www.drugabuse.gov Volume 21, Number 6 U.S. Department of Health and Human Services | National Institutes of Health

New Therapy Reduces Drug ALSO IN THIS ISSUE Abuse Among Patients With Research Findings 7 Smoking During Pregnancy Linked to Severe Mental Illness Behavioral Problems in Children 9 Morphine-Induced A specially designed group intervention also improves patients’ Immunosuppression, From functioning in the community. Brain to Spleen 12 Genetically Altered Mice Eschew persistent mental illness. These factors include 14 Animal Studies Elaborate BY NIDA NOTES STAFF ’s Effects frequent failure to meet their own and others’ new intervention enhances prospects expectations, inconsistent motivation, and social Director’s Perspective

for substance abusers whose mental and personal pressure to appear normal. 2 Neuroscience Blueprint illness complicates the path to recov- BTSAS therapy comprises six integrated Promotes Efficiency, A ery. In a recent clinical trial, a components: Synergy 6-month course of Behavioral Treatment for ■ motivational interviews (directive counseling Research in Brief in Severe and Persistent Mental that explores and resolves ambivalence) to 3 • Intervention Improves Illness (BTSAS) reduced drug abuse, boosted increase the desire to stop using drugs; Employment Outlook for Methadone Patients treatment-session attendance, and improved the ■ contingency contracts linking drug-free urine • Morphine Speeds AIDS quality of life of outpatients with a wide spectrum samples with small financial rewards; Onset in Monkeys • Methamphetamine of mental disorders. ■ realistic, short-term, structured goal-setting sessions; Restricts Fetal Growth, Increases Lethargy in A FOCUS ON EXTRA OBSTACLES ■ training in social and drug-refusal skills; Newborns Dr. Alan S. Bellack and colleagues at the Uni- ■ information on why and how people become versity of Maryland School of Medicine in Balti- addicted to drugs and the dangers of substance NIDA at Work more designed BTSAS to counter the factors that use for people with mental illness; and 4 NIDA’s International Program make recovery from addiction especially difficult ■ relapse-prevention training that inculcates for people who have co-occurring severe and behavioral strategies for coping with cravings, Bulletin Board lapses, and high-risk situations. 16 • Social Neuroscience TREATMENT OUTCOMES Twice-weekly sessions begin with urine tests. Meeting Advances Patients who have provided drug-free urine sam- Treatments • NIDA BTSAS STAR ples are praised by the therapists and group mem- Renames Addiction Journal Drug-free Urine Samples 59% 25% bers. They also receive financial incentives that Four Weeks of Abstinence 54% 16% start at $1.50 for the first drug-free sample and Tearoff increase in $0.50 increments for every consecutive 17 Booklet Explains Science Multiple 4-Week Blocks 44% 10% one thereafter, up to $3.50. The amount is set back of Addiction Eights Weeks of Abstinence 33% 8% to $1.50 after a drug-positive sample or an absence. When participants submit drug-positive sam- 18 Volume 21 Index BTSAS: Behavioral Treatment for Substance Abuse in Severe and Persistent Mental Illness; STAR: Supportive Treatment for Addiction ples, the group takes a nonaccusatory approach by Recovery. What the Numbers Say focusing on problem solving to help them achieve 20 [ Continued on page 6 ]

NIDA Notes | Volume 21, Number 6 1 ■ DIRECTOR’S PERSPECTIVE By NORA D. VOLKOW, M.D., NIDA Director NIDA Notes

EDITOR David Anderson Public Health Advisor, Office of Science Policy and Communications, National Institute on Drug Abuse

DEPUTY EDITOR Julie Ann Miller, Ph.D. Neuroscience Blueprint MasiMax Resources, Inc. MANAGING EDITOR Andrew Keegan Promotes Efficiency, Synergy MasiMax Resources, Inc.

SENIOR WRITER Lori Whitten, Ph.D. MasiMax Resources, Inc. n 2004, NIDA and 15 other NIH Institutes convened to address a challenge posed, in ASSOCIATE EDITOR a sense, by an embarrassment of riches. In recent decades, neuroscientists had Debra P. Davis developed powerful new tools and techniques that yielded extraordinary insights into MasiMax Resources, Inc. Ithe working of the brain. The potential for future discoveries appeared limitless. How- DESIGN/LAYOUT Maggie Bray ever, without an overarching plan to assimilate, coordinate, and disseminate this burgeoning MasiMax Resources, Inc. wealth of knowledge in an organized, coherent way, there was a risk that the resources could be wasted and progress slowed by inefficient or duplicative efforts. EDITORIAL BOARD David Anderson, Chair; Public The NIH Blueprint for Neuroscience Research is that plan. It provides a knowledge- and Health Advisor, Office of Science Policy resource-sharing system for NIH-funded neuroscientists, allowing them access to and Communications Nicolette Borek, Ph.D., Research an extraordinary array of data, advanced research tools, and technical assistance. More Psychologist, Division of Clinical Neuroscience than 125 neuroscience program directors and staff contribute to the Blueprint’s projects and Behavioral Research and initiatives. Jessica Campbell Chambers, Ph.D., Health Science Administrator, Division The Blueprint consortium assesses the field’s needs and sets annual goals. In 2005 and of Epidemiology, Services and Prevention 2006, it concentrated on strengthening resources applicable across broad areas of neuro- Research J.C. Comolli, Public Health Advisor, science research, including animal models, informatics, gene and protein expression, neu- Division of Pharmacotherapies and Medical roimaging, and behavioral assessments used in clinical research. From this focus emerged a Consequences of Drug Abuse variety of resources, all of which are available to all NIH researchers on the Blueprint Web site Jennifer Elcano, M.A., Science Writer, Office of Science Policy and Communications (neuroscienceblueprint.nih.gov). Among many other assets, researchers can find: Lynda Erinoff, Ph.D., Associate Director, ■ A comprehensive menu of animal models for neurological research, with training in AIDS Research Program, Division of Epidemiology, Services and Prevention their use. Through this site, researchers can obtain and learn to use the appropriate mod- Research els to study a particular neurological disease, for example, Alzheimer’s or Parkinson’s. Marsha F. Lopez, Ph.D. , Health Science The Neuroscience Information Framework (NIF), a Web site that organizes vast Administrator, Division of Epidemiology, ■ Services and Prevention Research amounts of neuroscience research data from around the world. Here investigators can Gerald McLaughlin, Ph.D. , Chief, Grants tap into, for example, databases of the as well as others involved with Review Branch, Office of Extramural Affairs neurological diseases. In addition, scientists can access research tools, resources, and Mary Ellen Michel, Ph.D., Deputy services for designing and interpreting gene expression studies. Director, Center for the Clinical Trials Network Ivan Montoya, M.D., M.P.H., Medical ■ An NIH Toolbox for Assessment of Neurological and Behavioral Function, containing Officer, Division of Pharmacotherapies and a set of standard assessment tests. Along with relieving researchers of the expenditures Medical Consequences of Drug Abuse of time, effort, and funds needed to develop assessments on their own, this resource Joni Rutter, Ph.D., Program Director, Genetics and Molecular Neurobiology Research facilitates comparison and compilation of data across studies. Branch, Division of Basic Neuroscience and In 2007, the Blueprint consortium initiated a 3-year plan to develop and share research Behavioral Research Anna Staton, M.P.A., Public Health tools in neurodegeneration, neurodevelopment, and neuroplasticity. NIDA and the Nation- Analyst, Office of Science Policy and al Institute of Mental Health are leading the planning for the 2009 neuroplasticity initia- Communications tive, which aims to accelerate advances in the understanding of how brain cells adapt to Frank Vocci, Ph.D., Director, Division of Pharmacotherapies and Medical experience by forming new neural circuits. We anticipate that it will provide a wealth of Consequences of Drug Abuse insights into how the healthy brain grows and learns, as well as how it changes when affect- Cora Lee Wetherington, Ph.D., Psychologist, Behavioral and Cognitive ed by diseases such as drug addiction. ■ Science Research Branch, Division of Basic Neuroscience and Behavioral Research

This publication was produced and printed by MasiMax Resources, Inc., under Contract No. N01DA-4-1117 from the National Institute on Drug Abuse. 2 NIDA Notes | Volume 21, Number 6 ■ RESEARCH IN BRIEF Highlights of recently published NIDA-supported studies

accompanied patients in their in on particular areas of the data from 1,618 mother-infant job searches; and helped viral envelope—a lipid-protein pairs, 84 of whom were meth- patients overcome barriers to covering that helps viruses exposed. The meth-exposed employment. Among 168 penetrate cells—they found newborns weighed 3,174 grams participants interviewed 6 and that morphine-exposed (7 pounds), on average, versus 12 months after beginning the monkeys demonstrated a 3,381 grams (nearly 7.5 pounds) study, 41 percent in the CES higher degree of change in the for unexposed newborns. The group, compared with 26 V4 region than control animals. meth-exposed newborns also percent of those who received This difference, which may had a lower gestational age at Intervention Improves standard counseling, reported expand the range of cells that birth (38.7 weeks versus 39.2 Employment Outlook paid employment at both HIV can infect, occurred in weeks). Although most infants For Methadone followup assessments. both CSF and blood. The were full term, methampheta- Patients > Substance Use and Misuse extent of V4 evolution mine infants were 3.5 times as Assertive outreach and motiva- 41(8):1125-1138, 2006; Substance corresponded with rapid likely to be small for gestational tional techniques can enhance Use and Misuse 42(5):811-828, disease progression. Studies age—a finding that suggests 2007. methadone patients’ participa- such as this aim to open new fetal growth restriction. tion in vocational counseling Morphine Speeds avenues for intervening against In a followup with 166 and increase subsequent AIDS Onset in HIV. infants from the study, the employment. In a study of 211 Monkeys > Virology 354(1):192-206, 2006; researchers assessed the unemployed methadone Dr. Anil Kumar and colleagues Virology 358(2):373-383, 2007. newborns’ behavioral capabili- patients at two facilities in New at the Ponce School of ties within the first 5 days of York City, Dr. Stephen Magura Medicine, Puerto Rico, have life. The 74 meth-exposed new- and colleagues at the National discovered key ways in which borns showed greater lethargy Development and Research morphine may accelerate the and were more difficult to Institutes found that 47 progression of AIDS: The drug awaken than the 92 unexposed percent of participants increases both viral replication newborns. Once aroused, assigned to the Customized and alterations in a particular however, meth-exposed Employment Supports (CES) part of the virus’s coating. newborns also showed a sign intervention attended five or Monkeys exposed to long-term of physiological distress— more vocational counseling morphine administration— difficulty maintaining normal, sessions within 6 months of 20 weeks prior to infection regular breathing. The beginning the study. In with simian/human Methamphetamine differences held when the contrast, only 12 percent of immunodeficiency virus Restricts Fetal researchers took into account those in the clinic’s standard (SIV/SHIV) and throughout Growth, Increases factors known to affect fetal vocational programs were as the 56-week study period— Lethargy in Newborns growth, including maternal assiduous. CES counselors progressed to AIDS faster and A NIDA-funded study found smoking and other drug abuse engaged patients in the showed more signs of compro- that newborns whose mothers and socioeconomic status. In program with tactics such as mised immune systems than abused methamphetamine addition, higher concentrations checking their clinic schedules comparison animals. Of the during pregnancy showed of methamphetamine in and arranging impromptu morphine-exposed animals higher rates of growth samples of the babies’ stool visits; spent more time with that developed AIDS, three restriction compared with were related to increased patients in counseling sessions demonstrated higher viral unexposed newborns. Dr. Barry central nervous system stress. than counselors in the replication in their blood and M. Lester and colleagues at > Pediatrics 118(3):1149-1156, standard program; responded cerebrospinal fluid (CSF). Brown Medical School and 2006; Neurotoxicology and promptly to requests for help; When the researchers zeroed other institutions analyzed 30(1):20-28, 2008.

NIDA Notes | Volume 21, Number 6 3 ■ NIDA AT WORK: other countries improve the quality of NIDA’s International Program regional data on drug abuse. Using exist- ing NIDA programs as models, DESPR and the IP have facilitated collaboration among epidemiologists, particularly in Linking NIDA to Researchers Southeast Asia and Latin America, through meetings and training activities. On a Global Scale The IP staff fulfill NIDA’s international mission through activities that:

BY LORI WHITTEN, staff assist NIDA Strengthen Global Research NIDA Notes Staff Writer “Fostering ■ scientists with addiction Infrastructure research-related In March 2006, NIDA launched its cientific opportunity and pub- international trav- research Latin American Initiative. The IP lic health responsibility have el, identify region- networks partnered with the six member no borders for NIDA, the al experts in par- in strategic nations of the United Nations Office Sworld’s largest supporter of ticular subjects, regions is on Drugs and Crime’s Regional research on drug abuse and its health and and determine our primary Central American Substance Abuse social consequences. Through its Inter- how U.S. investi- approach.” Treatment Network—Costa Rica, El national Program (IP), NIDA strengthens gators might con- Salvador, Guatemala, Honduras, research networks outside the United nect with international partners. Nicaragua, and Panama—to establish States—creating opportunities for global “Fostering addiction research net- a clinical research infrastructure and research collaboration, training, and sci- works in strategic regions is our primary identify areas of focus for science and entific exchange. approach to tackling the international training. The IP also partnered with International research and training challenges of drug abuse and its related the Inter-American Drug Abuse Con- have been a part of NIDA’s mission since health consequences. Ultimately, helping trol Commission at the Organization its inception in 1974. At that time, the IP regions build strong addiction research of American States to plan a network primarily focused on information infrastructure leads to self-sustaining sci- to monitor regional drug abuse pat- exchange. But its scope has grown over entific networks that generate knowledge terns at the community level and pro- the decades; today the program has on the causes, prevention, and treatment vide management training for the developed formal relationships with drug of drug abuse—an investment that bene- Latin American scientists who will abuse research institutions in four coun- fits the global community,” says Dr. Gust. lead the network. By working closely tries and programs that reach scores of For instance, when NIDA’s Division of with international organizations scientists and international organiza- Basic Neuroscience and Behavioral already active in the region, NIDA tions in Europe, Asia, and the Americas. Research identified a need to stimulate ensures that its activities comple- Dr. Steven Gust, a specialist in psy- international collaborative research on ment ongoing efforts. chology and pharmacology, leads the pro- abuse, the IP worked with the

gram. He directs and coordinates NIDA’s division to organize a scientific confer- ■ Facilitate Professional efforts to foster collaborative interna- ence with interested Canadian and Mexi- Development tional research involving other U.S. Gov- can organizations. To perpetuate the Since 1990, NIDA has supported 60 ernment agencies, foreign governments relationships and extend the progress drug abuse professionals from 33 and institutions, and nongovernmental made there, the IP is building an online nations through Hubert H. organizations. Working with Dr. Gust, platform with virtual meeting capabili- Humphrey Fellowships. The fellow- Ms. Dale Weiss, a program analyst, man- ties, application sharing, and a discussion ships bring mid-career professionals ages the IP’s Web-based training and sci- forum to help the participants advance from other countries to U.S. universi- entific exchange initiatives, bringing low- inhalant abuse research. The IP also ties for a year of academic coursework cost training and science-based works with the Division of Epidemiology, and participation in research with information to drug abuse researchers Services and Prevention Research NIDA-funded investigators. NIDA’s and public health workers worldwide. IP (DESPR) to help addiction researchers in INVEST Drug Abuse Research

4 NIDA Notes | Volume 21, Number 6 Fellowships, another program to build research capacity, has provided NIDA-SUPPORTED INTERNATIONAL RESEARCHERS SHARE KNOWLEDGE At the 2007 NIDA International Forum in Quebec City, Canada, Dr. Paulo Cunha of Hospital Israelite rigorous postdoctoral training for sci- Albert Einstein in Brazil describes his research on the effects of neurocognitive deficits on treatment entists from 26 nations since its retention to Dr. Nancy Phaswana Mafuya of the South African Human Sciences Research Council. inception in 1993. Traveling fellow- ship awards provide for brief research visits between international and U.S.- based NIDA grantees and enable international scientists to attend key meetings on drug abuse research.

■ Support Research and Collaboration The Program supports international research on the causes, prevention, and treatment of drug abuse and addiction. Formal agreements with goes to projects in Russia, Eastern provides science-based information research institutes in Mexico, the Europe, and Central and Southeast about the public health benefits of the Netherlands, Russia, and Spain Asia, where a high percentage of HIV . Another online resource, ensure ongoing collaboration. For infections result from injection drug created by the International Society example, NIDA and the Dutch Addic- abuse or sexual liaisons with injection of Addiction Journal Editors with sup- tion Program jointly fund several drug abusers. port from the IP, provides addiction ongoing collaborations between researchers with guidance on publish-

researchers in the United States and ■ Share Knowledge ing research, including information the Netherlands. In one project, a U.S. The IP cosponsors scientific meetings on preparing manuscripts, identifying team led by Dr. John Lochman of the with partner countries and interna- appropriate target journals, and the University of Alabama developed and tional organizations, providing a submission, acceptance, and revision successfully tested an intervention to forum in which drug abuse profes- processes (www.parint.org). The IP is reduce the chances that children with sionals can exchange information and now developing a Web space where disruptive behaviors will become sub- initiate collaboration. Via its Web site, international collaborators can work stance abusers in adolescence. Work- international.drugabuse.gov, the IP together in real time by using shared ing with partners in the Netherlands, describes program initiatives and software and databases. the researchers subsequently demon- resources, findings, and funding strated that the intervention could be opportunities. Looking to the future, Dr. Gust says successfully adapted to Dutch culture. Ms. Weiss oversees the initia- IP priorities will include drug abuse Another U.S.—Dutch collaborative tives that deliver relatively low-cost treatment as a way to reduce HIV project used imaging techniques to training and education programs to a transmission; adolescent smoking and examine the effects of adolescent diverse international audience— prenatal exposure; methamphet- marijuana abuse on brain develop- physicians and other medical profes- amine abuse; inhalant abuse; and ment and decisionmaking. sionals, scientists, community-based driving under the influence of drugs. International collaboration is organizers, policymakers, and public NIDA can best address these priorities vital to efforts to stem the global health officials. and respond quickly to emerging spread of drug-related HIV. NIDA One such training tool, the problems, Dr. Gust says, through its relies on the scientific relationships Methadone Research Web Guide development and support of networks fostered by the IP to facilitate collabo- (international.drugabuse.gov/methadone that train international investigators rations with international partners in /methadone_web_guide/toc.html), and health professionals in the about 20 countries, develop research reviews research findings on the science of addiction and by facilitating networks, and tailor the studies to effectiveness of methadone mainte- their collaboration with U.S.-based local needs and conditions. Priority nance to treat opiate addiction and researchers. ■

NIDA Notes | Volume 21, Number 6 5 ■ RESEARCH FINDINGS

■ NEW THERAPY SUCCEEDS BTSAS, those in STAR do not follow a struc- learning important skills for reducing drug [ Continued from page 1 ] tured format but instead select their own use,” says Dr. Bellack. “We were very grati- topics and work at their own pace. Patient fied that the data supported our clinical future abstinence. Each participant agrees interaction with other patients is encour- observations.” upon a personal goal for drug abuse reduc- aged but not required as it is with BTSAS. The researchers reported that the extra tion or abstinence that he or she believes is Although urine samples are collected before costs of running the BTSAS program were achievable during the coming week and signs each session, results are not discussed in modest. For the 6-month trial, monetary a contract stating that he or she will strive the group, and no systematic feedback is rewards averaged roughly $60 per patient; for it. The rest of the session consists of drug provided to the patient. total per-patient cost, including therapist abuse education plus training in social skills Assignments to the BTSAS and STAR time, was $372. and relapse-prevention strategies. groups were balanced for gender, psychiatric diagnosis, type of drug dependency, and ONGOING REFINEMENTS SUPERIOR RESULTS number of substance use disorders. Treat- The trial data indicate that patients who Substance abuse is common among the ment groups of four to six participants met remain in BTSAS for at least three mentally ill. For example, surveys estimate twice a week for 6 months. BTSAS and STAR sessions are much more likely to finish the that 48 percent of those with schizophrenia, group sessions were all led by trained thera- 6-month program than patients who do not 56 percent with bipolar disorder, and as pists and lasted from 60 to 90 minutes. make it through the third session. Because a many as 65 percent with severe and persistent Group meetings were videotaped weekly third of individuals initially recruited for the mental illness have abused substances. and then reviewed and assessed by inde- study left before the third treatment session, Dr. Bellack’s research team recruited 175 pendent reviewers to verify that the thera- the researchers are currently developing patients from community clinics and a Vet- pists were following the programs’ parame- new intervention strategies to keep people erans Affairs medical center in Baltimore. All ters correctly. in the program until they have truly given it a had a dual diagnosis of severe and persistent The BTSAS group fared better than chance. The innovation has two key compo- mental illness and an addiction to cocaine, the STAR group on a wide range of nents: a structured intervention to help heroin, or marijuana. Among the partici- treatment-related criteria. For example, patients overcome obstacles to treatment pants, 38.3 percent met the diagnostic crite- more people in the BTSAS group stayed in and an intervention to enlist family and ria for schizophrenia or schizoaffective dis- treatment throughout the 6-month trial friends as partners to connect patients orders, 54.9 percent for major affective period (57.4 percent versus 34.7 percent). with treatment. disorders, and the remainder for other men- The BTSAS group produced more “The BTSAS program will help clinicians tal disorders. Cocaine was the predominant drug-free urine samples and had longer peri- make a difference in the lives of a very drug abused by 68.6 percent of participants, ods of abstinence (see table, p. 1). They also difficult-to-treat population,” says Dr. opiates by 24.6 percent, and marijuana by had better clinical and general living Dorynne Czechowicz of NIDA’s Division of 6.8 percent. outcomes than people in the STAR group Clinical Neuroscience and Behavioral The researchers assigned half the trial (see table, below) and reported larger Research. “One of its key strengths is that it participants to BTSAS group therapy and improvements in their ability to perform the positively affects many aspects of patients’ half to a program called Supportive Treat- activities of daily living. lives. Moreover, as an outpatient treatment, ment for Addiction Recovery (STAR), which “It was apparent from watching video- it is well-suited to the situation. Most men- is the typical treatment at the University of tapes of treatment sessions that subjects in tally ill people who abuse drugs live in the Maryland clinics. Unlike participants in BTSAS valued the intervention and were community, not in a sheltered facility, and this is where the majority of clinicians must QUALITY-OF-LIFE OUTCOMES treat them.” ■ BTSAS STAR

Pretreatment* Posttreatment** Pretreatment Posttreatment SOURCES Frequency of Arrests 31.0% 12.8% 22.9% 27.3% Bellack, A.S., et al. A randomized clinical trial of a new behavioral treatment for drug abuse in people with Inpatient Admissions*** 29.5% 6.5% 20.4% 16.2% severe and persistent mental illness. Archives of General Living Standards**** 46.6% 69.2% 43.8% 51.5% Psychiatry 63(4):426-432, 2006. *Pretreatment: 90-day period before study **Posttreatment: 90-day period following study Kinnaman, J.E., et al. Assessment of motivation to ***Rates of inpatient admissions for either psychiatric problems or substance abuse change substance use in dually-diagnosed schizophre- ****Percentage of participants reporting having enough money for food, clothing, housing, and transportation nia patients. Addictive Behaviors 32(9):1798-1813, 2007.

6 NIDA Notes | Volume 21, Number 6 ■ RESEARCH FINDINGS Behavioral Problems Related to Maternal Smoking During Pregnancy Manifest Early in Childhood

Researchers find probable precursors of adolescent conduct disorders in the behavior of toddlers and schoolchildren.

BY NIDA NOTES STAFF study began. One hundred and sixty-six boys in this group had PATHWAY TO TROUBLE Children of mothers who smoked during pregnancy had higher rates of disruptive any studies have estab- mothers who smoked during behavior throughout development. Toddlers were evaluated lished that a pregnant pregnancy. These boys devel- for disruptive behavior; first grade boys for oppositional woman’s smoking raises oped the antisocial behavior pat- defiant disorder; and young teenage boys for serious delinquency. Mher child’s risk of disrup- tern known as oppositional defi- tive behavior disorders and of delinquency ant disorder (ODD) at more in the teen and young adult years, but its than double the rate of the rest Exposed Group behavioral effects in early life have been (see graph). Children with ODD Nonexposed Group Serious Delinquency been difficult to trace. Now, however, demonstrate defiant, disobedi- 50 NIDA-funded researchers have revealed ent, and hostile behavior associations between a child’s in utero towards authority figures that 40 Disruptive exposure to smoking and specific patterns persists for at least 6 months, Behavior in Clinical of aberrant behavior as a toddler, at school and they are touchy, easily Range age, and as a teen. The researchers propose angered, and resentful. ODD is 30 that these patterns form a continuum, unit- often considered a developmen- ed by an underlying theme of disrupted tal precursor of conduct disor- 20 social information processing. der (CD), a condition in older Oppositional Defiant children and adolescents char- Disorder AN EARLY START TO DISRUPTIVE acterized by persistent antisocial 10 BEHAVIOR behaviors such as lying, truancy, Percentage of Children with Problem Behaviors In an initial study, Dr. Lauren Wakschlag vandalism, and aggression. 0 of the Institute for Juvenile Research at the Boys whose mothers smoked Toddlers* First Grade Young Male Boys** Teens**

University of Illinois at Chicago and her col- while pregnant did not have a *Data from Family Health and Development Project leagues, Dr. Rolf Loeber of the University of higher incidence of attention **Data from Pittsburg Youth Study Pittsburgh and Dr. Kate Pickett of The Uni- deficit hyperactivity disorder versity of York in England, analyzed disrup- (ADHD) without ODD than the nonexposed meaning the disorder developed in the tive behavior patterns in first graders and boys. However, the incidence of co-occurring first 5 or 6 years of life. This provides evi- subsequent problems that have been associ- ODD and ADHD—a combination that often dence of a coherent developmental pathway ated with later delinquency. Data were results in chronic disruptive behavior prob- from prenatal exposure to cigarettes to a derived from the first-grade cohort of the lems—was nearly twice as high in the subsequent sequence of conduct problems,” Pittsburgh Youth Study (PYS), a community exposed group as in the nonexposed group. Dr. Wakschlag says. “While previous sample of boys at risk for delinquency who As the boys entered and traversed their teens, research established a link between prenatal were followed over several decades under the delinquent behavior began earlier and was exposure to cigarettes and CD in older direction of Dr. Loeber. more severe in the exposed group. children, this study is the first to establish The researchers concentrated on 448 “All the children with ODD in the connections to ODD and to do so as early as boys, who were roughly age 7 when the PYS PYS study were diagnosed in first grade, first grade.”

NIDA Notes | Volume 21, Number 6 7 TODDLERS WITH TROUBLES patterns of disruptive behavior, shown on unresponsive patterns of behavior demon- To look for exposure-related behavioral the ITSEA. strated in FHDP, PYS, and similar studies abnormalities at even younger ages, Dr. To more precisely determine the nature may reflect disruptions in social-information Wakschlag’s team conducted the Family of the boys’ behavior problems, the processing that resulted from prenatal expo- Health and Development Project (FHDP), in researchers examined four components of sure to cigarette smoke. To test this hypothe- collaboration with colleagues from the Uni- disruptive behavior, each of which is consid- sis, the team is conducting the NIDA-funded versity of Illinois, The University of York, the ered a precursor to disruptive behavior pat- East Boston Family Study (EBFS), which National Institute of Mental Health, and the terns seen at later ages: includes 272 adolescents and is a followup to

University of Massachusetts-Boston. The ■ Aggressive/destructive behavior, includ- the Maternal-Infant Smoking Study of East researchers recruited 96 expectant mothers, ing threatening, hitting, and throwing or Boston (MISSEB). Dr. Wakschlag and her col- age 18 and older, at several clinics. The smashing toys; leagues are also examining the influence of women were predominantly white and work- ■ Dysregulated negative affect, character- genetic makeup on exposure-related disrup- ing class. Along with the women’s self- ized by persistent, uncontrolled outbursts tive behavior among these young people. The reports, the researchers collected biological of anger with loud yelling, intense crying, researchers are using maternal exposure data data, such as measurements of the and temper tantrums; originally collected by MISSEB but applying metabolite cotinine in urine samples, to ■ Stubborn defiance, marked by obstructive more sophisticated methods to measure pre- assess fetal exposure to maternal smoking. behavior that persists after the mother has natal exposure to cigarette smoke. These These measurements, taken three times dur- increased expressions of support for her new techniques, which combine maternal ing pregnancy, indicated that 47 percent of child and has tried several strategies to self-report and biological data, were devel- the women smoked throughout their preg- change her child’s behavior; and oped from FHDP-derived data by Dr. Vanja nancies. Ninety-three infants and their moth- ■ Low social competence, where the child Dukic at the University of Chicago in collabo- ers completed the study's developmental misses social cues and exhibits low social ration with Dr. Neal Benowitz of the Univer- phase, which lasted until the babies were interest or concern. sity of California, San Francisco and 24 months old. These four behaviors, while viewed as Dr. Wakschlag. The babies were evaluated every 6 normal in toddlers, are considered precur- “Maternal self-reports are affected by months. At the 12-, 18-, and 24-month evalua- sors to clinical problems if they are severe memory lapses and social pressure not to tions, each mother filled out the Infant-Tod- or pervasive. smoke, and biological methods can be inac- dler Social Emotional Assessment (ITSEA). The children whose mothers had smoked curate because the smoke-derived chemicals During 20-minute laboratory observations of during pregnancy displayed lower social have a short half-life and rates of metabolism the toddlers and their mothers interacting at competence than other children and signifi- differ among individuals,” says Dr. 24 months, the researchers rated specific cantly higher levels of aggressive/destructive Wakschlag. “In addition, we know that smok- components of the toddlers’ behavior using behavior and stubborn defiance. They were ing levels fluctuate throughout a pregnancy. codes from the Disruptive Behavior Diagnos- not more likely to exhibit dysregulated The new technique incorporates the unique tic Observation Schedule. negative affect. information from both of these methods to The results indicated that toddlers whose “Dr. Wakschlag has teased out some provide a more precise estimate of prenatal mothers had smoked during pregnancy components of disruptive behavior exposure to cigarettes.” ■ demonstrated a high and escalating pattern problems when they first emerge between of disruptive behavior from 12 to 24 months, 18 and 24 months of age,” says Dr. Nicolette SOURCES whereas nonexposed toddlers exhibited a rel- Borek of NIDA’s Division of Clinical Wakschlag, L.S., et al. A developmental framework for atively stable pattern. A mother’s smoking Neuroscience and Behavioral Research. distinguishing disruptive behavior from normative mis- during pregnancy increased the likelihood of “This gives us a way to identify at- behavior in preschool children. Journal of Child Psychology, Psychiatry & Allied Disciplines 48(Special Issue the observed atypical trajectory of behavior risk children early and raises interesting on Preschool Psychopathology):976-987, 2007. independent of several associated risk fac- questions about the role of brain Wakschlag, L.S., et al. Is prenatal smoking associated tors, including parental antisocial behavior, development in later-stage behavioral with a developmental pattern of conduct problems in quality of parenting, and postnatal exposure issues.” young boys? Journal of the American Academy of Child and to tobacco smoke. At 24 months, toddlers Adolescent Psychiatry 45(4):461-467, 2006. whose mothers had smoked while pregnant ON TO ADOLESCENCE Wakschlag, L.S., et al. Elucidating early mechanisms of developmental psychopathology: The case of prenatal were more than 11 times as likely as nonex- Dr. Wakschlag and colleagues have smoking and disruptive behavior. Child Development posed peers to exhibit clinically significant hypothesized that the resistant, hostile, and 77(4):893-906, 2006.

8 NIDA Notes | Volume 21, Number 6 ■ RESEARCH FINDINGS Morphine-Induced Immunosuppression, From Brain to Spleen

Morphine sets off a chain of biological events that stifles the immune response.

BY LORI WHITTEN, ■ a train of biochemical events links stim- Dopamine’s main action in the NAc is to NIDA Notes Staff Writer ulation of these D1 receptors with interact with proteins called dopamine reduced NK cell activity in the spleen. receptors, which come in several subsets—

orphine and other In previous studies, the UNC team had D1, D2, for example. Accordingly, Dr. Lysle suppress the immune sys- established that blocking one of mor- and colleagues conducted experiments to tem, the body’s innate phine’s pharmacological effects in the determine whether any of these receptors Mdefense against infections. brain—a surge of dopamine into the NAc— were involved in morphine inhibition of Because of this effect, doctors weigh the averts suppression of NK cells in the NK cells. They began by giving rats mor- pain-relief benefits of opioids against the spleen. This being the case, the researchers phine (15 mg/kg) or saline. One hour later, added risk of infection they pose to reasoned that morphine-induced NK sup- they measured NK cell activity in the ani- patients, particularly those being treated pression must start with something that mals’ spleens and found it to be lower by for severe burns or certain cancers. dopamine does in the NAc. about 40 to 50 percent, on average, among abusers, many of whom are already infection-prone due to unclean needles, repeated injections, and poor nutrition and living conditions, are rendered even more Natural Killer Cells Eliminate vulnerable by these drugs. Compromised Cells Morphine affects the body’s immune cells in many ways, both direct and indirect. Natural killer (NK) cells constitute a rapid-response force against cancer and viral infec- Recently, NIDA-funded scientists pinpointed tions. These specialized white blood cells originate in the bone marrow, circulate in the the biochemical trigger that sets off a chain blood, and concentrate in the spleen and other lymphoid tissues. NK cells key their activ- reaction that ultimately inhibits an immune ities on a subset of the histocompatibility proteins that occur on the surfaces of healthy cell that is key in fighting viruses and cancer. cells but that virus- and cancer-weakened cells shed. When NK cells encounter cells that If validated in future studies, the work could lack histocompatibility proteins, they attack and destroy them—thus preventing the cells lead to interventions to bolster the immunity from further spreading the virus or cancer. NK cells are distinguished from other immune of those who regularly take opioids. system cells by the promptness RAPID-RESPONSE FORCE Two natural killer cells attack a cancer cell. MORPHINE, DOPAMINE, AND and breadth of NATURAL KILLERS their protective Morphine suppresses the activity of response. Other three different types of white blood cells: T white blood cells lymphocytes, B lymphocytes, and natural come into play killer (NK) cells (see box). NIDA-funded more slowly and investigators Dr. Donald Lysle, Dr. Timothy target specific Saurer, and their colleagues at the Universi- pathogens—can- ty of North Carolina (UNC), Chapel Hill, cers, viruses, or concentrated on NK cells, and found that bacteria—rather

■ morphine-induced immunosuppres- than damaged sion follows activation of dopamine-1 cells in general. © Eye of Science/Photo Researchers, Inc. (D1) receptors in the shell of the nucleus accumbens (NAc); and

NIDA Notes | Volume 21, Number 6 9 ■ RESEARCH FINDINGS

the morphine-exposed animals, compared sympathetic nerves are activated, is found The researchers next wondered whether with those given saline. They then conducted at the nerves of the spleen, and interacts Y1 receptor activation might underlie sup- a series of trials that showed: with receptors (Y1) in the membranes of pression of other white blood cells as well ■ Morphine-induced NK cell suppression white blood cells. “Most important in ele- as suppression of NK cells. To find out, they depends on the activation of D1 receptors. vating NPY as a candidate, however, was stimulated rats’ Y1 receptors with injections Rats injected with a compound (SCH- other researchers’ finding that it sup- of NPY (20 or 200 ␮g). 23390) that prevents dopamine from pressed the ability of natural killer cells The infusion inhibited NK cell activity

accessing D1 receptors did not develop to attack cultured tumor cells,” says by 55 percent, on average, but had no effect immunosuppression when subsequently Dr. Saurer. “This suggested that it might on T and B white blood cells in the spleen. injected with morphine. In contrast, modulate natural killer activity and perhaps Similarly, rats infused with morphine while

rats pretreated with a compound (raclo- the suppressive effects of morphine in rats.” their Y1 receptors were blocked did not pride) that blocks D2 receptors did lose The investigators confirmed their hypoth- develop NK cell inhibition, but their T and NK cell activity. esis with an experimental strategy parallel to B white blood cells became inhibited.

■ Specifically, D1 receptors that reside in the one they had used to link the brain’s D1 The specificity of NPY’s actions—affect- the part of the NAc called its shell must receptors to morphine-induced NK cell ing NK cells but not other white blood be activated for morphine NK cell sup- immunosuppression: They showed that cells—is not surprising, says Dr. Lysle, pression to occur. Morphine inhibition neither NK cell inhibition induced by mor- because the brain generally seems to com-

of NK cell activity was abolished when phine nor D1-related NK inhibition occurs municate with different immune system researchers infused SCH-23390 into when NPY is prevented from interacting components in the body in very selective

rats’ NAc shell (see graph, left panel), with its main receptor (Y1) (see graph, right ways. “Our team has identified the language but not the NAc core. panel). for the suppression of natural killer cells, but

■ D1 receptor activation in the shell of the NAc lowers NK cell activity even in the absence of morphine. Rats given no mor- HOW TO PREVENT MORPHINE-INDUCED SUPPRESSION OF NATURAL KILLER phine but a test compound (SKF 38393) CELLS Blocking the D1 receptor in a particular area of rats’ brains (the nucleus accumbens shell) prevented morphine-induced inhibition of natural killer cells—key immune system cells that fight that activates D receptors demonstrat- 1 viral infections and cancers. Preventing neuropeptide Y from interacting with its Y1 receptors in the ed 35 to 39 percent less NK cell activity body also counters morphine-induced inhibition of natural killer cells. than a comparison group of rats injected with saline.

Morphine (15 mg/kg) PATHWAY THROUGH THE BODY Saline 80 Dr. Lysle and colleagues next turned 70 their attention to the signaling chain that 60 links D1 activity in the NAc to NK cell inhi- bition in other organs. Prior studies had 50 indicated that morphine activates the sym- 40 pathetic nervous system, and sympathetic 30 (lytic units*) nerves communicate signals from the brain 20 to NK and other white blood cells in the 10 spleen. The specific chemical involved in

Killer Cell Activity in Spleen Killer Cell Natural 0 conveying the message of NK inhibition 0 0.015 0.15 0 1.0 from brain along the sympathetic system to Dose of D Receptor Blocker 1 Dose of Y1 Receptor Blocker the spleen, however, was unknown. (µg/0.5µl) (mg/kg) Dr. Lysle and colleagues focused on neu- *One lytic unit is the number of natural killer cells required to destroy 20 percent of tumor cells. A higher number of lytic units indicates a more effective immune response. ropeptide Y (NPY) as a likely candidate because it is released in the brain when

10 NIDA Notes | Volume 21, Number 6 Conditioned Responses Can Also Impair Natural Killer Cells

An environment linked with an immune system trigger such as an allergen will, after repeated pairings, incite an immune response in the absence of the trigger. Similarly, an environment associated with an immunosuppressant such as morphine weakens immune responses.

In these conditioned responses, the brain generates the initiating signal for immunosuppression. But where in the brain does the message start? And how does it travel to the distant organs where immune cells reside?

Dr. Donald Lysle, Dr. Timothy Saurer, and their colleagues at the University of North Carolina, Chapel Hill, proposed that the biochemical chain of events in conditioned immunosuppression recapitulates the one set off by the original immune-system-weakening stimulus. To put this idea to the test, they conducted experiments on rats that were similar to those they had performed to establish the mechanisms of morphine-induced natural killer (NK) cell suppression.

The researchers gave rats a dose of morphine (15 mg/kg) to suppress NK cell activity. They immediately placed the rats for 1 hour in spe- cial conditioning chambers that were distinct from the home cages—with different walls and floors and featuring a unique sound and smell. They returned the animals to the home cages and repeated the process 2 days later.

After two conditioning sessions and a 12-day break, the researchers left some rats in the home cages and returned others to the morphine-paired conditioning chambers. None of the rats was given morphine at this stage. After 1 hour, NK cell activity in the spleen was lower by about 50 percent, on average, among the animals in the morphine-linked chambers, compared with those in the home cages. The researchers then conducted a series of trials that showed:

■ For conditioned NK cell suppression to occur,D1 receptors must be activated.

■ In conditioned NK cell suppression, D1 receptors that reside in the part of the nucleus accumbens called its shell are critical.

■ In conditioned NK cell suppression, Y1 receptors in the spleen must be activated.

The findings confirm the researchers’ hypothesis that the same biological train of events that underlies morphine immunosuppression also drives conditioned immunosuppression, which occurred, in this case, in response to an environment previously paired with morphine expo- sure. “The findings expand on the team’s prior descriptions of the neurobiological mechanisms underlying the ability of opiates and envi- ronments associated with them to suppress various immune responses in animals,” says Dr. Paul Schnur of NIDA’s Division of Basic Neu- roscience and Behavioral Research. “They suggest that opiate abusers are vulnerable to a weakened immune system in places previously associated with taking the drug.”

Source: Saurer, T.B. et al. Neuroimmune mechanisms of opioid-mediated conditioned immunomodulation. Brain, Behavior, and Immunity 22(1):89-97, 2008.

other drugs of abuse and different immune NIDA’s Division of Basic Neuroscience and SOURCES Saurer, T.B., et al. Suppression of natural killer cell system responses may speak distinct Behavioral Research. “In future studies, activity by morphine is mediated by the nucleus languages—ones that may be discovered in researchers might examine immune accumbens shell. Journal of Neuroimmunology 173(1- future research,” he says. responses after chronic self-administration 2):3-11, 2006. “The team’s findings suggest a brain-to- of morphine to model more closely the Saurer, T.B.; Ijames, S.G.; and Lysle, D.T. Neuropeptide body pathway whereby morphine weakens possible immunosuppressant effects of drug Y Y(1) receptors mediate morphine-induced reduc- tions of natural killer cell activity. Journal of the body’s defenses,” says Dr. Paul Schnur of abuse.” ■ Neuroimmunology 177(1-2):18-26, 2006.

NIDA Notes | Volume 21, Number 6 11 ■ RESEARCH FINDINGS Mice With Genetic Alteration Eschew Cocaine

A South American caterpillar inspired a successful 10-year quest to desensitize the dopamine transporter to the drug.

nucleus accumbens (NAc). If BY LORI WHITTEN, NIDA Notes Staff Writer an animal reliant on coca for FOOD NOT DRUG A coca leaf—the source of cocaine—is just food to the South American caterpillar Eloria noyesi. Like nutrition were to be subject to some other insects, its dopamine transporters are much less IDA researchers have desensi- this effect, however, surges of sensitive to cocaine than those of mice. tized mice to cocaine by genet- euphoria would occur when- ically altering their dopamine ever it ate and presumably be Ntransporters—proteins that very disruptive of its function- are a key target of cocaine—to resemble ing. “Because the caterpillar is ones found in the brains of some insects. interested in coca leaves as a If investigators can identify a compound that food source, we hypothesized alters these transporters in the same that its DATs might not inter- manner, they might be one step closer to act with cocaine,” Dr. Gu says. developing to treat cocaine addiction. A SURPRISING TWIST A South American caterpillar started the Dr. Gu undertook a 10-year researchers on their path to the discovery. project that ultimately estab- Larvae of the Eloria noyesi moth have a par- lished a mutated form of DAT ticular appetite for leaves of the coca plant. that is cocaine-insensitive. But he encoun- how to alter the mouse DAT to be cocaine- This preference has captured the interest of tered several surprising twists—and frus- insensitive like the insects’,” he says. drug-control authorities, who view the cater- trating letdowns—along the way. As a first step, Dr. Gu switched fragments pillar as a potential tool for eradication of Chief among these, Dr. Gu was disap- of insect DAT sequences with mouse DAT coca crops. To Dr. Howard Gu at Ohio State pointed to find that the DAT from Eloria is sequences and identified key regions that University (OSU), however, the caterpillar’s not substantially less sensitive to cocaine affect how tightly cocaine binds to the DAT apparent immunity to the psychoactive than the DAT from other insects they protein. He then randomly generated a large properties of the coca leaf suggested some- tested, such as a silkworm that does not eat number of alterations in these regions of the thing else: Perhaps cocaine’s target protein coca leaves. He quickly recognized that there mouse DAT sequence. Working with cul- in the caterpillar’s brain—the dopamine was nothing unique about the Eloria cater- tured cells, he tested them one by one to see transporter (DAT)—does not respond to the pillar in this regard and was forced by that if the changes they introduced would desen- leaf. If so, he reasoned, an understanding of evidence to relinquish the elegant evolution- sitize mouse DAT to cocaine. Through this how the insect’s DAT functions might ary theory he had held about how its insensi- laborious process, he eventually identified provide a template for pharmacological tivity to the stimulating effects of the the sequence changes that make the trans- agents to block the effects of the coca leaf’s coca leaf might have developed. porter cocaine-resistant. potent derivative, cocaine. But what he learned in the process was Dr. Gu created mutant mice with the Scientists generally believe that cocaine more important than a busted theory: Dr. Gu same DAT sequence changes. The mutant produces its high by preventing DATs from reg- discovered that the DATs from a number of mice produced cocaine-resistant DAT. But ulating dopamine levels in the brain’s reward insect species are just 5 percent as sensitive were the animals truly immune to the system, resulting in a euphoria-producing to cocaine as is mouse DAT. “I seized rewarding sensations of the drug? Dr. Gu buildup of the neurotransmitter in the on the difference to generate clues about joined with colleagues at OSU and the

12 NIDA Notes | Volume 21, Number 6 University of Tennessee College of Medicine MICE WITH MUTATED DOPAMINE TRANSPORTERS GET NO KICK FROM COCAINE to answer this question. Normal mice spent more time in a chamber where they had received cocaine injections than in one where they had received saline. But mice with a cocaine-insensitive dopamine transporter (DAT) SELECTIVE INDIFFERENCE showed no preference (left panel). In contrast, both normal mice and those with an insensitive DAT lingered in the -paired chamber longer than saline-treated animals (right panel). When normal mice are exposed to cocaine in one compartment of a split cage, they demonstrate liking for the drug by later spending the bulk of their time in that com- Normal Mice Cocaine-insensitive DAT Mice partment. The proportion of time the ani- 500 mals spend in the drug-associated compart- 400 ment provides a quantitative behavioral 300 measure of the intensity of the drug’s 200 rewarding effects. In Dr. Gu’s trials, the mutant mice spent no more time in a cage 100 0 area where they received the injections of Time* (in seconds) cocaine (5 mg/kg or 20 mg/kg) than they did -100 Saline Cocaine Cocaine Saline Amphetamine in a compartment where they were given (5 mg/kg) (20 mg/kg) (2.5 mg/kg) saline injections—a clear demonstration that they were not experiencing cocaine’s *Time indicates preference for the chamber where mice received the injections. rewarding effects (see graph, left panel). To ensure that the mutant mice retained normal responses to stimuli other than vital for life-promoting activities, such as eat- In light of their work with the mutants, cocaine, the researchers gave them amphet- ing. NIDA is supporting research to screen the researchers now attribute the persist- amine. This triggers dopamine for such compounds with a protocol and cell ence of cocaine response in DAT-less mice surges by mechanisms different from those lines provided by Dr. Gu. to adaptation. “The brains of DAT knock-out that cocaine triggers. The researchers found mice seem to undergo significant adaptive that both mutant and normal mice devel- A THEORY BOLSTERED neurobiological changes that alter how oped elevated extracellular dopamine in the Beyond yielding leads for medication cocaine produces its effects,” says Dr. Gu. NAc after amphetamine exposure. In development, Dr. Gu’s findings alleviate “Dr. Gu and colleagues have verified deci- addition, the mutants exhibited as much doubts that have arisen about the strategy sively that cocaine’s inhibition of DAT is nec- behavioral evidence of amphetamine reward of selective DAT desensitization to reduce essary for its behavioral effects, answering as did a comparison group of normal mice cocaine reward. In some studies, animals an important question in addiction (see graph, right panel). continued to exhibit dopamine surges research,” says Dr. Nancy Pilotte of NIDA’s “The mutants’ response to amphetamine and behavioral responses to cocaine Division of Basic Neuroscience and Behav- demonstrated that the neural machinery despite having been genetically altered to ioral Research. She notes, however, that the works properly in these animals, and they lack DAT. strong confirmation of DAT’s role in cocaine are not generally deficient in drug-induced “The results from mice without DAT reward does not rule out the idea of redun- reward,” says Dr. Gu. represented a milestone in cocaine dant systems. “If the dopamine system is Dr. Gu’s team is now seeking to identify a research—it was remarkable that these mice damaged, as it is in the DAT-less mice, the chemical compound that will prevent still experienced a high from cocaine,” brain may ‘train’ norepinephrine and sero- human DATs—like the mouse’s altered explains Dr. Gu. “In view of that observation, tonin neurons to take over reward and other DAT—from responding to cocaine. Such a it is reasonable to question the approach of functions,” she says. ■ compound would eliminate the drug high finding compounds that prevent cocaine and limit the frequency and length of from binding to the DAT as a therapeutic SOURCE relapses. Yet it would not interfere with the strategy for cocaine abuse. The results from Chen, R., et al. Abolished cocaine reward in mice with a DAT’s ability to regulate dopamine, which our mutant mice, however, indicate that cocaine-insensitive dopamine transporter. Proceedings produces feelings of reward and motivation DAT altering can block cocaine reward. ” of the National Academy of Sciences 103(24):9333-9338, 2006.

NIDA Notes | Volume 21, Number 6 13 ■ RESEARCH FINDINGS Animal Studies Elaborate Toluene’s Effects

Toluene abuse can harm the nervous system and body, yet scientists know relatively little about its specific actions.

BY LORI WHITTEN, REPEATED TOLUENE EXPOSURE DEPRESSES BRAIN ACTIVITY Researchers used NIDA Notes Staff Writer microPET imaging to compare brain activity of a rat before and after chronic toluene exposure. Yellow indicates high activity. Three weeks after the last exposure, the brain showed recovery, but activity in oluene, a solvent found in paint the auditory cortex and some other areas remained depressed throughout the 2-month study. removers, glues, and other com- mon household products, is often Before Toluene 2 Hours After Last 3 Weeks After Last Exposure Toluene Exposure Toluene Exposure Tthe first substance abused by young people, who inhale its dangerous fumes. A recent NIDA-funded study has shown that toluene’s behavioral and neurobiological effects bear similarities to those of both and depres- sants, while another study mapped the drug’s impact on brain metabolism. The findings lay groundwork for new prevention strategies. Various animal studies have indicated that abused have subjective effects like those of central nervous system depressants. Now, Dr. Scott E. Bowen at Enhancement Underlies a Toluene Behav- the response to another stimulant experi- Wayne State University in Detroit has ioral Effect,” NIDA Notes, Vol. 19, No. 5). enced subsequently. “Young people who demonstrated that, in adult mice, the subjec- After exposure to the highest concentra- abuse inhalants may increase their risk tive experience of toluene also, in some tion of toluene—6,000 parts per million for later drug abuse,” says Dr. Lynch. “An ways, resembles that produced by ampheta- (ppm)—the animals’ lever-pressing important next step is to determine whether mine. Dr. Bowen injected mice alternately responses indicated that they were still animals exposed to inhalants, particularly with amphetamine and saline and trained experiencing stimulant-like effects 15 to 20 during adolescence, are then more prone to them to seek rewards by pressing the correct minutes later, says Dr. Bowen. When tested use stimulants upon exposure.” lever—one after amphetamine and the other again 30 minutes after exposure, the lever- after saline. He showed that under the influ- pressing responses of the mice were similar TOLUENE DEPRESSES BRAIN ence of toluene, the animals pressed the to those after saline, suggesting that METABOLISM drug-associated lever, indicating that the toluene’s effects had worn off. In a separate NIDA-funded study, Dr. inhalant felt something like amphetamine to “Dr. Bowen’s results indicate that toluene Wynne K. Schiffer and colleagues at them (see chart, p. 15). and amphetamine share, to some extent, Brookhaven National Laboratory and New Dr. Bowen’s findings add to emerging evi- similar subjective effects, which may reflect a York University School of Medicine used dence that, in addition to its depressant common neurochemical action,” says Dr. positron emission tomography (PET) to effects, toluene induces stimulant-like Minda Lynch of NIDA’s Division of Basic measure brain metabolism in adolescent rats behavioral effects (e.g., increased locomotor Neuroscience and Behavioral Research. The exposed to toluene. activity) by augmenting dopamine activity finding is worrisome because, in animals, During the 2-month study, the in the brain’s reward pathway (“Dopamine exposure to one stimulant often enhances researchers tested the effects of repeated

14 NIDA Notes | Volume 21, Number 6 exposure to toluene at a TOLUENE HAS AMPHETAMINE-LIKE EFFECTS Mouse responses in the drug-discrimination protocol indicated dose they previously that the animals experienced the commonly abused solvent toluene as if it were a stimulant. established to be reward- ing to adolescent animals. Drug discrimination training Toluene exposure and testing Results Two hours after the last Adult mice in a training chamber learn To test a substance like toluene, which 100 to press levers for a milk reward. To is not injectable, scientists let the mice Air Only toluene exposure, the ani- 500 ppm Toluene receive the reward after a saline injec- inhale it and then return them to the 2000 ppm Toluene mals’ whole-brain meta- 75 4000 ppm Toluene tion, they must press a certain lever; to lever-equipped chamber. A high level 6000 ppm Toluene bolic activity had declined receive the reward after an ampheta- of responding on the drug-associated 50 20 percent compared mine injection, they must press a dif- lever indicates that toluene exposure ferent lever. The trained mice thus sig- and amphetamine exposure feels 25 with levels seen prior to nal, by their choice of levers, which similar to the mice. exposure and with those substance they have just experienced. Presses) (Percentage of Total 0

In the first experiment, mice received Amphetamine-Lever Responses 0-5 15-20 30-35 45-50 60-65 75-80 of control animals. Meta- Scientists can find out if a test sub- either air only or toluene vapors during Minutes Since Toluene Exposure bolic activity in the brain stance feels like amphetamine to the a 10-minute exposure. Immediately mice by injecting the test substance after the exposure, mice were placed All concentrations of toluene elicited continued to drop, reach- and determining whether mice respond in the test cage for 5 minutes to meas- amphetamine-linked lever-pressing to the amphetamine-linked lever or the ure their lever-press choices. They were ing 40 percent below behavior, and similarity to ampheta- saline-linked lever. If response to the then removed for a 10-minute break baseline after 24 hours; at mine increased with toluene concen- drug-associated lever is high (around in a cage with no toluene and no tration. At the highest concentration of this time, brain regions 80 percent of total lever presses), levers. The animals experienced alter- toluene, mice continued to feel its the scientists conclude that the test nating assessments and breaks for involved in movement stimulant-like effects for at least 20 agent feels like the drug to the mice. 80 minutes. minutes. coordination, memory, An intermediate response (60 to 79 and learning showed the percent) indicates that the test agent feels somewhat like the drug. In a second experiment, mice received greatest effect. 100 Air Only The depression in six 10-minute exposures to either 6000 ppm Toluene toluene or air. After each exposure, the 75 overall brain activity per- mice were placed into the test cage for 5 minutes. sisted for a week. Two 50 months after the last 25 exposure, the now- (Percentage of Total Presses) (Percentage of Total

0 mature rats showed Amphetamine-Lever Responses 1st 2nd 3rd 4th 5th 6th recovery of overall brain Exposure metabolism. However, In repeated exposures, toluene contin- activity in the temporal ued to produce similar amphetamine- cortex—an area involved like responses. in the processing of sounds and memories—remained about 10 brain and the changes that underlie its Schiffer. Because of their usefulness as sol- percent below the baseline level. behavioral effects,” says Dr. Rao Rapaka of vents and for other practical purposes, “In humans, PET imaging has revealed a NIDA’s Division of Basic Neuroscience and toluene and other abused inhalants are not great deal about the characteristic metabolic Behavioral Research. likely to become less available, says Dr. signature of the addicted brain—that is, one Toluene’s with chronic exposure Bowen. “Prevention efforts with youth and can immediately see by the pattern of and its availability in household and indus- further research on the neurobiological and depressed activity in particular brain regions trial products drive scientists’ efforts to iden- behavioral effects in animals, particularly that a person has abused cocaine or . tify the mechanisms that underlie its abuse. during gestation and adolescence, are keys

Our findings indicate that repeated toluene Clinical reports have linked chronic toluene to countering the problem.” ■ exposure has a similar signature, further abuse with a profound reduction in brain linking its neurobiological effects to those of white matter, together with associated neu- SOURCES traditional drugs of abuse,” says Dr. Schiffer. rological problems such as impaired move- Bowen, S.E. Increases in amphetamine-like discrimi- “Dr. Schiffer’s findings help shorten the ment, cognition, hearing, and vision. native stimulus effects of the abused inhalant toluene list of brain areas we need to examine dur- “Toluene appears typical of abused in mice. Psychopharmacology 186( 4):517-524, 2006. ing future studies of toluene and may guide inhalants and may have the greatest poten- Schiffer, W.K., et al. Metabolic correlates of toluene abuse: Decline and recovery of function in adolescent research on the drug’s distribution in the tial for abuse and damaging effects,” says Dr. animals. Psychopharmacology 186(2):159-167, 2006.

NIDA Notes | Volume 21, Number 6 15 ■ BULLETIN BOARD

Social Neuroscience Meeting NIDA Renames Addiction Journal Aims to Improve Prevention, Treatment NIDA’s journal on addiction, formerly Scientists and clinicians gathered in Rockville, Maryland, on called Science & Practice October 1–2, 2007, to review initial research results from the bur- Perspectives, is now being geoning field of social neuroscience—the study of how published as Addiction neurobiology and the social environment interact. Science & Clinical Practice. The NIDA-sponsored meeting, “Social Neuroscience: The new name highlights Developing More Powerful Behavioral Interventions,” was part of the publication’s goal the institute’s ongoing efforts to advance knowledge about the of encouraging the neural underpinnings of interpersonal interactions, emotional exchange of ideas responses, and social behaviors that relate to addiction between researchers, prevention and treatment. The payoff could be great. For clinicians, and others example, an understanding of how effective patient-counselor in the field of addiction interactions modulate patients’ brain function could be used to science. assess and improve therapeutic relationships. Charting the brain The first issue of the dynamics that occur in healthy, positive social relationships, renamed journal—December 2007—introduced two other which protect against drug abuse, could open the door to more major changes: an increase in the number of issues from one to effective prevention interventions. two per year and the journal’s inclusion in the National Library of The October meeting explored seven topics: empathy, disrup- Medicine’s MEDLINE (Medical Literature Analysis and Retrieval tion of social reward in drug abuse, self-monitoring and respond- System Online) database. MEDLINE is the largest component ing to cues from others, prejudice and self-stigmatization, of PubMed, an online database of biomedical journal citations parent-child interactions among substance abusers, social and abstracts. networks and decisionmaking in adolescents, and mirroring the “Changing the name to Addiction Science & Clinical Practice behavior of others. reflects our ongoing commitment to bringing the latest in addic- What are the interactions between drug abuse and tion science from the laboratory to the clinical field as quickly as companionship and other social rewards? The answer may rely possible,” says NIDA Director Dr. Nora D. Volkow. “In addition, on combining what is already known about how addiction usurps publishing the journal more frequently and broadening its access the reward system with research on less-studied brain circuits— through MEDLINE will increase visibility and impact.” including the interoceptive system, which is made up of neural The journal promotes dialog between scientists and addiction circuits that monitor and process sensations including pain, treatment professionals with the aim of improving drug abuse temperature, hunger, thirst, and touch, and has been linked with treatment and research. It helps their programs keep pace with emotion and motivation. NIDA-funded neuroscientist Dr. Martin emerging knowledge and maximize treatment outcomes, while Paulus reported that his team at the University of California, providing researchers with tools to construct new hypotheses San Diego, is developing a method to assess interoceptive system and to design studies highly relevant to the needs of providers functioning during brain imaging. The team plans to examine and patients. Each issue includes: whether activity of the interoceptive circuit differs between drug ■ Reviews by leading researchers of critical topics in the science abusers and nonabusers. of drug abuse prevention and treatment;

Dr. Michael Otto of Boston University envisioned one way ■ Service providers’ perspectives on what can and does work in such investigations might eventually find application in diverse community treatment settings; treatment. Noting that brain activity arising from disrupted inte- ■ Panel discussions on the practical implications of most roceptive processing may underlie a heightened vulnerability to articles; and anxiety, he imagined counselors training substance abusers to ■ Examples of successful addiction research-practice collabora- use biofeedback—real-time brain scans—to reverse the tions. abnormal activity. The benefits of such “weightlifting for the brain” could include reducing patients’ risks of stress-induced For more information and free subscriptions, go to: relapses to substance abuse. www.drugabuse.gov/acsp/. ■

16 NIDA Notes | Volume 21, Number 6 ■ TEAROFF Information to clip, save, and share

Booklet Explains the Science of Addiction

learing up common misconceptions and reducing the stigma associated with drug addiction are the goals of a Cnew book from NIDA. Drugs, Brains, and Behavior: The Science of Addiction explains in plain language what scientists know about how drug addiction alters the brain and affects behavior. “Thanks to science, our views and our responses to drug abuse have changed dramatically, but many people today still do not understand why people become addicted to drugs or how drugs change the brain to foster compulsive drug abuse,” says NIDA Director Dr. Nora D. Volkow. “This booklet aims to fill that knowl- edge gap by providing scientific information about the disease of drug addiction in language that everyone can understand.” The booklet discusses the reasons people take drugs, why some people become addicted while others do not, how drugs work in the brain, and how addiction can be prevented and treated. It also explains the consequences of abuse and addiction for substance abusers, their offspring, their sexual partners, and others.

Some of the key points made in the publication are:

■ Drug addiction is a disease, not a moral failing. Drugs change the brain, disrupting and hijacking its normal functions. For most people, the initial decision to take drugs is voluntary, but over time, drug abuse can cause changes to the brain that impair a person’s self-control and ability to make sound deci- sions, while generating intense impulses to take drugs.

■ Drug addiction is preventable. Researchers have developed a NIDA hopes that a better understanding of the basics of addic- broad range of programs that are effective in preventing early tion will empower substance abusers to make informed choices use of tobacco, alcohol, and illicit drugs and in curbing abuse about their own lives and treatment providers to adopt science- that has already begun. Preventing substance abuse early in life, based policies and programs to reduce abuse and addiction in their especially during adolescence, can reduce the chances of later communities. The need is clear: In the United States, abuse of abuse and addiction. illicit drugs and alcohol annually contributes to more than 100,000 deaths, while tobacco is linked to an estimated 440,000 more.

■ Drug addiction is treatable. Like diabetes, asthma, and heart disease, drug addiction is a chronic disease that can be man- Print copies of the 30-page, full-color booklet can be requested aged successfully. Relapse is not a sign of treatment failure, but without charge, by sending an e-mail to [email protected]. rather an indication that treatment should be reinstated or The publication is also available online at NIDA’s Web site, adjusted to help addicted individuals fully recover. www.drugabuse.gov. ■

NIDA Notes | Volume 21, Number 6 17 ■ VOLUME 21 INDEX

*Issue numbers appear in parentheses, plasticity: (2)11 depression: See disorders Girdler, Susan: (1)3 followed by the page number(s). prefrontal cortex: (2)10; (4)2 detoxification: (1)4, 7 Glatt, Stephen: (5)11 receptors: (4)12, 13 dextromethorphan: (5)15 glutamate: See brain acetylcholine: (4)4, 12 dialectical behavior therapy: (2)14 glycyl-glutamine: (4)7 A cannabinoid: (4)2; (5)3, 14 Digital Vigilance Test: (5)13 Gordon, Harold: (2)8; (5)11, 13 abstinence: (2)7; (3)1, 12 kappa opioid: (5)7 Dimeff, Linda: (2)14 Grant, Igor: (4)18 incentives: (1)1, 6, 8; (5)1; (6)1 mu opioid: (5)7 Ding, Yu-Shin: (4)3 Grant, Steven: (2)13; (4)4 See also vouchers nicotinic cholinergic: (2)10 disorders: Grossman, Debra: (3)6; (5)6 acculturation: (2)3 opioid: (4)13 alcohol use: (5)8 Gu, Howard: (6)12 acetaldehyde: (2)5 See also dopamine and attention deficit hyperactivity Gust, Steven: (4)19; (6)4 acetylcholine: See brain serotonin (ADHD): (1)3; (2)2; (3)4; (4)3; (6)7 addiction: reward circuit/system: (4)15; (5)7 bipolar: (6)6 risk: (2)3 synapse: (2)10; (4)13, 15 conduct: (2)2; (6)7 H transporter: (4)13 co-occurring: (1)3; (2)2 HAART: See HIV/AIDS research: (6)4 Hall, Sharon: (3)1 science: (6)17 See also dopamine and serotonin depression: (4)3; (5)4 ventral tegmental area (2)10; (4)6; (5)7 mental/psychiatric: (2)2, 15; (6)1 Harris, Glenda: (4)1 See also drug abuse and addiction Harrison, Murelle: (5)14 Addiction Science & Clinical Practice: Budney, Alan: (5)1 oppositional defiant: (6)7 (6)16 buprenorphine: (1)3, 4, 7 posttraumatic stress: (1)10; (2)2 Hawks, Richard: (3)7 adolescents: (1)7; (4)3, 16, 18 bupropion: (3)2; (5)3 respiratory: (1)12 health care quality: (2)15 Heaps, Melody: (1)15 See also children, teenagers, and substance use: (2)15; (4)20 youth/young people dopamine: (2)1; (3)2; (4)12, 15; (5)3, 7 heart impairment: (5)3 adrenocorticotropic hormone: (2)9 C Henderson, Leslie: (4)16 Carroll, Kathleen: (4)5 receptor: (4)5, 13, 15; (6)9, 11 African-Americans: (5)3 hepatitis C: (1)3; (3)7; (4)19 caterpillar: (6)12 transporter: (6)12 pain tolerance: (1)3 heroin: See also opiates/opioids Chausmer, Allison: (2)11 See also brain aggression: (1)2; (4)16 abuse and addiction: (1)3; (3)7, 10; children: (6)7 drug abuse and addiction: (6)20 Ahmed, Mahmoud: (3)4 See also adolescents, boys, teenagers, dual addiction: See co-occurrence treatment: (1)4, 7 AIDS: See HIV/AIDS and toddlers gender differences: (4)16, 18 high school: (1)2, 16; (3)15 Alberini, Cristina: (1)11 chromatin remodeling: (4)8; (5)2 genes: (5)10 Hilton, Thomas: (3)11; (5)17; (6)13 Albright, Lonnetta: (1)6 cigarettes: (1)12; (6)7 prevention of: (2)3 Hispanic/Latino Americans: (2)3, 14 alcohol: See also nicotine, smoking, and tobacco racial differences: (1)3; (5)9 HIV/AIDS: abuse: (5)8 clinical trial(s): (1)3, 4, 7; 2(4); (3)7; (6)1 risky behaviors: (4)18, 19 antiretroviral treatment/HAART: Amaro, Hortensia: (2)14 See also National Drug Abuse treatment: See treatment (5)20 amphetamine: (5)15; (6)13, 14 Treatment, Clinical Trials Network vulnerability: CD4 count: (5)20 animal studies: (1)2, 10; (6)14 clonidine: (1)4, 7 age differences: (2)1 disease progression: (6)3 See also mice, monkeys, and rats club drugs: See MDMA (ecstasy) attention deficit hyperactivity infection: (3)15 Appelbaum, Paul: (2)15 cocaine: disorder symptoms: (4)3 research: (2)5; (3)15 appetite: (4)1 abuse and addiction: (1)3, 9; (2)7, 12; drug discrimination protocol: (3)12 transmission: (4)18, 19; (5)14 (3)12; (4)15; (5)3, 12 Aston-Jones, Gary: (4)1 drug-seeking behavior: (1)9, 10; (4)1 Holtzman, Stephen: (4)3 abstinence: (3)16; (5)12 attention deficit hyperactivity disorder Dukic, Vanja: (6)8 Horti, Andrew: (5)3 (ADHD): See disorders craving: (2)7, 12; (4)6 hospital visits: (2)3 cues: (1)9 Hubert H. Humphrey Fellowship: (6)4 effects: (2)1; (4)8, 15; (5)3 E East Boston Family Study: (6)8 hypocretin: (4)1 B relapse: (2)4, 7; (3)13 Beatty, Lula: (5)14 ecstasy: See MDMA treatment: (1)9; (6)12 behavior(s): Eddy, J. Mark: (2)3 withdrawal: (2)3; (4)8 delinquent/disruptive: (6)7 electroencephalography (EEG): (5)13 I cognitive-behavioral therapy: (5)1 Iguchi, Martin: (2)14 drug-seeking: (1)9, 10 Ellen, Jonathan: (4)18 college students: (4)3; (5)8 immune response: (6)9 sexual: (1)2 employment: (6)3 Collins, Eric: (1)4 impulse control: (3)8 behavioral therapy: (1)7; (2)9; (3)15; endorphin: (4)12 Collins, Stephanie: (1)3 incentives: (3)3 (6)16 enkephalin: (4)12 Colliver, James: (5)9 low-cost: (1)1, 6 See also cognitive behavioral therapy epigenetics: (5)2 and dialectical behavior therapy Comer, Sandra: (3)7 motivational: (1)1; (6)1 Evans, Timothy: (1)15 Behavioral Treatment for Substance community-based treatment: See treatment See also abstinence extracellular signal-regulated kinase Abuse in Severe and Persistent Mental comorbidity: See co-occurrence Infant–Toddler Social Emotional Illness: (6)1 (ERK): (1)9 Assessment: (6)8 Bellack, Alan: (6)1 conditioned hyperactivity: (3)12 conditioned place preference: (1)9, 11; inhalants: (4)18; (6) 4, 14 Belluzzi, James: (2)5 (4)1, 7, 10 F intervention: See prevention of drug abuse Benowitz, Neal: (6)8 conditioned response: (6)11 factors in drug abuse : Berridge, Kent: (3)3 Condon, Timothy: (4)18 epigentic: (4)8; (5)2 Bickel, Warren: (1)14 J contingency management: (5)4 genetic: (3)2; (5)10 Jacob P. Waletzky Memorial Award for Blacks: See African-Americans co-occurrence/comorbidity: Family Health and Development Project: Innovative Research in Drug Addiction Blending Initiative: (1)6 substance abuse and mental disorders: (6)7 and : (3)14 Bolshakov, Vadim: (2)3 (4)4; (6)1 fast-scan cyclic voltammetry: (4)14 Jacobsen, Leslie: (4)5 Bonci, Antonello: (4)1 cortisol: (2)9 fluoxetine: (5)5 JDTic: (2)3 Borek, Nicolette: (6)8 cough medicine: (5)15 Frankenheim, Jerry: (1)11 Johnston, Lloyd: (5)15 Borgland, Stephanie: (4)1 counseling: Frascella, Joseph: (4)4 Bowen, Scott: (6)14 employment/vocational: (6)3 Friedmann, Peter: (2)3 boys: (6)7 “Frontiers in Addiction Research” mini- K motivational: (3)1 ketanserin: (3)13 brain: conference: (1)10 relapse prevention: (1)1, 7 Kirstein, Cheryl: (2)1 amygdala: (2)3; (5)7 functional magnetic resonance imaging craving: (1)9; (2)9; (4)1 (fMRI): (2)7, 12; (3)14; (4)4, 14 Kolb, Bryan: (2)5 cingulate cortex: (2)7, 13 criminal activity: (3)10 See also brain imaging Kosten, Thomas: (2)7 hypothalamus: (4)1, 2 criminal justice: Kranzler, Henry: (5)10 imaging: (2)7, 12; (3)14; (4)4 populations: (1)15 Kumar, Anil: (6)3 limbic system: (4)2 Cunha, Paulo: (6)5 G medial preoptic nucleus: (4)16 Cunningham, Kathryn: (3)12 Galvan, Adriana: (3)8 neurotransmitters: (4)11 Customized Employment Supports: (6)3 gamma-aminobutyric acid (GABA): (1)2; (4)12, 13, 16 L acetylcholine: (4)12 Czechowicz, Dorynne: (6)6 Lai, Shenghan: (5)3 anandamide: (4)12 gamma-hydroxybutyrate (GHB): (2)16 Landry, Charles: (2)10 glutamate: (2)3; (4)12, 14 receptors: (4)13, 16 “liquid ecstasy”: See gamma-hydroxybu- norepinephrine: (1)3; (4)12 D Gelernter, Joel: (5)10 tyrate Daley, Richard: (1)15 See also dopamine, gamma- gender: Lin, Woody: (5)7 aminobutyric acid (GABA), Daniels, David: (3)14 differences: (4)16, 18 Linehan, Marsha: (2)14 and ser otonin deCharms, R. Christopher: (3)14 genes/genetics: (3)2; (4)8; (5)2, 10 Lochman, John: (6)5 neuropeptides: De La Garza II, Richard: (5)3 genetic engineering: (6)12 Loeber, Rolf: (6)7 orexin: (4)1 delinquency: (6)7 Gil, Andres: (1)3 Logan, Jean: (4)3 nucleus accumbens (NAc): (1)9; delta-9-tetrahydrocannabinol (THC): Gilbert, David: (4)4 LSD: (5)15 (2)6, 10, 12 (3)3, 8; (4)12; (5)7; (6)9 (1)12 Lynch, Minda: (2)4; (3)13; (6)14 orbitofrontal cortex: (2)13; (3)8 deoxyribonucleic acid (DNA): (4)8 Lysle, Donald: (6)9, 11

18 NIDA Notes | Volume 21, Number 6 See also cigarettes, smoking, and research: Addiction Technology Transfer Center M tobacco global: (6)4 (1)7 Mafuya, Nancy Phaswana: (6)5 NicVAX: (3)4 neuroscience: (6)2 Sullivan, Lynn: (1)3 magnetic resonance imaging (MRI): NIDA International Program: (4)19; (6)4 reward response: (3)8 Supportive Treatment for Addiction Recovery: (6)6 See brain imaging and functional NIDA’s Division of Basic Neuroscience Rice, Kenner: (5)14 magnetic resonance imaging and Behavioral Research: (2)4 Risinger, Robert: (2)12; (4)4 Magura, Stephen: (6)3 NIDA’s Division of Clinical Malaka, Dorothy: (5)14 Neuroscience and Behavioral risk: T Research: (4)4 Tashkin, Donald: (1)13 Malison, Robert: (5)12 behaviors: (3)8, 5; (4)18 NIDA’s Southern Africa Initiative: (5)14 teenagers: (1)2; (3)15; (6)7 marijuana: Roach, John: (5)3 norepinephrine: brain See also adolescents and youth abuse: (1)12; (4)18; (5)15 See Robinson, Terry: (2)5 novelty: (2)1 Rutter, Joni: (4)10 Thadani, Pushpa: (4)17 effects: (1)12 therapy: See behavioral therapy and treatment: (5)1 cognitive behavioral therapy Marsch, Lisa: (1)7 O S Thomas, David: (4)7 Marshall, John: (1)9 obesity: (3)13; (4)2, 6 Saurer, Timothy: (6)9, 11 tobacco: Martinez, Charles: (2)3 Onken, Lisa: (4)5 Schiffer, Wynne: (6)14 addiction: (2)5 Matrix Model: (5)4 opiates/opioids: (4)12, 13 schizophrenia: (2)2, 15; (4)9; (6)6 use: (1)12; (2)2; (3)16 McCabe, Sean Esteban: (5)8 abuse and addiction: (1)4, 7; (3)3, 7, 14; Schnur, Paul: (6)11 See also cigarettes, nicotine, and McNamara Spitznas, Cecilia: (2)14 (4)7, 12; (5)10, 14 Schochet, Terri: (2)11 smoking MDMA (ecstasy): (3)15; (5)15 detoxification: (1)4 Schoenbaum, Ellie: (1)14 toddlers: (6)7 memory: effects: (6)9 school-age children: (6)7 toluene: drug-related: (1)9, 11 tolerance: (3)3 See also adolescents, college students, abuse: (6)14 molecular basis: (1)9, 10 treatment: (1)3, 4, 7; (3)7, 10; (4)7 high school, middle school, effects: (6)14 withdrawal: (1)4 Monitoring the Future survey, and methadone treatment: (1)3, 6; (2)3; teenagers tracer: (5)3 Opiate Total Synthesis: (5)14 (3)3, 10; (6)3 schools: See also radiotracer orexin: (4)1 methamphetamine: See college students and Monitoring treatment: See also listings for specific abuse and addiction: (4)18; (5)3, 15 Otto, Michael: (6)16 the Future survey drugs craving: (5)3 oxycodone (OxyContin): (1)7, 12; (5)8, 15 science: (4)4 behavioral: See behavioral therapy prenatal exposure: (6)3 Schwartz, Robert: (3)10 combination: (5)1 treatment: (5)4 P : (1)16; (5)8 community-based: (1)1 withdrawal: (5)4 pain: selective serotonin reuptake inhibitors: co-occurring substance abuse and methylphenidate: (1)3 (5)4 mental disorders: (6)1 management: (3)14 criminal justice: (1)15 methylreboxetine: (4)3 tolerance: (1)3 serotonin: (3)12; (4)12, 14 mice: (1)2; (3)3; (4)16; (6)12, 14 receptor: (3)12, 13 drug abuse: (1)1 treatment: (3)3, 14; (4)7 office-based: (1)3 microdialysis: (4)14 Palmer, Pamela: (3)14 transporter: (4)3 middle school: (3)15 sertraline: (2)7; (5)4 outcome: (2)7 parents, parenting: (2)3 trifluoperazine: (3)3 Miller, Courtney: (1)9 paroxetine: (5)5 sexual behavior: (4)16, 18, 20 Millington, William: (4)7 sexually transmitted disease(s): (4)20 Tsuang, Ming: (5)11 Patel, Amrat: (3)5 Turner, Jay: (2)3 Monitoring the Future survey: (1)2, 16; Paulus, Martin: (4)4; (6)16 See also hepatitis C and HIV/AIDS (3)15; (5)15 twins: (3)2; (5)10 Peciña, Susana: (3)3 Shaham, Yavin: (3)14 monkeys: (6)3 Pentel, Paul: (3)4 Sharp, Burt: (2)10 monoamine oxidase-B: (4)14 performance-enhancing substances: Shoptaw, Steven: (5)4 U Montoya, Ivan: (1)5; (1)8; (5)5 See steroids Shurtleff, David: (2)4 Upadhyaya, Himanshu: (4)3 Moore, Brent: (1)12 Petry, Nancy M.: (1)1 Sifunda, Sibusiso: (5)14 Morgan, Peter: (5)13 Pickett, Kate: (6)7 single nucleotide polymorphisms morphine: (1)11; (4)1 Pilotte, Nancy: (2)4, 6; (6)13 (SNPs): (3)2 V effects: (4)3, 7; (6)3, 9 Sinha, Rajita: (2)8, 9 varenicline: (3)2 Pittsburgh Youth Study: (6)7 Vega, William: (1)3 tolerance: (3)3 Pollard, Robert: (2)14 sleep impairment: (5)12 withdrawal: (4)7 Smeriglio, Vincent: (4)4 vesicles: (4)13 Pollock, Jonathan: (2)4 Vicodin: (1)7; (5)8, 15 motor-sequence task: (5)13 positron emission tomography (PET): Smissman Award: (5)14 smoking: Volkow, Nora: (1)2, 14, 15; (2)2, 14; (3)2, (4)14; (6)14 14, 15; (4)2; (5)2, 15; (6)2, 16, 17 adolescent: (1)3; (5)15 See also brain imaging Volman, Susan: (1)10, 11; (4)6 N cessation: (3)1, 3, 4; (4)4 Nader, Karim: (1)10 posttraumatic stress disorder: See disorders vouchers: (1)8; (5)1 co-occurring with mental disorders: naloxone: (1)3; (4)7 prenatal exposure: (4)4 See also incentives nicotine: (2)10; (3)4 (2)2; (3)1 naltrexone: (1)4, 7; (3)3, 7 initiation: (1)3 vulnerability to drug abuse/addiction: National Advisory Council on Drug smoking: (6)7 (2)1; (4)11 Abuse: (1)14 prescription drug(s): prenatal exposure: (2)10; (3)4; (6)7 National Drug Abuse Treatment, abuse: (1)5, 7, 16; (3)14; (5)8, 15 vulnerability: (3)2; (4)3 Clinical Trials Network (CTN): (1)1; See also opiates/opioids See also cigaret tes, marijuana, W nicotine, and tobacco Wakschlag, Lauren: (6)7 (2)3, 4; (3)3 Preston, Kenzie: (4)18 Smyth, Breda: (6)20 Wang, Zaijie Jim: (3)3 National Epidemiologic Survey on prevention of drug abuse: (6)17 Alcohol and Related Conditions: (5)8 Sorg, Barbara: (1)10 Watson, Donnie: (5)14 interventions: (1)1; (6)16 National Health and Nutrition South African National Council on Weiss, Dale: (6)4 PRISM Awards, 10th Annual: (1)14 Examination Survey: (1)12 Alcoholism and D rug Dependence: White, David: (4)3 National Household Survey on Drug Use prisoners: See criminal activity and (5)14 and Health: (4)18 criminal justice spleen: (6)9 Wightman, R. Mark: (5)3 National Institute of Diabetes and Staged Care Intervention: (3)1 Williams, John: (5)7 Digestive and Kidney Diseases: (4)2 See also treatment Winston, Scott: (3)4 National Survey on Drug Use and R Stanford, Laurence: (3)10 Wise, Roy: (3)14 Health: (3)15 radiolabel: (5)3 Stansfield, Kirstie: (2)1 withdrawal symptoms: (1)4; (2)3; (4)7 National Treatment Improvement radiotracer: (4)3 Wolf, Marina: (1)14 Evaluation Study: (2)3 See also tracer Stephens, Torrance: (5)14 steroids: (1)2; (3)15; (4)16 women: (1)2; (2)3; (3)4; (4)19 natural killer cells: (6)9 Rapaka, Rao: (2)4; (6)15 See also gender differences Neisewander, Janet: (3)13 Rataemane, Solomon: (5)14 stimulants: (1)1, 3; (3)3, 12; (4)3, 13 Stitzer, Maxine: (1)1; (3)3 Wong, Dean: (5)3 Nestler, Eric: (2)5; (4)8 rats: (1)9, 11; (2)1, 3, 10; (3)3, 12; (4)1, 3, 7, Wood, Janet: (1)14 neuropeptide Y: (6)10 13, 14; (6)9, 14 Strathdee, Steffanie: (4)18 neuroscience: (6)2 Rawson, Richard: (4)18 stress: social: (6)16 receptor: See brain cues: (2)9 Y See also brain Reference Series: exposure: (2)3; (3)14 young adults: (4)20 Newton, Thomas: (5)3 neurotransmission: (4)11 response: (1)3 youth/young people: (1)2; (2)3 nicotine: relapse: substance abuse: See also adolescents, children, and teenagers addiction: (2)5 cue-induced: (3)13 co-occurring with mental disorders: effects: (4)7 prevention: (1)4; (3)12 (2)2, 14, 15; (3)1; (4)3 patch/replacement therapy: (3)1, 2, 3 risk: (2)7, 9 genes: (5)10 stress-induced: (3)14 Substance Abuse and Mental Health Z prenatal exposure: (2)10 Services Administration (SAMHSA): Zerhouni, Elias: (5)2 vaccine: (3)4 vulnerability: (2)7, 9 (1)6 withdrawal: (4)7

NIDA Notes | Volume 21, Number 6 19 ■ WHAT THE NUMBERS SAY Reduced Longevity Among Male Heroin Abusers, 1962–1997

Stroke 2% Drug and Alcohol Disorders Other Even before the era of HIV/AIDS, the lifespan of 5% 2% heroin abusers was drastically curtailed compared to that of the general U.S. population. A recent study 4% looked at the fates of 581 California men who, from Heroin Overdose Other Overdose 22% 1962 to 1964, were mandated by a court to enter 4% heroin addiction treatment. Their average age was 25. By 1997, 282 of the men had died, at an average Suicide age of 47. Positing a hypothetical life expectancy of 5% 65, the deceased men fell short by an average of 18 years. Heroin overdose caused 17 percent of the or Injury Chronic Liver 5% Disease deaths, but—because it tends to occur at young 14% ages—22 percent of the loss in life expectancy (see Cancer 5% chart). Chronic liver disease, which is associated with hepatitis B, hepatitis C, and , Homicide Accidents accounted for 15 percent of deaths and 14 percent 9% 10% of the reduction in longevity. Cardiovascular Disease 9%

SOURCE: Smyth, B. et al. Years of potential life lost among heroin addicts 33 years after treatment. Preventive Medicine 44(4):369-374, 2007.

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