Abstinent Smokers

Topiramate, an anticonvulsant medication, may be effective as a treatment for alcohol and cocaine addiction. While a recent clinical study has demonstrated the potential utility of topiramate for smoking cessation in alcohol-dependent smokers, the effects of topiramate on tobacco addiction have not been systematically examined in humans. The purpose of this study is to determine topiramate's effects on acute physiological and subjective responses to intravenous (IV) nicotine in overnight abstinent smokers. Seven male and five female smokers participated in a double-blind, placebo-controlled, crossover study, which consisted of one adaptation and three experimental sessions. Before each session, participants were treated orally with either a single 25 or 50 mg topiramate dose or with placebo. Starting 2 h following the medication treatment, participants received an IV saline injection, followed by 0.5 and 1.0 mg/70 kg IV nicotine. Topiramate treatment at 50 mg, compared to 25 mg or placebo, attenuated heart rate increases induced by nicotine. Topiramate, compared to placebo, enhanced the ratings of subjective effects from nicotine including "drug strength," "good effects," "head rush," and "drug liking." Topiramate treatment did not affect performance on the Stroop test. These results suggest that topiramate may enhance the subjective effects of nicotine and attenuate the heart rate response to nicotine. While the exact mechanisms are unclear, enhancement of the dopaminergic system and attenuation of the noradrenergic system may mediate topiramate's effects on the subjective and cardiovascular responses to nicotine, respectively. The utility of topiramate for smoking cessation needs to be examined further in controlled clinical trials. Sofuoglu, M., Poling, J., Mouratidis, M. and Kosten, T. Effects of Topiramate in Combination with Intravenous Nicotine in Overnight Abstinent Smokers. Psychopharmacology (Berl), 184, pp. 645-651, 2006.

Research on Medical Consequences of Drug Abuse and Infections

Drugs of Abuse and the Endocrine System

Cortisol Levels and Depression in Men and Women Using Heroin and Cocaine

Abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are well documented in men using illicit drugs and/or infected with HIV; however, less is known about HPA function, or the health consequence of HPA dysfunction, in their female counterparts. People with depression exhibit hypercortisolemia, and depression is common in people with HIV or substance use problems. The current study investigated cortisol secretion in 209 demographically matched men and women, stratified by their HIV and drug use status. Self-reported depressive symptoms were evaluated using a standardized, validated questionnaire (CES-D). Women reported more depressive symptoms than men (p=.01). Male and female drug users exhibited higher cortisol concentrations (p=.03), and were more likely to report depressive symptoms (p=.04), than non-users. Depression was related to elevated cortisol concentrations for the study population (p=.03), and women with elevated cortisol concentrations were significantly more depressed than all other participants (p=.05). While it is unknown whether high cortisol concentrations precede depressive symptoms or vice versa, these data indicate that higher cortisol concentrations are associated with depressive symptoms in heroin and cocaine users, and that this association is more pronounced in women than men. HIV status did not act in an additive or synergistic way with drug use for either cortisol or CES-D measures in the current study. Unique therapies to treat the endocrine and mental health consequences of illicit drug use in men and women deserve consideration as depressive symptoms, and high cortisol concentrations associated with depressive symptoms, differ by gender. Wisniewski, A.B., Brown, T.T., John, M., Cofranceso, J.Jr., Golub, E.T., Ricketts, E.P., Wand, G. and Dobs, A.S. Cortisol Levels and Depression in Men and Women Using Heroin and Cocaine Psychoneuroendocrinology, 31(2), pp. 250-255, 2006.

Drug-Drug Interactions

Effect of Buprenorphine and Antiretroviral Agents on the QT Interval in Opioid-Dependent Patients

Cardiac arrhythmias have been linked to treatment with methadone and levacetylmethadol. HIV-positive patients often have conditions that place them at risk for QT interval prolongation including HIV-associated dilated cardiomyopathy, coronary artery disease as a consequence of highly active antiretroviral (ARV) therapy-associated metabolic syndrome, and uncorrected electrolyte abnormalities. As of February 14, 2006, no cases of adverse events related to QT interval prolongation have been reported in patients receiving buprenorphine, an opioid partial agonist and the newest drug approved for the treatment of opioid dependence. The objective of this study was to evaluate the effects of buprenorphine/naloxone alone and in combination with 1 of 5 ARV agents (efavirenz, nelfinavir, delavirdine, ritonavir, lopinavir/ritonavir) on the QT interval. This study was prospective, open-label, and within-subject in design, with subjects serving as their own controls. In 50 HIV-negative, opioid-dependent subjects, electrocardiogram recordings were obtained at baseline, after receiving buprenorphine/naloxone for 2 weeks, and then following buprenorphine/naloxone plus ARV administration for 5-15 days at steady-state. QTc interval measurements were compared using mixed-model, repeated-measures ANOVA. Recent cocaine use and gender were considered covariates. Buprenorphine/naloxone alone and often in the presence of evidence for recent use of cocaine did not significantly alter the QT interval (p = 0.612). Buprenorphine/naloxone in combination with ARVs caused a statistically, but not clinically, significant increase (p = 0.005) in the QT interval. Subjects receiving buprenorphine/naloxone in combination with either delavirdine or ritonavir had the greatest increase in QTc intervals. Prolonged QT intervals were not observed in opioid-dependent subjects receiving buprenorphine/naloxone alone. QT interval increases were observed with buprenorphine/naloxone in combination with either delavirdine or ritonavir, which inhibit CYP3A4. Baker, J.R., Best, A.M., Pade, P.A. and McCance-Katz, E.F. Effect of Buprenorphine and Antiretroviral Agents on the QT Interval in Opioid-Dependent Patients. Ann Pharmacother. 40(3), pp. 392-396, 2006.

Medical Illness and Comorbidities in Drug Users: Implications for Addiction Pharmacotherapy Treatment

Providing effective medical care to those with substance use disorders can be a challenge to clinicians. In this article, the authors briefly summarize issues that occur frequently in the medical treatment of substance users. The focus of this article is twofold. The first is to briefly summarize common co-occurring medical illnesses in those manifesting substance use disorders with an emphasis on issues related to providing effective treatment for these diseases in this population. Using specific examples of frequently occurring comorbid medical illness in substance users, including infectious diseases (hepatitis C and HIV disease), sexually transmitted diseases, and pregnancy as examples, the complexities of medical care for this population is demonstrated. Second, this article addresses some of the difficulties encountered in pharmacotherapy aimed specifically at treatment of substance use disorders. For example, difficulties in managing concomitant opiate therapy in those requiring medications for medical illness that may have strong and adverse interactions with opiates are addressed. Adverse events reported for some substance use disorder pharmacotherapies are also highlighted. The authors conclude with a brief review of models of care that have been effective in addressing the needs of this challenging population that can provide additional means for enhancing the clinical care of substance users. Draper, J.C. and McCance-Katz, E.F. Medical Illness and Comorbidities in Drug Users: Implications for Addiction Pharmacotherapy Treatment. Subst Use Misuse. 40(13), pp. 1899-1921, 2005.

Services Research

Pathways in the Relapse, Treatment, Recovery Cycle

For many individuals, substance use leads to a chronic cycle of relapse, treatment reentry, and recovery, often lasting for decades. This study replicates earlier work, documents the transition patterns within the cycle during a 3-year period, and identifies variables that predict these transitions. Data are from 1,326 adults recruited from sequential admissions to 12 substance abuse treatment facilities in Chicago, IL, between 1996 and 1998. Participants were predominantly female (60%) and African American (88%) adults. Participants were interviewed at intake, and at 6, 24, and 36 months post-intake. Follow-up rates ranged from 94% to 98% per wave. At each observation, participants' current status in the cycle was classified as (1) in the community using, (2) incarcerated, (3) in treatment, or (4) in the community not using. The transitional probabilities and correlates of pathways between these states were estimated. Over 83% of the participants transitioned from one point in the cycle to another during the 3 years (including 36% two times, 14% three times). For the people in the community, about half remained in the same status (either using or abstinent) and just under half transitioned to incarceration or treatment. The majority of people whose beginning status was incarceration or in-treatment also transitioned to in the community by the end of the observation period. While there was some overlap, predictors typically varied by pathway and direction (e.g., using to not using vs. not using to using). These results help demonstrate the need to adopt a chronic vs. acute care model for substance use. While exploratory and observational, several of the predictors are time-dependent and identify promising targets for interventions designed to shorten the cycle and increase the long-term effectiveness of treatment. Scott, C., Foss, M. and Dennis, M. Pathways in the Relapse--Treatment--Recovery Cycle Over 3 Years. J Subst Abuse Treat, 28(Suppl 1), pp. S63-S72, 2005.

HIV Intervention for Indigent Women Substance Abusers in the US Virgin Islands

As the HIV/AIDS epidemic continues to expand and penetrate new communities around the globe, risk reduction intervention initiatives must continue to evolve and adapt to new challenges and populations. This is especially true in the Caribbean Basin, where the feminization of the HIV epidemic is tied to a cultural milieu characterized by pervasive gender inequality. HIV intervention programs in the Caribbean must treat women's risks as a function of the social context, standards, and meanings of sexual behaviors and practices in the local community. As such, this article describes an initiative to develop an HIV prevention-intervention protocol for the cultural context of substance abusing women in the US Virgin Islands. Through street-based survey research combined with focus groups and in-depth interviews with such "cultural insiders" as members of the substance-abusing target population, members of the local public health and social services system, and community leaders, a culturally sensitive HIV/AIDS protocol was developed which addresses the supports and barriers to risk reduction faced by substance abusing women in the Virgin Islands. The intervention, which is delivered in three sessions, was pilot tested with 20 active or former substance abusing women. Results from the pilot test revealed that the women were engaged and found the material relevant to their lifestyles and concerns. Surratt, H., and Inciardi, J. Developing an HIV Intervention for Indigent Women Substance Abusers in the United States Virgin Islands. J Urban Health, 82(3-4), pp. iv74-iv83, 2005.

Substance Use, Sexual Risk, and Violence: HIV Prevention Intervention with Sex Workers in Pretoria

This paper describes an HIV prevention intervention designed in the US that was adapted and implemented in South Africa. Using an experimental design, 93 women who reported recent substance use and sex trading were randomly assigned to a modified Standard HIV intervention or to a Woman-Focused HIV prevention intervention. Eighty women completed the one-month follow-up interview. Participants reported high rates of sexual risk and violence at baseline. At follow-up, findings showed decreases in the proportion of women reporting unprotected sex and the daily use of alcohol and cocaine. Daily alcohol and cocaine use decreased more for women receiving the Woman-Focused intervention. Although violence continued to be a problem, at follow-up Woman-Focused participants reported being victimized less often than women receiving the Standard intervention. This study demonstrates the feasibility of implementing cross-cultural behavioral HIV prevention interventions, and supports the need for future studies of women's contextual issues and the effectiveness of targeted interventions. Wechsberg, W.M., Luseno, W.K., Lam, W.K., Parry, C.D. and Morojele, N.K. Substance Use, Sexual Risk, and Violence: HIV Prevention Intervention with Sex Workers in Pretoria. AIDS & Behavior, pp. 1-5, 2006.

Sexual Risk Behavior and Substance Use among a Sample of Asian Pacific Islander Transgendered Women

This study examined the prevalence and correlates of HIV-related sexual risk and substance use behaviors among Asian Pacific Islander (API) male-to-female (MTF) transgendered individuals, referred to here as API transgendered women. As part of a larger study on HIV risk among transgendered women of color (Nemoto, Operario, Keatley, Han, & Soma, 2004), a sample of 110 API transgendered women in San Francisco completed individual interviews, of which 13% reported being HIV-positive. In the past 30 days, one fifth of the sample engaged in unprotected receptive anal intercourse (URAI) with any male partner, nearly one half had sex while under the influence of substances, and over half used illicit drugs. In multivariate models, URAI was associated with commercial sex work (odds ratio [OR] = 4.23, 95% confidence interval [CI] = 1.10, 16.25) and previous attempted suicide (OR = 5.83, 95% CI = 1.02, 33.44). Sex under the influence of substances was associated with commercial sex work (OR = 3.35, 95% CI = 1.11, 10.13) and having a college degree (OR = 5.32, 95% CI = 1.34, 21.18). Illicit drug use was associated with commercial sex work (OR = 7.15, 95% = 2.26, 22.63). Findings suggest that API MTF transgenders are on the front line of HIV risk for the API community, and provide insight into factors within this group that might contribute to unsafe sex and substance use. Operario, D., and Nemoto, T. Sexual Risk Behavior and Substance Use Among a Sample of Asian Pacific Islander Transgendered Women. AIDS Educ Prev, 17(5), pp. 430-443, 2005.

Addiction Treatment Utilization among Homeless and Housed

Research on addiction treatment utilization in indigent samples mainly has been retrospective, without the measures of three factors: addictive consequences, social network influences, and motivation. In this prospective study, the researchers focus upon these three factors as they are associated with utilization of addiction treatment and mutual help groups among substance-dependent persons with high rates of homelessness. Patients detoxified from alcohol or drugs at baseline were followed for 2 years in a randomized clinical trial of linkage to primary care (n = 274). Outcomes included utilization of Inpatient/Residential, Outpatient, Any Treatment, and Mutual Help Groups. Predictor variables in longitudinal regression analyses came from the literature and clinical experience, organized according to theoretical categories of Need, and non-Need (e.g., Predisposing and Enabling). Many subjects used Inpatient/Residential (72%), Outpatient (62%), Any Treatment (88%) or Mutual Help Groups (93%) at least once. In multivariable analyses, addictive consequences (odds ratio [OR] 1.38, 95% confidence interval [CI] 1.12-1.71), motivation (OR 1.32, 95% CI 1.09-1.60), and female gender (OR 1.80, 95% CI 1.13-2.86) were associated with most treatment types. Homelessness was associated with Residential/Inpatient (for Chronically Homeless vs. Housed, OR 1.75, 95% CI 1.04-2.94). Living with one's children (OR 0.51, 95% CI 0.31-0.84) and substance-abusing social environment (OR 0.65, 95% CI 0.43-0.98) were negatively associated with Any Treatment. Addictive consequences, social network variables, and motivation were associated with treatment utilization in this sample. Non-need factors, including living with one's children and gender, also were found to be significant influences on treatment utilization. Kertesz, S., Larson, M., Cheng, D., Tucker, J., Winter, M., Mullins, A., Saitz, R., and Samet, J. Need and Non-Need Factors Associated with Addiction Treatment Utilization in a Cohort of Homeless and Housed Urban Poor. Med Care, 44(3), pp. 225-233, 2006.

Gender Differences in the Prediction of Condom Use Among Incarcerated Juveniles

This research study applied the Information-Motivation-Behavioral skills (IMB) model in predicting condom-protected vaginal intercourse among incarcerated youth. The IMB model is a three-factor conceptualization of HIV preventive behavior. According to the IMB Model, there are three fundamental determinants of AIDS risk reduction including: information on HIV/AIDS transmission and information on specific prevention methods, motivation to act on the knowledge and change risky behavior, and behavioral skills in performing the specific prevention acts. Self-report measures of AIDS knowledge, pro-condom peer influence, risk perception, condom attitudes, condom use self-efficacy, frequency of vaginal intercourse, and frequency of condom-protected vaginal intercourse were collected from predominately African-American adolescent juvenile detainees (N=523). Study results found that for males and females combined condom use was significantly predicted by being male, peer influence, positive condom attitudes, and condom self-efficacy. In separate gender analyses, condom use among adolescent males was predicted by peer influence and positive condom attitudes, whereas condom use among females was predicted by peer influence, self-efficacy, and influence, higher perceived risk for infection, more positive condom attitudes, and more self-efficacy, but females also reported less condom use. The investigators conclude that girls may find it more difficult to consistently use condoms despite awareness of their efficacy. Power imbalances or other dynamics operating in their relationships with boys need further exploration. Robertson, A.A., Stein, J.A., and Baird-Thomas, C. Gender Differences in the Prediction of Condom Use Among Incarcerated Juvenile Offenders: Testing the Information-Motivation-Behaviors Skills (IMB) Model. Journal of Adolescent Health, 38, pp. 18-25, 2006.