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National Institute on Drug Abuse
Women and Sex/Gender Differences Research
Director's Report to Council
Research Findings Excerpts
September, 1997
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Basic Research |
Carboxypeptidase E Activity Is Deficient in Mice with the Fat Mutation
Carboxypeptidase E (CPE) is involved in the biosynthesis of many peptide hormones and neurotransmitters. In collaboration with Dr. Leiter of the Jackson Laboratory, Dr. Lloyd D. Fricker of Albert Einstein College of Medicine was fortunate to find a mouse that has a normally occurring point mutation within CPE. This mutation (Cpefat/Cpefat), which completely eliminates CPE activity, causes the mice to be sterile and obese. Male mice, but not female mice, show markedly elevated serum glucose levels. These defects are due to the absence of CPE activity, presumably to a folding defect that causes the mutant CPE to be degraded in the endoplasmic reticulum. Peptide processing is abnormal in these mice, but not completely eliminated. This raised the possibility that a second carboxypeptidase is involved in peptide processing, and that this second enzyme can partially compensate for the defective CPE in the Cpefat/Cpefat mice. Dr. Fricker and his coworkers recently found a novel enzyme, carboxypeptidase D (CPD), that has CPE-like enzymatic properties. Recently they have discovered that in bovine and rat tissues CPD has a broad distribution. This is consistent with a role for this enzyme in the processing of numerous peptides, which would explain the ability of the Cpefat/Cpefat mice to produce small amounts of peptides.
Dr. Fricker and his coworkers also found that the opiate peptide precursor, prodynorphin, is not correctly processed in the Cpefat/Cpefat mouse brain. The processing of prodynorphin by the endopeptidases (the step that precedes CPE) is decreased in the Cpefat/Cpefat mice, suggesting that the CPE defect somehow feeds back on the previous step. CPE could play a role in the sorting of peptide precursors into the regulated secretory pathway, and the absence of CPE in the Cpefat/Cpefat mice causes mis-sorting which then alters the processing. J. Biol. Chem., 271, 30619, November, 1996.
Placenta and Neurotransporter
Dr. Ganapathy and his research team has recently published reports that demonstrate that tyrosine phosphorylation is an essential component in the signaling pathways participating in the regulation of the human serotonin transporter gene expression. Regulation of the transporter gene expression also appeared to be modulated by a neuro-protective agent, aurin tricarboxylic acid (ATA) and epidermal growth factor (EGF) as both agents increased the transporter activity in JAR human placental choriocarcinoma cells. However, ATA appeared to elicit this, at least in part, by activating the EFG receptor through tyrosine phosphorylation. Other findings demonstrated that interleukin-1' turned on the human serotonin transporter gene expression by activating the transcription factor NF-kB via the mitogen-activated protein kinase signaling pathways. Although the physiologic role of the serotonin transporter in normal human placenta remains to be established, these data suggest a possibility that the placental serotonin transporter may be involved in the maintenance of serotonin levels in the intervillous space and thereby optimize utero placental blood flow. A defective clearance of serotonin from the maternal circulation due to dysfunctional serotonin expression in the placenta may play a role in the pathogenesis of intra-uterine growth retardation. Prasad, P.D. et al., European J Pharmacology, 325, pp. 85-92, 1997; Kekuda, R. et al., J Neurochemistry, 68, pp. 1443-1450, 1997.
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Behavioral Research |
Evidence for a Sex-Specific Residual Effect of Cannabis on Visuospatial Memory
Dr. Harrison Pope and his colleagues at Harvard Medical School used a novel computerized battery of neuropsychological tests of attention to assess residual cognitive impairment in 25 college students who were heavy smokers of marijuana (having smoked a median of 29 days in the last 30 days). These were compared with 30 light smokers (having smoked marijuana for one day in the last 30 days). They were assessed after they had abstained from marijuana use for at least 19 hours (monitored by urine toxicology). In the visuospatial tests, the subjects were required to examine a 6x6 'checkerboard' of squares in which certain squares are shaded. The shaded squares were then erased and the subject was required to indicate with the mouse which squares had formerly been shaded. Increasing numbers of shaded squares were presented at each trial. The heavy smoking women performed poorly on the visuospatial memory tasks. They remembered significantly fewer squares and made significantly more errors than the light-smoking women. Authors concluded that it may be important to study the residual effects of marijuana on men and women separately-particularly since women have been greatly underrepresented in previous studies in this area. Pope, H.G., Jacobs, A., Mialet, J.-P. and Gruber, S. Psychother Psychosom, In press.
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AIDS Research |
Increased Vertical Transmission of HIV from Hepatitis C Co-infected Mothers
A recent study from the Women & Infant Transmission Study (WITS), an NIH supported HIV cohort study co-funded by NIDA, demonstrated that maternal infection with hepatitis C virus is associated with increased HIV maternal-infant transmission. Among 487 women infected with HIV either heterosexually or through injection drug use, 33% were found to be HCV infected. HIV vertical transmission occurred in 26% of HIV/HCV infected mothers vs. 16% of HCV uninfected mothers (OR, 1.82, p=0.01). Drug use during pregnancy was highly correlated with HCV infection (53% vs. 16% in non-drug users, p=0.001) and with HIV perinatal transmission (24% vs. 16% in non-drug users, OR, 1.66, p=0.03). These data suggest that maternal HCV infection either enhances perinatal HIV transmission directly or is a marker for another co-factor such as maternal drug use. Further study is needed to confirm the findings of this study and to determine whether the association represents a biologic effect of HCV infection or is due to a confounding interaction with drug use or other factors. Hershow R.C., Riester, K.A., Lew, J et al. J of Infectious Diseases, 176, pp. 414-419, 1997.
Predictors of Behaviors and Beliefs of Female Drug Users in Two Cities
This study was conducted to examine predictors of behaviors and beliefs about the use of condoms among women who use drugs and who report having recent vaginal sex with main and/or paying partner s. A total of 338 drug-using women were recruited for the study, all of whom reported vaginal sex during the past 30 days. Forty percent of the women resided in East Harlem, N.Y., a high HIV seroprevalence area, and 60% of the women resided in Long Beach, California, a low HIV seroprevalence area. Recruitment site was identified as a significant predictor for a number of variables for both main and paying partners: Women recruited in East Harlem were more likely than those recruited in Long Beach to believe that use of condoms for sex with a main partner would harm the relationship, for example. They were also more likely to have used condoms with a main partner in the past 30 days, and to believe that condoms provided protection from disease. Race/ethnicity was a significant predictor for main sex partners, with African American women significantly more likely to have positive cognitions about use of condoms and to report greater self-efficacy for, and greater intention of, using condoms with main partners. The researchers discuss the implications of their findings in terms of intervention development to prevent HIV and other diseases. Specifically, because factors which predict condom beliefs, intention to use, and behaviors are different for main and paying partners, interventions which are designed to increase condom use should recognize that cognitive factors associated with condom use may vary by partner type, race/ethnicity, and recruitment site, particularly when contextual variables, such as local seroprevalence levels, vary. Wood, M. Tortu, S., Rhodes, F., and Deren, S. Differences in Condom Behaviors and Beliefs among Female Drug Users Recruited from Two Cities. Women and Health, In press.
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Epidemiology, Etiology and Prevention Research |
Antisocial Behavior and Affiliation with Adult Boyfriends Predicts Female Adolescents' Substance Use and Risky Sexual Behavior
In a study of pathways to substance use and risky sexual behavior, investigators at the Center for Education and Drug Abuse Research (CEDAR) at the University of Pittsburgh used behavioral, psychiatric interview, and self-report measures to index behavioral dysregulation, negative affectivity, childhood victimization, internalizing symptomatology, antisocial behavior, affiliation with adult boyfriends, and outcome variables in 125 substance abusing female adolescents and 78 controls 14-18 years old. Results of structural equation modeling indicated that behavioral dysregulation, negative affectivity, and childhood victimization were related to substance use and risky sexual behavior. Age of menarche was correlated with affiliation with an older boyfriend and risky sexual behavior. Antisocial behavior mediated the associations of behavioral dysregulation, negative affectivity and childhood victimization with substance use and risky sexual behavior. Affiliation with an adult boyfriend was directly associated with substance use and accounted for the relationship between chronological age and risky sexual behavior. From a prevention and treatment standpoint, these results suggest that reducing dysregulation through behavior modification procedures developed for conduct-disordered children might provide a mechanism for interrupting the development of substance use and risky sexual behavior in young females.Mezzich A.C., Tarter, R.E., Giancola, P.R., Lu, S., Kirisci, L., and Parks, S. Substance Use and Risky Sexual Behavior in Female Adolescents. Drug and Alcohol Dependence, 14; 44 (2-3), pp. 157-166, 1997.
Psychiatric Disorders Associated with Substance Use Among Children and Adolescents
The relationships between specific quantities and frequencies of alcohol, cigarette, and illicit substance use and substance use (SUD) and other psychiatric disorders were investigated among 1,285 randomly selected children and adolescents, aged 9 to 18, and their parents, from the Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) Study. Logistic regressions indicated that daily cigarette smoking, weekly alcohol consumption, and any illicit substance use in the past year were each independently associated with an elevated likelihood of diagnosis with SUD and other psychiatric disorders (anxiety, mood, or disruptive behavior disorders), controlling for sociodemographic characteristics (age, gender, ethnicity, family income). The associations between the use of specific substances and specific psychiatric disorders varied as a function of gender. Kandel, D. B., Johnson, J. G., Bird, H. R., Canino, G., Goodman, S. H., Lahey, B. B., Regier, D. A., and Schwab-Stone, M. Psychiatric Disorders Associated with Substance Use Among Children and Adolescents: Findings from the Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) Study. Journal of Abnormal Child Psychology, 25 (2), pp. 121-132, 1997.
The Influence of Spouses' Behavior and Marital Dissolution on Marijuana Use: Causation or Selection
Similarity between spouses may result from prior similarity (selection) or interpersonal influence (causation) or both. Spouses' mutual influences on marijuana use were studied in a two-wave longitudinal cohort of 490 married pairs, using data obtained twice from each spouse over a 5.5 year interval. To estimate processes during marriage free of sample selection bias, marriages that dissolved during the interval were used, and the impact of divorce on the drug use of the spouse was analyzed using reinterview data. Causation effects of spouse (or event) were distinguished from selection effects involved in assortative mating (or divorce) using models with and without controls for latent individual propensities to use marijuana. Marital selection effects were found to predominate over causation effects, and divorce was found to affect spouses' continued marijuana use. These findings have implications for understanding the persistence of drug use in adulthood, gender differences in the relationship of substance use with marriage and divorce, and the study of interpersonal influences. Yamaguchi, K., and Kandel, D. The Influence of Spouses' Behavior and Marital Dissolution on Marijuana Use: Causation or Selection. Journal of Marriage and the Family, 59, pp. 22-36, 1997.
Cigarette Smoking Among Mexican American Youth
A self-report survey of cigarette use among 10th- and 12th-grade Mexican American students found no differences in rates of use by migrant status. Male students reported higher levels of lifetime, experimental, and daily smoking than female students, and 12th-grade students reported higher levels of daily smoking than 10th-grade students. A socialization model of cigarette use based on peer cluster theory was evaluated using structural equation methods, examining the effects of family strength, family tobacco use, school adjustment, religious identification, and peer tobacco associations. The basic latent-structure socialization model was supported in all groups, but final models including specific effects identified both unique and common relationships by gender and migrant status. Common patterns across groups suggest that completely different prevention programs may not be necessary for these youth. However, program elements based on subtle group differences may serve to tailor prevention efforts and make them more effective. Swaim, R.C., Oetting, E.R., and Casas, J.M. Cigarette Use Among Migrant and Nonmigrant Mexican American Youth: A Socialization Latent- Variable Model. Health Psychology, 15, pp. 269-281, 1996. A self-report survey of cigarette use among 10th- and 12th-grade Mexican American students found no differences in rates of use by migrant status. Male students reported higher levels of lifetime, experimental, and daily smoking than female students, and 12th-grade students reported higher levels of daily smoking than 10th-grade students. A socialization model of cigarette use based on peer cluster theory was evaluated using structural equation methods, examining the effects of family strength, family tobacco use, school adjustment, religious identification, and peer tobacco associations. The basic latent-structure socialization model was supported in all groups, but final models including specific effects identified both unique and common relationships by gender and migrant status. Common patterns across groups suggest that completely different prevention programs may not be necessary for these youth. However, program elements based on subtle group differences may serve to tailor prevention efforts and make them more effective. Swaim, R.C., Oetting, E.R., and Casas, J.M. Cigarette Use Among Migrant and Nonmigrant Mexican American Youth: A Socialization Latent- Variable Model. Health Psychology, 15, pp. 269-281, 1996.
Prevalence and Demographic Correlates of Past Year Dependence on Four Substance
Dr. Denise Kandel and her associates conducted secondary analyses based on three aggregated waves (1991, 1992 and 1993) of nationally representative samples of the general population aged 12 and over interviewed in the National 7,915). An approximate measure of DSM-IV drug-specific past-year dependence for each drug class was derived from self-reported symptoms of dependence, data on frequency and quantity of use, and drug-related problems. Although the measure of dependence has limitation, the inclusion of cigarettes, the large number of cases and the wide age range of respondents permitted drug, age, gender and ethnic comparisons on liability for dependence not otherwise possible. Five major findings were obtained regarding rates of dependence experienced among last year users of each drug class: (1) nicotine is more addictive than alcohol, marijuana and cocaine; (2) among adolescents, rates of dependence on alcohol, marijuana and cocaine are higher among females than males; (3) among adults, rates of dependence are higher among males than among females for alcohol and marijuana, but lower for nicotine; (4) adolescent females are significantly more at risk for dependence on alcohol and marijuana than any other age group of women; (5) whites are more likely than any other ethnic group to be dependent on nicotine and blacks to be dependent on cocaine. This is the first report in the literature in which the liability for dependence could be compared among adolescents and adults, and nicotine dependence could be systematically compared with dependence on other drugs. Adolescent girls constitute an especially high risk group for drug dependence. Kandel, D.B., Chen, K., Warner, L., Kessler, R., Grant, B. Prevalence and Demographic Correlates of Symptoms of Dependence on Cigarettes, Alcohol, Marijuana and Cocaine in the U.S. Population. Drug and Alcohol Dependence, 44, pp. 11-29, 1997.
Nicotine Withdrawal in Women
Associations between self-report symptom profiles for nicotine withdrawal, personality (TPQ, EPQ-R), life-time history of psychopathology and smoking history were examined in data obtained from 553 female adult Australian twins (246 regular smokers), ages 32-48 years, who had participated in a telephone interview survey that included life-time assessments of smoking history, nicotine dependence, and symptoms of withdrawal. Two hundred and two respondents were from high-risk pairs where either the respondent or the respondent's co-twin had reported a life-time history of alcohol dependence; 351 were from control pairs. Latent class analysis was used to identify subtypes ('classes') of smokers reporting similar withdrawal symptom profiles. Three major classes were identified which appeared to represent a continuum from mild to severe nicotine withdrawal. Smokers from the severe withdrawal class were best characterized by hands shaking and by the prominence of depressive features. There were marked increases in lifetime alcohol dependence rates as a function of severity class. In contrast, significantly elevated rates of major depression, conduct disorder and anxiety disorder were observed only among smokers from the most severe withdrawal class. Neuroticism was the only personality factor strongly associated with the development of withdrawal symptoms. Madden, P. A. F., Bucholz, K. K., Dinwiddie, S. H., Slutske, W. S., Bierut, L. J., Statham, D. J., Dunne, M. P., Martin, N. G., and Heath, A. C. Nicotine Withdrawal in Women. Addiction, 92 (7), pp. 889-902, 1997.
Parent Substance Use As A Predictor of Adolescent Use: A Six-Year Lagged Analysis
The present study investigated the role of parental use of alcohol, cigarettes, and marijuana on lagged change in the specific substance abuse of their adolescent offspring over a six year period. The analyses also examined the relative influence of mothers and fathers and their interaction as moderated by marital status and age and gender of the adolescent. A generalized estimating equations approach was employed to estimate regression coefficients through an iterative weighted least squares algorithm. Findings indicated that, when employed as time varying covariates, parental substance use resulted in substance-specific effects on fluctuations in the adolescent's own use. Age, parent marital status, and each parent's marijuana use independently were found to significantly affect adolescent marijuana use. In contrast, the complex relationship between parent and adolescent use of alcohol and cigarettes showed variation by substance, age, and gender text. The results suggest that parent use of substances must be considered risk factors with particular effects on their younger offspring. Thus, prevention efforts should be directed at middle childhood and include components aimed at parents as well as their children. Hops, H., Duncan, T. E., Duncan, S. C., Stoolmiller, M. Parent Substance Use As A Predictor of Adolescent Use: A Six-Year Lagged Analysis. Ann Behavior Medicine, 18 (3) pp. 157-164, 1996.
Smokeless Tobacco: Demographic Differences in Prevalence and Place in Drug Involvement Continuum
In a study of 2,525 Southern California high school seniors, Dr. Brian Flay and his affiliates examined patterns of smokeless tobacco (ST) use and the place of ST in a unidimensional model of drug involvement based on latent trait analysis. Among male students, lifetime ST use was reported by 31.9% of Whites, 3.0% of Blacks, and 16.1% of Hispanics; among females, comparable rates were 6.3%, 1.8%, and 1.9% for these respective racial/ethnic groups. In the total sample, the ordering of drugs along the hypothesized involvement continuum was, from least to most involved: alcohol, cigarettes, marijuana, ST, LSD, "uppers", cocaine, "downers", PCP, and heroin. Analyses showed that although ST use fits the unidimensional model of drug involvement, the place of ST use along the continuum of drug involvement is not stable and differs by gender and ethnicity. Particularly for males, ST use is likely to be preceded by soft drug use and followed by hard drug use; for females, however, ST use is closely associated with hard drug use. The analyses also revealed that the fit of the unidimensional model and the location of ST use along the dimension vary with different ethnic groups. Hu, F.B., Hedeker, D., Day, L.E., Flay, B.R., Siddiqui, O., Sussman, S., and Richardson, J. Patterns of Use of Smokeless Tobacco and the Unidimensional Model of Drug Involvement. Addictive Behavior, 22 (2), pp. 257-261, 1997.
Gender and Hostility Effects on Alcohol Use and Aggression
In a study at Rutgers, investigators working with Dr. Robert Pandina used a series of nested structural equation models to examine the interrelationships among alcohol use, aggressive behavior, and episodes of acute alcohol-related aggression. Both prior aggressive behavior and prior alcohol use predicted later episodes of acute alcohol-related aggression. In addition, early aggressive behavior predicted later alcohol use, but alcohol use was not related to subsequent increases in aggressive behavior. Gender interaction effects were significant. Prior alcohol use was a better predictor of alcohol related aggression for females, while prior aggression was a better predictor for males. However, the relationships among alcohol use and aggression did not vary by levels of hostility as measured by the SCL-90R. In sum, these data suggested that the nature and direction of the relationship between alcohol use, aggression, and alcohol-related aggression over time are conditioned by gender. White, H. R., and Hansell, S. The Moderating Effects of Gender and Hostility on the Alcohol Aggression Relationship. Journal of Research on Crime and Delinquency, 33, pp. 451 472, 1996.
Narcotic Addicts' Parenting Practices
This survey study of male and female narcotic addicts participating in methadone maintenance programs examined self-reported retrospective data on parental behavior experienced by addicts during their adolescent years. These findings were contrasted with the addicts' self-report of their current parenting practices with their own adolescent children. Results showed addicts as perceiving their mothers as significantly more functional in their parenting practices than their fathers on indices of parental involvement, attachment, and responsibility. Significant parenting differences between addicts and their parents were reported for the three indices mentioned, as well as for parent discipline and punitive actions, with the addicts rating their current parenting practices as more effective than those of their parents. Reported parenting practices were further analyzed in the context of how the ratings of parental functioning were related to problems of drug and alcohol abuse exhibited in the home. Findings are discussed in terms of the implications for prevention and treatment approaches with addicts and their children. Nurco, D.N., Blatchley, R.J., Hanlon, T.E., O'Grady, K.E., and McCarren, M. The Family Experiences of Narcotic Addicts and their Subsequent Parenting Practices. The American Journal of Drug and Alcohol Abuse, In press.
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