THE TRANSITION FROM DRUG USE TO ADDICTION: UNEARTHING THE SWITCH Release Date: November 21, 2000 RFA: DA-01-004 National Institute on Drug Abuse (http://www.nida.nih.gov) Letter of Intent Receipt Date: January 23, 2001 Application Receipt Date: February 23, 2001 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The National Institute on Drug Abuse (NIDA) invites applications for research to broaden our understanding of the transition from drug use to drug addiction. NIDA-supported research has significantly advanced our understanding of the behavioral, biological, and molecular factors both underlying initial drug use and characterizing the state of being addicted. As a result, we have accumulated a significant knowledge base about why people start using drugs, the risk factors for continued use and dependence, the patterns of use among individuals and groups, the effects of drugs on behavior, mood, cognitive processes, and performance, and the effects of drugs on the basic neurobiology of the brain. We can now begin to describe the biological and behavioral differences between a voluntary drug user and an addict. However, we actually know very little about the predisposing factors, cellular and neural mechanisms, and behavioral and social processes associated with the transition from drug use to drug addiction. There is a tremendous gap in our understanding of how individuals move from early stages of drug use to later stages of drug addiction and the mechanisms that underlie the actual transition from one state to another. Research is needed to better characterize the stages of drug addiction and transitions to and from them. The knowledge gained will form the basis for improving our understanding of addiction and developing improved prevention and treatment programs. This topic has been identified by the National Advisory Council on Drug Abuse as a major area of research need, requiring new, innovative, intensive, and focused attention. The intent of this Request for Applications (RFA) is to stimulate research on the processes and mechanisms underlying the transition from drug use to drug addiction from a wide variety of academic disciplines and approaches. Research from epidemiologic, basic, and clinical disciplines, including research on other transitional states with relevance to addiction, will be supported under this RFA. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS- led national activity for setting priority areas. This RFA, "The Transition from Drug Use to Addiction: Unearthing the Switch," is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grants (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 5 years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2001. FUNDS AVAILABLE NIDA intends to commit approximately $4 million in FY 2001 to fund 10 to 15 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $400,000 per year. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of NIDA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES Background Drug addiction is a chronic relapsing disease that may have many characteristics, including a persistent desire or compulsion to use a drug, loss of control of drug intake, reduction in other important activities because of drug use, continued use despite knowledge of harm, marked tolerance, characteristic withdrawal symptoms, and an increased negative emotional state or stress when the drug is unavailable. The process of becoming addicted to drugs often begins with non-compulsive or less frequent use, which, over time, can lead to compulsive uncontrollable drug taking. Relapse to drug use occurs following short or long periods of abstinence and may result from stress and/or re-exposure to a drug or environments previously associated with drug use. Individuals addicted to drugs have been known to report intense "craving" for an abused drug. There is a need to learn more about both how the brain changes and how behavior changes from first drug use (a voluntary behavior) to compulsive use (behavior characterized by a loss of control). How does taking a drug repeatedly over time change the brain in such a way as to lead to the compulsive patterns of drug use that characterize addiction? Why do some drug users intensify their use and others do not? What are the experiences of individuals making such transitions in drug use, and how do these experiences relate to changes in brain function? What are the genetic and environmental factors that predispose individuals to make such transitions or be resistant to them? Is addiction a defined neurobiological state of the brain, and is it dependent upon the environmental conditions in which drug use takes place? Does addiction occur suddenly, as if a switch is flipped, or is it a more gradual, incremental process? Answers to these and related questions will (1) provide a logical and strategic basis for the development of new and more effective prevention and treatment approaches, (2) allow more accurate identification of individuals at high risk for addiction and the environmental conditions related to risk, (3) further our basic understanding of the behavioral, cognitive, neurobiological, molecular, and biochemical effects of drugs, and (4) provide a more complete understanding of the basic mechanisms of brain function. To begin to address some of these questions, NIDA is developing and beginning to implement a multi-staged, strategic effort to stimulate research to address these issues from a variety of disciplines and perspectives. The overall research objective of this initiative is to gain a better understanding of the processes and mechanisms underlying the transition to addiction, and to ultimately use that knowledge to improve prevention and treatment approaches. NIDA envisions that such new knowledge will come from a wide variety of experimental approaches and disciplines and plans to support studies to: o Identify and characterize specific neurobiological changes in the brain related to drug-seeking behavior. o Identify the genes and gene products expressed during the process of addiction and their functions. o Develop and improve animal models of the addiction process, including the study of drug-induced narrowing of the behavioral repertoire and compulsive drug use, and determine the behavioral, neurobiological, and molecular mechanisms associated with these addiction processes. o Investigate the role of behavioral, psychological, cognitive, and environmental factors in the transition from initial to compulsive drug use and their interaction with neurobiological factors. o Characterize the changes in drug use patterns and the phenomenological experiences in individuals as they transition from drug use to addiction. Areas of Interest The following are illustrative examples of the types of research that would be responsive to this RFA. They are intended as a guide only and not meant to limit the themes or approaches that could be proposed: o Studies of neurobiological responses to repeated drug administration and identification of long-term neuroadaptations that may underlie the transition to compulsive drug taking. o Cross-disciplinary research to combine basic and clinical approaches to identify candidate neurobiological mechanisms underlying transitional states in addiction. o Collaboration between genetic epidemiologists, molecular geneticists, and behavioral scientists to more fully characterize the genes and their actions that may contribute to drug use initiation vs. compulsive use and drug dependence. o Studies of learning and memory in the development of addiction, including those measuring or characterizing state change and plasticity in the central nervous system and relating these changes to how knowledge is organized and how that organization can change with experience. Also, studies applying operant and associative learning models to transitional states in drug addiction, consolidation of memories, encoding, perseveration, and the transition of learned actions into habits. o Studies of the specificity of the transition. Is there a discrete transition point (i.e., the set point at which one goes from nonaddicted to addicted the switch ), and is it related to a particular biological state, or is it dependent upon particular behavioral or environmental variables? Is the transition point different for different drugs or drug classes, routes of administration, stage of drug use, age, drug use history, environmental conditions, etc.? o Studies of behavioral/neurobehavioral markers that may predict the transition from drug use to drug addiction and individual differences in the rate of the transition. o Research to characterize the cognitive, neurobiological, environmental, and genetic factors that contribute to vulnerability or confer resilience against the progression to addiction. o Studies of cellular, physiological, and/or behavioral changes related to transitional states normal and pathological outside of addiction that could have relevance to addiction. These could include studies of learning and memory (or other cognitive processes), fixed action patterns (e.g., imprinting), and parental behaviors. o Research to determine how transcription factors and signaling molecules activated during learning and by drugs of abuse produce changes in cell physiology, cell morphology, and synaptic transmission in neural systems that underlie transitional states in addiction. o Studies to identify and compare stages of transition relevant to addiction in other diseases/disorders, such as bulimia, anorexia nervosa, obsessive compulsive disorders, etc. o Studies using computational approaches/mathematical models of transition dynamics and state dependence in neural networks. o Studies of variables (e.g., drug pharmacology, drug availability, behavioral alternatives) that differentiate or predict the characteristics of the transition for single drugs or classes of drugs. o Studies to examine the role of conditioned environmental stimuli and other environmental factors (e.g., stressors) in the transition process. o Studies of the variability in susceptibility to addiction, including resiliency to addiction, such as the subset of cigarette smokers who regularly smoke but do not become addicted ( chippers ), and rapid development of addiction, such as the subset of adolescent smokers who develop symptoms of nicotine dependence after only a few exposures to the drug. o Epidemiological and ethnographic investigations of drug use patterns during transitional periods, characterization of different trajectories of drug involvement, and the effects of genetic and environmental (community, social, familial) factors. o Prospective multidisciplinary studies of high-risk drug users to track the onset of addictive use and of specific symptoms of addiction, associated phenomenological experiences, and neurobiological profiles. o Studies of differential patterns of transition in individuals with different psychiatric comorbidities. SPECIAL REQUIREMENTS All applications must include plans to share data, reviewers will assess the adequacy of the proposed plan. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS - UPDATED AUGUST 2, 2000 It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning these policies. NATIONAL ADVISORY COUNCIL ON DRUG ABUSE RECOMMENDED GUIDELINES FOR THE ADMINISTRATION OF DRUGS TO HUMAN SUBJECTS The National Advisory Council on Drug Abuse recognizes the importance of research involving the administration of drugs to human subjects and has developed guidelines relevant to such research. Potential applicants are encouraged to obtain and review these recommendations of the Council before submitting an application that will administer compounds to human subjects. The guidelines are available on NIDA"s Home Page at http://www.nida.nih.gov/ under Funding or may be obtained by calling (301) 443-2755. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIDA staff to plan the review. The letter of intent is to be sent to the following office by the letter of intent receipt date listed above: Director, Office of Extramural Affairs National Institute on Drug Abuse 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, Maryland 20892-9547 Telephone: (301) 443-2755 FAX: (301) 443-0538 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers, and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE - Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and their role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all all personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications with full citations, o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The sample RFA label is available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Director, Office of Extramural Affairs National Institute on Drug Abuse 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, Maryland 20892-9547 Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by NIDA. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIDA in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Advisory Council on Drug Abuse. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o The adequacy of the proposed plan to share data. Schedule Letter of Intent Receipt Date: January 23, 2001 Application Receipt Date: February 23, 2001 Peer Review Date: June/July/Aug 2001 Council Review: September 2001 Earliest Anticipated Start Date: December 2001 AWARD CRITERIA Award criteria that will be used to make award decisions include: scientific merit (as determined by peer review), availability of funds, and programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Steven Gust, Ph.D. National Institute on Drug Abuse 6001 Executive Boulevard, Room 5274, MSC 9581 Bethesda, MD 20892-9581 Telephone: (301) 443-6480 FAX: (301) 443-9127 Email: sgust@mail.nih.gov Direct inquiries regarding review matters to: Teresa Levitin, Ph.D. Office of Extramural Affairs National Institute on Drug Abuse 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, Maryland 20892-9547 Telephone: (301) 443-2755 FAX: (301) 443-0538 Email: tl25u@nih.gov Direct inquiries regarding fiscal matters to: Gary Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse 6001 Executive Boulevard, Room 3131, MSC 9541 Bethesda, MD 20892-9541 Telephone: (301) 443-6710 FAX : (301) 594-6847 E-mail: gf6s@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.279. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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