This Program Announcement (PA) expires on October 31, 2004, unless reissued. ROLE OF LIMBIC SYSTEM AND BRAIN ONTOGENY IN DRUG ABUSE Release Date: October 19, 2001 PA NUMBER: PA-02-015 March 2, 2006 (NOT-OD-06-046) Effective with the June 1, 2006 submission date, all R03, R21, R33 and R34 applications must be submitted through using the electronic SF424 (R&R) application. A Replacement R21 (PA-06-445) funding opportunity announcement has been issued for the submission date of June 1, 2006 and submission dates thereafter. In addition, a replacement R01 (PA-06-444) has been issued. EXPIRATION DATE: October 31, 2004 National Institute on Drug Abuse ( THIS PA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS UP TO $250,000 PER YEAR. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT PURPOSE This version will replace in its entirety, PA-98-032, Role of Limbic System and Brain Ontogeny in Drug Abuse, published in the NIH Guide February 25, 1998. Specific cortical and subcortical forebrain structures, often referred to as the limbic system, play a significant role in mediating emotional and motivated behavior as well as memory storage. The proper development of forebrain structures and the formation of neural circuitry in the forebrain are essential for the normal development of pathways that mediate the hedonic properties of food, sex, and drugs of abuse. Elucidation of the processes underlying the development of the limbic system may provide critical insights into the adaptive processes associated with addiction and provide insights into mechanisms that might underlie increased vulnerability to addiction. This initiative is designed to support basic research into the fundamental mechanisms of development of the midbrain and basal forebrain structures that mediate the euphoric properties of drugs as well as understanding how drugs of abuse affect the cellular and molecular mechanism underlying nervous system development. In the past, vertebrate model systems (such as chick, frog, mouse, and zebrafish) and invertebrate systems (such as Drosophila and C. Elegans) have provided insights into mechanisms of development and are also likely to provide new information about the formation and specification of the limbic system. Approaches using these or other model systems both in vitro and in vivo are applicable to this program announcement. 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 PA, Role of Limbic System and Brain Ontogeny in Drug Abuse, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, 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 PA will use the National Institutes of Health (NIH) research project grant (R01) and exploratory/developmental grant (R21) award mechanisms. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The research project grant (R01) application may not exceed 5 years. An exploratory/developmental (R21) application is limited to 3 years. The R21 mechanism is intended to encourage exploratory research projects with sound methodology and strong rationales in underdeveloped areas of drug abuse, and is limited in direct cost amounts of $100,000 per year. Specific information on this research mechanism can be obtained from NIDA’s homepage ( Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the NIH. Complete and detailed instructions and information on Modular Grant applications have been incorporated into the PHS 398 (rev. 5/2001). Additional information on Modular Grants can be found at RESEARCH OBJECTIVES Examples of research that may be considered responsive to this program announcement include, but are not limited to, those listed below. In all research areas, investigators are encouraged to analyze developmental mechanisms that contribute to sexual dimorphisms. Neural Induction and Pattern Formation. o Studies on the cellular and molecular mechanisms by which the midbrain, nucleus accumbens, striatum, prefrontal cortex and limbic area are specified from neural ectoderm including regionalization of gene transcription, cell-cell interaction, and secreted signals that influence these processes. o How psychostimulants (cocaine, amphetamine, etc.), opiates, barbiturates, hallucinogens, benzodiazepines, cannabinoids, inhalants, and any other class of abused drugs affect the cellular and molecular mechanisms of neural induction and pattern formation. Stem Cells and Progenitors. o The cellular and molecular mechanisms of stem cell and progenitor cell induction, proliferation, and phenotypic restriction in the midbrain, nucleus accumbens, striatum, prefrontal cortex and limbic regions of the brain. o Studies on how abused drugs influence fundamental processes controlling stem cell, progenitor cell induction, and phenotypic restriction in all parts of the nervous system. Cell Fate and Specification. o The mechanisms by which neuronal and glial cell fate is specified by cell-cell interaction, growth factor, cytokines, hormones, and by neurotransmitters in the midbrain, nucleus accumbens, striatum, prefrontal cortex, and limbic regions. o How drugs of abuse modulate the molecular mechanisms are involved in determining cell fate and specifications in all brain regions. Neural and Glial Differentiation. o The transcriptional and post-transcriptional regulation of the acquisition of the differentiated phenotype of dopamine neurons in the ventral tegmental area and substantia nigra, as well as neurons and glia in the midbrain, nucleus accumbens, striatum, prefrontal cortex, and limbic areas (including cell morphology, excitability, growth factor responsiveness, and expression of neurotransmitters and receptors). o The molecular and cellular processes by which drugs of abuse alter neuronal differentiation by interrupting or augmenting the signal transduction mechanisms involved in the acquisition of the differentiated neuronal and glial phenotypes in all brain regions. Cell Migration. o The cellular and molecular substrates that direct and guide glial and neuronal migration in the areas that form the midbrain, nucleus accumbens, striatum, prefrontal cortex, and limbic areas. o How drugs of abuse modulate or alter fundamental mechanisms are involved in cell migration in all areas of the brain. Process Outgrowth, Navigation, and Target Selection. o The cellular and molecular mechanisms that regulate dendritic and axonal outgrowth, navigation, and target selection (including axonal guidance, branching, fasciculation, the formation of topographic and laminar-specific projections in the midbrain, nucleus accumbens, striatum, prefrontal cortex and limbic areas). o How drugs of abuse affect the fundamental cellular mechanisms mediating process outgrowth, navigation, and target selection in all areas of the brain. Synapse Formation and Plasticity During Development. o The cellular and molecular mechanisms governing the formation of synapses and developmental plasticity as well as the role of cell-cell recognition molecules, growth factors, electrical activity, and experience in the development of the midbrain, nucleus accumbens, striatum, prefrontal cortex, and limbic systems. o Analysis of how abused drugs affect the cellular and molecular mechanisms governing the formation of synapses and developmental plasticity throughout the central and peripheral nervous system. Programmed Cell Death. o Investigations into the cellular and molecular mechanisms of programmed cell death in the midbrain, nucleus accumbens, striatum, prefrontal cortex, and limbic systems during development. o Investigations on how abused drugs may modulate signal transduction pathways that mediate cell survival and cell death in vertebrate and invertebrate systems. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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 ( A complete copy of the updated Guidelines is available at 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: Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: 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. 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. APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at must be used in applying for these grants and will be accepted at the standard application deadlines ( as indicated in the application kit. This version of the PHS 398 is available in an interactive, searchable format. Although applicants are strongly encouraged to begin using the 5/2001 revision of the PHS 398 as soon as possible, the NIH will continue to accept applications prepared using the 4/1998 revision until January 9, 2002. Beginning January 10, 2002, however, the NIH will return applications that are not submitted on the 5/2001 version. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS 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 NIH staff. The research grant application form PHS 398 (rev. 5/2001) at is to be used in applying for these grants, with modular budget instructions provided in Section C of the application instructions. Applicants are permitted, however, to use the 4/1998 revision of the PHS 398 for scheduled application receipt dates until January 9, 2002. If you are preparing an application using the 4/1998 version, please refer to the step-by-step instructions for Modular Grants available at Additional information about Modular Grants is also available on this site. The title and number of the program announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and five 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. 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. 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. Applications will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Jonathan D. Pollock, 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: 301-443-6300 FAX: 301-594-6043 Email: 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 Email: 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 and contract 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, and 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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