CHRONIC STRESS AND ITS RELATION TO DRUG ABUSE AND ADDICTION RELEASE DATE: September 16, 2002 RFA: DA-03-004 National Institute on Drug Abuse (NIDA) ( LETTER OF INTENT RECEIPT DATE: November 19, 2002 APPLICATION RECEIPT DATE: December 19, 2002 THIS REQUEST FOR APPLICATIONS (RFA) CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations: PURPOSE OF THIS RFA The National Institute on Drug Abuse (NIDA) is encouraging research on adaptive changes within the brain brought about by chronic stress or repeated stressors and their functional relevance to drug use, abuse, and addictive processes. The relationship between drugs of abuse such as cocaine and heroin, activation of the hypothalamo-pituitary-adrenal (HPA) axis, and neural substrates subserving cognitive or behavioral processes under conditions of chronic stress is complex, but studies of these relationships may provide clues as to how drugs of abuse can produce persistent changes in the brain that in turn modulate behavioral processes, including drug-seeking and drug-taking behavior. Much of the preclinical literature in the area of stress and drug use has focused on endocrine measurements and behavior in acutely stressed animals. NIDA-supported research emphasizes the role of acute stress in relapse, evaluates endocrine parameters following an acute stressor, or employs acute footshock as a stressor to maintain or reinstate drug-seeking behaviors in preclinical models. Few studies evaluate the effects of chronic stressors on neurobiological substrates, or combines the effects of stress on the neurobiology and associated behaviors related to drug use. Even fewer evaluate the effects of chronic or repeated stress during early development on drug-directed behaviors in adulthood. The purpose of this request for applications (RFA) is to encourage investigations into the neural and behavioral consequences of exposure to physiologically relevant chronic or repeated stressors that can increase our understanding of drug abuse and addiction. As drugs of abuse themselves or repeated withdrawal from drugs can also be stressors, studies examining the effects of these variables on stress systems and drug abuse relevant behavioral or cognitive measures are encouraged, however, studies focusing solely on alcohol will not be considered responsive to this RFA. Both studies using chronic or repeated stress manipulations in animals, and human laboratory-based investigations that propose to study individuals who are or continue to be chronically stressed are encouraged. Study of the neural and behavioral adaptive changes that occur in individuals chronically exposed to stress, the duration of those changes, and their relationship to drug seeking behavior and relapse to drug use are also of interest. Preclinical applications employing footshock, learned helplessness, or other physically debilitating experimental paradigms as stressors, will not be considered responsive to this RFA because data obtained under such conditions are subject to multiple interpretations. RESEARCH OBJECTIVES The goal of the research areas outlined below is to understand the neurobiological mechanisms that underlie the interaction between stress and drug abuse and lead to behavioral change in all phases of the addictive process. "Stress" refers to both a physiological state of heightened arousal/vigilance/discomfort often accompanied by activation of the HPA, and to stimuli that can provoke that physiological state. Individuals under chronic stress can experience a progressive sensitization in their subsequent response to stress, and undergo pronounced physiological changes that are typified by dysregulation of important bodily systems leading to serious illnesses such hypertension and diabetes. These altered physiological states in turn influence subsequent adaptive responding in the face of additional stress. In fact, stress is often associated clinically with chronic drug use and is recognized as a major factor contributing to the relapse to drug use in abstinent individuals. Parallel findings in the preclinical literature also indicate that stress may enhance the vulnerability to acquire, maintain and relapse to drug-taking behavior. Data obtained from some animal models of chronic stress and from humans experiencing repeated stress document that neural adaptations in brain regions associated with the rewarding effects of drugs of abuse occur in response to chronic or repeated exposure to stress. Recent evidence also suggests that different types of stressors may affect specific components of brain circuitry in regions of the brain that serve as substrates of reward, stress, cognitive processes, motor systems, and autonomic regulation. Examples of such findings come from animal models of maternal separation, studies on dominant and submissive members of social hierarchies, and reactivity to novelty as a predictive factor for the acquisition and maintenance of drug self-administration. Chronic stress induces behavioral and neurobiological cross-sensitization to some drugs of abuse. Chronic stress has also been shown to decrease cells within the hippocampus in animals and decrease its volume in humans. The hippocampus is a structure implicated in learning and memory, and this cell loss may be related to the persistence of drug-taking behavior. While deficits are most often reported in response to chronic or repeated stress, adaptation to stress also includes an allostatic process, which represents an organism"s attempt to regain homeostasis, and suggests that certain compensatory adaptations occur in response to chronic or repeated stress. However, few reports document this effect, or its relationship to drug abuse, and further work in this area is encouraged. NIDA would like to promote and support research in the area of chronic or repeated stress on adaptations within the neural circuits involved in all aspects of drug abuse as well as the individual components of the circuits, and determine the functional impact of such alterations, particularly on drug seeking behavior and relapse to drug abuse. To that end, research topics that would be considered responsive to this RFA may include (but are not limited to) the following: o Development of objective measures of chronic and repeated stressors in preclinical studies. o Studies that manipulate stress as an experimental variable or as an outcome variable interacting with or influencing drug abuse-relevant behavioral or cognitive assessments. o Studies that examine the interaction of components of neural circuitry underlying both reward and stress, investigations of compensatory neuroadaptations brought about by stress and their reversal are also encouraged. Variables of interest might include alterations in the elements of reward circuits as a result of chronic stress and repeated exposure to drugs of abuse, neuroadaptive and behavioral responses to novelty, complexity or change in the environment, or changes in gene expression as a function of chronic stress and exposure to abused drugs. The persistence of such neuroadaptations is also of interest. o Studies of how drug exposure may affect response to repeated exposure to stressors. o Development of animal models of chronic or repeated stress and examination of neuroadaptations in macro- and micro-circuits in the brain produced as a result of chronic or repeated exposure to stressful stimuli, including their consequence for behavioral or cognitive phenomena relevant to understanding drug abuse and addiction. These might include studies of graded (incremental) levels of physical and psychological stressors and examining cumulative or synergistic effects on one or more outcomes. Stressful stimuli such as restraint, exposure to cold, and socially-induced stress such as early maternal separation or aggression or other manipulations that may mimic stressful experiences likely to be encountered by humans are suitable candidates for study. o Assessment of cognitive abilities, changes in behavioral repertoire, including choice behaviors in chronically stressed animals or humans who are or have been subjected to chronic stress. Cognitive abilities of interest may include, but are not limited to, tasks that assess "executive function," learning and memory, or tasks designed to assess choices between drugs of abuse, or between drugs and other natural rewards. It is also of interest to determine the consequences of and subsequent response to additional stressful situations or adverse events, stress manipulations, or availability of drugs after chronic stress, and stress plus drug exposure. o Cognitive and behavioral studies of humans with HIV-AIDS who are exposed to or experience chronic or repeated stress are also encouraged. For example, studies of the positive or negative influence of acute stress against the baseline of chronic stress may be useful in identifying variables (cognitive, behavioral, neurobiological or immunological) that affect response to behavioral or pharmacological treatment. o Studies on the consequences of repeated exposure to stressors in concert with abused substances on the immune system, especially in the brain are also encouraged. These may include studies of the effects of chronic stress on cytokines in the brain, and the effects of cytokines on the regulatory elements of neurotransmission (receptors, transporters, signal transduction factors, etc.). o Studies of individual differences in neurobiological and hormonal responses to acute drug challenges in the chronically stressed subject are also of interest. Such studies might also include pharmacological dose-response studies to determine the sensitivity of the stressed individual to treatment aimed at blocking drug-induced or cue-induced reinstatement of drug-taking behavior or its neurobiological correlates. Differential responses to acute challenges in chronically stressed individuals might help differentiate the likelihood of an individual"s response to stress and drugs. These might be reflected, for example, in the relative proportions of adrenal steroids released upon challenge with a stressor. o Imaging studies in animals and humans to delineate stress pathways and their activity in living brains. These might include the study of environmental cues for stress or drug-taking, or the effects of a pharmacological intervention on the activity of a so-called "stress circuit." o Studies of the effects of early (developmental) stress in animal models or in human subjects on sensitization of the CNS to psychoactive substances. Such studies may also include examination of early stress on adult behaviors and neuroadaptations that are specifically associated with the increased probability of drug seeking, such as impulsivity, and aggression (vulnerability). o Pharmacological modification of stress responses and its consequences on drug-related behaviors. o Studies that explore the role(s) of gender in chronically or repeatedly stressed individuals on any of the research areas noted thus far. MECHANISMS OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project (R01), NIDA small grant (R03) and NIDA exploratory/developmental (R21) award mechanisms. The total project period for an R01 application submitted in response to this RFA may not exceed 5 years. For R21 applications, the project period cannot exceed 3 years and $100,000 in direct costs in each of those years. For R03 applications, the project period cannot exceed 2 years and $50,000 in direct costs in each of those years, and the application research plan (items a-d) cannot exceed 10 pages. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is July 2002. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see FUNDS AVAILABLE NIDA intends to commit approximately $2.5 million in FY 2003 to fund 7 to 12 new and/or competitive continuation grants in response to this RFA. For the R01 mechanism, an applicant may request a project period of up to four years and a budget for direct costs of up to $200,000 per year for all years. For the R03 mechanism, an applicant may request up to $50,000 in direct costs in each of the 2 years. For an R21 mechanism, an applicant may request up to $100,000 in direct costs in each of the 3 years. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration 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. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about preclinical scientific/research issues to: Nancy Pilotte, Ph.D. Division of Neuroscience and Behavioral Research National Institute on Drug Abuse 6001 Executive Boulevard, Room 4282, MSC 9555 Bethesda, MD 20892-9555 Telephone: 301-443-6975 Email: o Direct your questions about human laboratory-based scientific/research issues to: Minda Lynch, Ph.D. Division of Neuroscience and Behavioral Research National Institute on Drug Abuse 6001 Executive Boulevard, Room 4282, MSC 9555 Bethesda, MD 20892-9555 Telephone: 301-445-1322 Email: o Direct your questions about peer 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 Email: o Direct your questions about financial or grants management matters to: Gary Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse 6001 Executive Boulevard, Room 3131 MSC 9541 Bethesda, Maryland 20892-9541 Telephone: 301-443-6710 E-mail: LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA 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 IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Director Office of Extramural Affairs National Institute on Drug Abuse 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, Maryland 20892-9547 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-2755 Email: SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 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 RFA label is also available at: SENDING AN APPLICATION TO THE NIH: 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 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-2755 APPLICATION PROCESSING: 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. PEER REVIEW PROCESS 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: o Receive a written critique o 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 and assigned a priority score o 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 your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application"s overall score, weighting them as appropriate for each application. Your 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, you 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 your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? 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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: 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 INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: November 19, 2002 Application Receipt Date: December 19, 2002 Peer Review Date: February/March 2003 Council Review: May 2003 Earliest Anticipated Start Date: July 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a clear and compelling justification is 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 clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (, a complete copy of the updated Guidelines are available at The amended policy incorporates: the use of an NIH definition of clinical research, updated racial and ethnic categories in compliance with the new OMB standards, clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398, and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy 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 is available at REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at and at Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. 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 is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.279, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 described at and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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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