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National Institute on Drug Abuse
Women and Sex/Gender Differences Research
Director's Report to Council
Research Findings Excerpts
February, 2002
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Behavioral Research |
Sexual Experience Activates Neurons in the Nucleus Accumbens and Cross Sensitizes Female Hamsters to the Behavioral Effects of Amphetamine
Dopamine transmission in the nucleus accumbens from neurons originating in the midbrain ventral tegmental area is important both for the regulation of appetitive behaviors and for self-administration of drugs of abuse. Dr. Robert Meisel and his graduate student Katherine Bradley recently carried out a study to examine the effects of female sexual experience on cellular activity in the nucleus accumbens and to determine whether previous sexual experience could sensitize animals to the behavioral effects of amphetamine. They found that sexual activity elevated c-Fos induction (a measure of neuronal activity) in the core, but not the shell, of nucleus accumbens. Drugs of abuse have most often been observed to activate neurons in the shell of nucleus accumbens. Nevertheless, the investigators were able to demonstrate that prior sexual activity made female hamsters more sensitive to the locomotor effects of amphetamine. These experiments in female animals join a growing list of studies indicating that the prior experiences of an animal -- such as exposure to mild stress, environmental novelty, or highly palatable food, and male sexual behavior -- can sensitize the responsiveness of the mesolimbic dopamine pathway to the effects of drugs of abuse. Research on cross-sensitization between experience and drug effects may shed light on the neural mechanisms underlying individual vulnerability to the effects of drugs. Bradley, K.C. and Meisel, R.L. Sexual Behavior Induction of c-Fos in the Nucleus Accumbens and Amphetamine-stimulated Locomotor Activity are Sensitized by Previous Sexual Experience in Female Syrian Hamsters. Journal of Neuroscience, 21, pp. 2123-2130, 2001.
Repeated Maternal Separation in Neonatal Rats Alters Sensitivity to Chronic Morphine in a Sex-Dependent Manner
Research has shown that neonatal rat pups separated from their mothers for several hours each day, during the first few weeks of life, subsequently exhibit elevated stress-reactivity during adulthood. Exaggerated responsivity is evident from both behavioral and physiological indices. Moreover, animals exposed to early separation distress with this paradigm are also more sensitive to the locomotor activating effects of acute psychostimulant drugs and are more vulnerable to acquire psychostimulant self-administration. Dr. Steve Holtzman and his colleagues at Emory University School of Medicine have been examining the behavioral and physiological effects of opiates in animals exposed to the early separation procedure, and using this paradigm to uncover influences of early post-natal stress on neuroadaptations to chronic drug administration. These investigators report that 3 hours of separation from the dam, in comparison to handled and nonhandled controls, alters subsequent sensitivity to morphine's antinociceptive effects. Notably, after this extended period of early separation, male but not female offspring were less sensitive to the antinociceptive effects of morphine. Also, the development of tolerance to antinociceptive effects was enhanced in males exposed to early maternal separation, but not in females. In both male and female rats, daily 3 hour maternal separations over 12 days was also associated with an increase in the severity of withdrawal from chronic morphine, suggesting the development of a greater degree of opiate dependence in animals exposed to early maternal separation. The authors speculate that maternal separation alters morphine sensitivity via stress-induced stimulation of opioid peptides in separated pups, providing additional evidence that early deleterious environmental influences may have an impact on subsequent response to drugs of abuse. Kalinichev, M., Easterling, K.W. and Holtzman, S.G. Early Neonatal Experience of Long-Evans Rats Results in Long-Lasting Changes in Morphine Tolerance and Dependence. Psychopharmacology, 157, pp. 305-312, 2001.
Progesterone Effects in Healthy Postmenopausal Women and Normally-Cycling Women
There is accumulating evidence that the stage of the menstrual cycle influences subjective responses to abused drugs. Certain neurosteroid metabolites of progesterone, e.g. allopregnanolone, are known to bind to the GABA-A receptor and there has been some evidence that they produce sedative-like effects, suggesting that progesterone may have behavioral and subjective effects in women and could perhaps influence responses to abused drugs in women. Dr. Harriet de Wit and her colleagues at the University of Chicago examined the behavioral and subjective effects of acute injections of progesterone in two groups of women, healthy normally cycling women and postmenopausal women. Normally cycling women (n=10) who were not on hormone replacement received a single injection of progesterone (100 mg im) or placebo in two sessions conducted a month apart during the follicular phase when endogenous progesterone and estrogen are low. Postmenopausal women (n=10) received progesterone (25, 50, 100 mg im) or placebo at four one-week intervals. Extensive behavioral assessments (including measures of motor, cognitive, and memory impairment) and evaluations of subjective effects (including mood and physiological states) were conducted following each injection. The progesterone injections produced time and dose-related increases in plasma concentrations of progesterone and allopregnanolone that were similar in the two groups. Yet, the behavioral and subjective effects were only modest. In cycling women there were mild sedative effects consisting of a decrease in ratings of "vigor," "friendliness," and "arousal," and paradoxically, there was a small improvement on the motor task (digit-symbol substitution test). In post-menopausal women, only the highest dose (100 mg) slightly increased ratings of feeling "sluggish" and in "positive mood." These modest sedative-effects occurred at plasma concentrations well beyond those attained during normal menstrual cycles and suggest that brief increases (i.e., several hours) in plasma levels of allopregnanolone produce only marginal sedative-like effects. The authors suggest that the allopregnanolone may produce stronger sedative-like effects only in other phases of the menstrual cycle or when estrogen is present, or alternatively, only in certain vulnerable populations, such as women with anxiety disorders. These results indicate that allopregnanolone can affect subjective states in women, albeit weakly, and could play a role in the changes in the response to abuse drugs across the menstrual cycle. de Wit, H., Schmitt, L., Purdy, R. and Hauger, R. Effects of Acute Progesterone Administration In Healthy Postmenopausal Women and Normally-Cycling Women. Psychoneuroendocrinology, 26, pp. 697-710, 2001.
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Treatment Research and Development |
Opioid-dependent Women: Maternal and Neonatal Outcomes
Researchers at the Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine reported an open-label prospective study that examined maternal and neonatal safety and efficacy outcome measures during and following prenatal buprenorphine exposure. Three opioid-dependent pregnant women received 8 or 12 mg sublingual buprenorphine tablets daily for 15-16 weeks prior to delivery. Results showed that buprenorphine in combination with comprehensive prenatal care was safe and effective in these women. Prenatal exposure to buprenorphine resulted in normal birth outcomes, a mean of 4.33 days (minimum possible=4) hospitalization, and a 'relatively mild' neonatal abstinence syndrome comprised primarily of tremors (disturbed), hyperactive moro and shortened sleep after feeding. The infants required no pharmacological treatment. Onset of neonatal abstinence signs occurred within the first 12 h after birth, peaked by 72 h and returned to below pre-12 h levels by 120 h. It is concluded that buprenorphine has potential utility for the treatment of pregnant opioid-dependent women. Johnson, R.E., Jones, H.E., Jasinski, D.R., Svikis, D.S., Haug, N.A., Jansson, L.M., Kissin, W.B., Alpan, G., Lantz, M.E., Cone, E.J., Wilkins, D.G., Golden, A.S., Huggins, G.R., and Lester, B.M. Buprenorphine Treatment of Pregnant Opioid--Dependent Women: Maternal and Neonatal Outcomes. Drug Alcohol Depend, 63(1), pp. 97-103, 2001.
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Research on AIDS and Other Medical Consequences of Drug Abuse |
Association of Alcohol Consumption with HIV Sex- and Drug-Risk Behaviors Among Drug Users
The relationship between alcohol use and HIV transmission is well recognized but not fully understood. In particular, the role of alcohol abuse as a mediator of HIV risk behavior among drug users is not well documented. We hypothesized that alcohol use in drug users will result in greater HIV risk-taking behavior. Participants were 354 drug users, of whom 105 were recent injection drug users. Multiple regression models were used to characterize the association between alcohol use, sexual risk behavior and injection drug use. HIV risk behavior was related to alcohol consumption, controlling for other potentially associated factors. We found that sexual HIV risk-taking behavior is associated with increased alcohol consumption among women (p = 0.02), with women having more risky sexual behavior than males. However, contrary to our hypothesis, there was no significant association of alcohol consumption with risky injection drug behavior. Addressing alcohol problems among drug users, particularly women, may be an important opportunity to reduce HIV sexual risk behavior among this high-risk population. Rees, V., Saitz, R., Horton, N.J. and Samet, J. Journal of Substance Abuse Treatment, 21(3), pp. 129-134, 2001.
Drug Use, Sex Partners, and Behaviors of 18-24 Year-Olds in a High Risk Neighborhood
Researchers sought to determine how stigmatized drug use is related to sexual risk behaviors and network characteristics among youth. They conducted in-person interviews with a probability household sample (n=363) and a targeted, street-recruited sample of cocaine, heroin, crack, or injecting drug users comprising 18-24 year-olds in an inner city neighborhood. Drug use in the preceding 12 months was scaled hierarchically on the basis of lowest to highest social stigma, from none, to marijuana, non-injected cocaine, non-injected heroin, crack, and injected drugs. Findings indicate that users of the more stigmatized drugs had more sex partners. They were more likely to report a history of concurrent sex partners, sex with someone who also had engaged in sex with a network member, commercial sex work, and unprotected sex. Findings also showed crack use and drug injection to be associated more strongly with increased sex risk among women than among men. Young users of the more stigmatized drugs are at much greater network and behavior risk for sexually transmitted diseases. Drug use prevention and treatment programs can help to reduce sex risk because young people who use drugs engage in more sex risk behaviors and are more likely to have concurrent or shared partners than those who do not use drugs. Risk reduction interventions that address sex risk of drug users can also help to encourage condom use and fewer sex partners, and to refer drug users to screening and treatment services for sexually transmitted infections. Flom, P., Friedman, S., Kottiri, B., Neaigus, A., Curtis, R., Des Jarlais, D., Sandoval, M., and Zenilman, J. Stigmatized Drug Use, Sexual Partner Concurrency, and Other Sex Risk Network and Behavior Characteristics of 18- to 24-Year Old Youth in a High-Risk Neighborhood. Sexually Transmitted Diseases, 28(10), pp. 598-607, 2001.
Longitudinal Predictors of Depressive Symptoms Among Low Income IDUs
In this study, researchers assessed the effects of changes in physical health status and drug use, and prior social support on depressive symptoms in low income IDUs. Data are from 503 participants enrolled at baseline who remained at 1-year follow up (393 IDUs, or 79%); 37% were HIV+ and 36% female. Physical health was measured by HIV symptoms, AIDS, CD4 count and functional limitation. One third scored high on depressive symptoms at 1-year follow up, representing no statistically significant change from baseline (38%). In multiple logistic regression, after controlling for baseline depression scores (OR=6.11, p<0.001) and drug use (OR=1.20, p=0.192), baseline functional limitation (OR=3.28, p<0.001) and declining functioning (OR=3.60, p<0.001) were positively, and quitting drug use was negatively, associated with depressive symptoms at follow-up. Low social support at baseline (OR=0.58), p<0.10) was marginally predictive of depressive symptoms. Depressive symptoms did not differ by gender. For HIV-positive respondents, functional limitation was predictive of depressive symptoms, but HIV illness and drug use were not. Facilitating drug treatment and preventive medical care may aid in reducing depression in this population. For HIV-positive drug users, drug treatment prior to AIDS may help reduce depressive symptoms, with potential implications for HIV service utilization and medical adherence. Knowlton, A., Latkin, C., Schroeder, J., Hoover, D., Ensminger, M., and Celentano, D. Longitudinal Predictors of Depressive Symptoms Among Low Income IDUs. AIDS Care, 13(5), pp. 549-559, 2001.
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Epidemiology, Etiology and Prevention Research |
Effects of Aggregating High Risk Youth
This paper focuses on three-year outcomes associated with a preventive intervention trial in which high-risk youth were aggregated into cognitive-behavioral groups. Participants were 158 at-risk youth between the ages of 11 and 14. The participating youth and their teachers were interviewed each year over a three-year period following the intervention. Analyses of covariance and latent growth modeling revealed that the intervention contributed to three-year escalations in self-reported smoking and teacher-reported delinquency. Interactions between participants' characteristics (i.e., initial status, age, and gender) and intervention were also tested. A statistically reliable interaction was found, suggesting that those with initially low levels of delinquency were especially affected by the peer intervention group. Poulin, F., Dishion, T. J., and Burraston, B. 3-year Iatrogenic Effects Associated with Aggregating High-risk Adolescents in Preventive Interventions. Applied Developmental Science, 5(4), pp 214-224, 2001.
Self-Reported High-Risk Locations of Drug Use Among Drug Offenders
The present study used a detailed, multiple-choice, self-report questionnaire to collect and analyze data on home, work, and other public locations where drug offenders report using drugs. In addition, these settings were examined as a function of gender, ethnicity, type of drug used, and drug abuse/dependence status. The participants for the present study were 462 individuals attending drug diversion programs in southern California. The single most frequently reported location of use was the subjects' living room with a small group of friends. However, heavier users used different drugs across a greater variety of locations. Not surprisingly, drugs were used least at work (though a surprising 47% had used at work). Popular situations of drug use among drug offenders are similar to that of high-risk youth. Sussman, S., Ames, S.L., Dent, C.W., and Stacy, A.W. Self-Reported High-Risk Locations of Drug Use Among Drug Offenders. American Journal of Drug and Alcohol Abuse, 27 (2), pp. 281-299, 2001.
The Adult Antisocial Syndrome with and without Antecedent Conduct Disorder: Comparisons from an Adoption Study
DSM antisocial personality disorder (ASPD) requires a retrospective diagnosis of conduct disorder-historical behavior not present in everyone with adult ASPD criteria. Using adoption study data, we examined the impact of this requirement on biological and environmental risk associations. We defined three subgroups: DSM-III ASPD (n = 30), adult antisocials without conduct disorder (n = 25), and controls (n = 142). Having an antisocial biological parent was a specific risk factor for ASPD. In contrast, fetal alcohol exposure, male gender, and adverse environment were associated with the adult antisocial syndrome, regardless of conduct disorder history. The two antisocial groups were similar with respect to sociopathy scales, co-occurring diagnoses, and the incidence of most individual symptoms. However, the phenotypic expression of the biological-possibly genetic-risk for ASPD appears to be manifest before adulthood. Despite this, we could not detect clinically important differences between the two sociopathic groups. The conduct disorder requirement therefore may be more relevant to etiological than clinical understanding of adult antisocial behavior. Langbehn, D.R., and Cadoret, R.J. Comprehensive Psychiatry, 42(4), pp. 272-282, 2001.
Gender Differences in the Relationship of Homelessness to Symptom Severity, Substance Abuse, and Neuroleptic Noncompliance in Schizophrenia
This study examined gender differences in the relationship of homelessness in schizophrenia to symptom severity, risk behaviors, and prognostic features. Four hundred subjects with schizophrenia were studied: 100 homeless men, 100 homeless women, 100 never homeless men, and 100 never homeless women. Assessments included derivation of five symptom factors by using the Positive and Negative Syndrome Scale (PANSS). Homelessness for the entire sample was associated with greater severity of positive, activation, and autistic preoccupation symptoms, younger age at first hospitalization, and substance abuse (SA). For men only, homelessness was associated with neuroleptic noncompliance (NN). When NN and SA were statistically controlled, symptom severity was not different between the homeless and never homeless. Women, independent of residential status, had more severe negative, activation, and autistic preoccupation symptoms that were not associated with prognostic features or risk behaviors. For both men and women, SA was associated with homelessness, but independent of residence, SA was less severe in women. Additionally, SA was less severe in homeless women than never homeless men. Thus, symptom severity in homeless individuals with schizophrenia appears as an interaction of symptom profiles and risk behaviors that are gender specific. Although cross-sectional analyses cannot distinguish cause from effect, these findings suggest gender-specific routes to homelessness among indigent urban adults with schizophrenia. Opler, L.A., White, L., Caton, C.L., Dominguez, B., Hirshfield, S., and Shrout, P.E., J Nerv Ment Dis, 189(7), pp. 449-456, 2001.
The Effects of a High-risk Environment on the Sexual Victimization of Homeless and Runaway Youth
Based on the structural-choice theory of victimization, the current study examines the effects of a high-risk environment on the sexual victimization of 311 homeless and runaway youth. Results from logistic regression revealed that survival sex, gender, and physical appearance were significantly associated with sexual victimization. Results from a series of interactions also revealed that the effects of deviant behaviors on sexual victimization varied by gender and age. Although males and females engaged in similar activities, young women were more likely to be victims of sexual assault. These findings suggest that engaging in high-risk behaviors predispose some people to greater risks but it is the combination of these behaviors with gender and/or age that determines who will become victimized. Tyler, K.A., Hoyt, D.R., Whitbeck, L.B., Cauce, A.M., Violence Vict.,16(4), pp. 441-455, 2001.
Risk Factors for Adolescent Marijuana Use across Cultures and across Time
This integrated analysis of data from 3 different longitudinal studies was conducted to examine the early psychosocial predictors of later marijuana use among adolescents. The data used in the analysis were derived from (a) a sample of 739 predominantly White adolescents representative of the northeastern United States, (b) a sample of 1,190 minority adolescents from the East Harlem section of New York City, and (c) a sample of 1,374 Colombian adolescents from two cities in Colombia, South America. In 2 of the samples, participants were interviewed in their homes, and in the 3rd study, participants were assessed in school. The predictors included a number of variables from (a) the personality domain, reflecting the adolescents' conventionality and intrapsychic functioning; (b) the family domain, representing the parent-child mutual attachment relationship and parental substance use; (c) the peer domain, reflecting the peer group's delinquency and substance use; and (d) the adolescents' own use of legal drugs. The dependent variable was adolescent marijuana use. The results of the analysis demonstrated remarkable consistency in the risk and protective factors for later marijuana use across the 3 samples, attesting to the robust nature of these predictors and their generalizability across gender, time, location, and ethnic/cultural background. These findings have important implications for designing intervention programs. Programs aimed at preventing adolescent marijuana use can be designed to incorporate universal features and still incorporate specific components that address the unique needs of adolescents from different groups. Brook, J.S., Brook, D.W., Arencibia-reles, O., Richter, L., and Whiteman, M. J Genet Psychol, 162(3), pp. 357-374, 2001.
Dramatic-erratic Personality Disorder Symptoms: II. Developmental Pathways from Early Adolescence to Adulthood
This study examined the relationship over time between Cluster B personality disorder symptoms (borderline, histrionic, and narcissistic symptoms) and comorbid internalizing and externalizing symptoms in a community sample of 407 adolescents. Cross-lagged longitudinal models tested (a) the hypothesis that Cluster B symptoms reflect primary disturbances that give rise to co-occurring internalizing and externalizing symptoms; and (b) the alternative hypothesis that these Axis I symptom clusters reflect primary problems that interfere with normal personality development. Internalizing and externalizing symptoms each predicted subsequent Cluster B symptoms in girls, although these effects occurred only at specific developmental stages. Cluster B symptoms in boys and girls at ages 10 to 14 years predicted externalizing symptoms two years later. Instead of clearly supporting one hypothesis over the other, longitudinal models suggested gender-specific developmental effects that were partially consistent with both hypotheses. Crawford, T.N., Cohen, P., and Brook, J.S. J Personal Disord, 15(4), pp. 36-50, 2001.
The Decline of Substance Use in Young Adulthood: Changes in Social Activities, Roles, and Beliefs
The Monitoring the Future team at the University of Michigan published a new book based on their longitudinal panel data. This volume examines how changes in social and religious experiences and changes in attitudes towards substance use among young adults are related to changes in substance use, family transitions, living arrangements, education, and employment. The analysis included over 38,000 young people followed from the initial survey, when they were high school seniors (age 18), into adulthood (up to age 32) and covers the last 25 years, a period when drug use and views about drugs underwent important changes. An earlier book by the MTF investigators showed that the new freedoms of young adulthood are associated with increases in substance use, while the responsibilities of adulthood--marriage, pregnancy, parenthood--contribute to later declines in substance use. The new findings clarify some of the mediators involved in these changes, such as religiosity and perceived risk and disapproval of substance use, factors whose importance is borne out even when controlling for a number of possible confounders. The initial freedoms of young adulthood often lead to frequent evenings out, parties and visits to bars, patterns that may be associated with increases in substance use, but later these behaviors are often crowded out by adult responsibilities to spouse and children. In addition to removing individuals from these higher-risk venues, engagement, marriage, pregnancy, and parenthood tend to heighten both disapproval and perceptions of risk of substance use. The study suggests that while these attitudinal variables are fairly stable, it is important to intervene early to strengthen them if substance use is to be reduced. The authors also discuss the need to intervene with younger adults prior to assumption of full adult roles to involve them in prosocial activities that will compete with substance use. Bachman, J.G., O'Malley, P.M., Schulenberg, J.E., Johnston, L.D. Bryant, A.L., and Merline, A.C. The Decline of Substance Use in Young Adulthood: Changes in Social Activities, Roles, and Beliefs. Mahwah, NJ, US: Lawrence Erlbaum Associates, Inc., Publishers, 2002.
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Services Research |
12-step Program Participation and Effectiveness: Do Gender and Ethnic Differences Exist?
Although 12-Step is increasingly utilized as a recovery resource and is viewed by many addiction specialists as an integral component of treatment and long-term recovery, questions regarding participation and effectiveness of 12-Step programs for women and ethnic minorities have been raised. Utilizing data from the Los Angeles Target Cites Evaluation Project (n = 356), participants in adult outpatient alcohol and drug treatment were followed for 24 months and rates of 12-Step participation and effectiveness were assessed for all gender and ethnic groups. Contrary to reports that 12-Step is more appropriate for European-American males, statistical analyses reveals that women and ethnic minorities are equally likely to attend 12-Step programs, and to recover in conjunction with such participation as European-American males. Although 12-Step may not appeal to all seeking to cease alcohol and drug use, the clinical implications for treatment providers and other addiction specialists points to the benefits of integrating 12-Step components into traditional treatment programs and recommending 12-Step participation for clients of all gender and ethnic groups. Hillhouse, M.P., and Fiorentine, R. J Drug Issues, 31(3), pp. 767-780, 2001.
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