NEUROBIOLOGICAL AND BEHAVIORAL RESEARCH ON NICOTINE AND TOBACCO COMPONENTS Release Date: January 19, 2000 PA NUMBER: PA-00-045 National Institute on Drug Abuse THIS PROGRAM ANNOUNCEMENT (PA) 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 PA. PURPOSE Nicotine is one of thousands of chemicals in tobacco products, but it is considered the primary compound that affects brain function. Reports from the U.S. Surgeon General, the American Psychiatric Association, and the World Health Organization, among others, have supported four major conclusions: (1) cigarettes and other forms of tobacco are addictive, (2) half of the people who continue to use cigarettes will die from diseases related to smoking, (3) nicotine is the drug in tobacco that causes addiction, and (4) physiological and behavioral processes that determine tobacco addiction are similar to those that determine addiction to heroin and cocaine. A critical goal of the National Institute on Drug Abuse (NIDA) is to increase our knowledge of the behavioral and neural mechanisms involved in addictive processes. The purpose of this PA is to expand the basic science knowledge base on the neurobiological and behavioral effects of nicotine and associated tobacco chemicals, as part of continuing efforts to explain and prevent their use and to develop effective treatments for nicotine addiction. This PA encourages research on any aspect of the effects of nicotine and other tobacco components, using neurobiological, behavioral, or other methods in humans, animals, or in vitro systems, that seeks to explain nicotine use, addiction, or other effects in humans. 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, Neurobiological and Behavioral Research on Nicotine and Tobacco Components, is related to all 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 Support mechanisms include the research project grant (R01), small grant (R03), and developmental/exploratory grant (R21). Applicants are advised to contact NIDA program staff listed under INQUIRIES for additional information. Refer to the guidelines for the specific eligibility requirements for the small grant (R03) and the developmental/exploratory grant (R21). Because the nature and scope of the research proposed in response to this PA may vary, it is anticipated the size of an award will also vary. Awards under the R01 mechanism may not exceed 5 years. Awards under the R03 mechanism are limited to 2 years, and R21 awards are limited to 3 years. Modular budgeting procedures apply for grants up to $250,000. See for further information about modular budgets. RESEARCH OBJECTIVES Background The habit of smoking, ingesting, or otherwise using tobacco products has been commonplace throughout the history of the United States. The most prevalent usage is the inhalation of tobacco smoke: more than 60 million people in the U.S. reported the regular use of cigarettes, cigars, or pipes in 19961. In addition, it has been estimated that each day in the U.S. more than 3000 people under the age of 18 start smoking cigarettes on a regular basis. Nicotine, the major psychoactive agent in tobacco, is widely accepted to be the primary cause of the habitual use of tobacco products. Although the 1964 report of the Advisory Committee of the U.S. Surgeon General on Smoking and Health, which raised early warnings about the dangers to human health from cigarette smoking, classified chronic tobacco use as a habit rather than an addiction, subsequent reports from the Surgeon General and other prestigious national and international forums (including the Royal College of Physicians, the American Psychiatric Association, and the World Health Organization) have left little doubt as to the addictive nature of nicotine. These conclusions were summarized in the 1988 Surgeon General"s Report2, which incorporated more than 2500 published papers and the contributions of more than 50 scientists. Because of the widespread use of cigarettes and other nicotine-containing products and the recent suggestion that nicotine activates brain areas that mediate reward and, indeed, may be as addictive as cocaine (3,4), the NIDA is seeking additional research on the causes of nicotine addiction and on other neurobiological and behavioral effects of nicotine and tobacco components. Areas of Research This PA solicits research in two general categories (1) neurobiology and (2) behavioral sciences. Neurobiological, cognitive, behavioral, and social processes, methods, and models are all relevant to this announcement. For both neurobiological and behavioral studies, approaches are encouraged that consider differences in gender, race, ethnicity, and age or developmental stage. The research topics listed below are not intended to be all-inclusive but are posed as examples of the types of research that may be explored in the search to understand the basic mechanisms of nicotine use and addiction, the possible roles of other tobacco components in this behavior, and the neurobiological and behavioral consequences of nicotine use and addiction. Studies that integrate behavioral and neurobiological perspectives are encouraged, and topics listed in one of the two sections below do not exclude similar studies relevant to the other section. I. Neurobiological Research Applications are encouraged that examine the neurobiological correlates and consequences of nicotine or tobacco use. Of interest, for example, are studies that seek to define the role of cholinergic mechanisms in the maintenance of tobacco or nicotine dependence, which might include investigations of the role of nicotinic receptor subtypes and possible interactions between the function of central nicotinic and muscarinic receptors. Also of interest are neuropharmacological studies such as the role of nicotine, nicotine metabolites, or cigarette smoke by-products in activating nicotine receptors or interacting with other central receptors that may play a role in the subjective experience of tobacco use. Pharmacokinetic/pharmacodynamic studies are also of interest, and might include investigation of the mechanisms by which monoamine oxidase is inhibited when a cigarette is smoked or of the correlation between nicotine metabolism and dependency. Also of interest is the development of animal and in vitro model systems that replicate the blood/brain levels of nicotine obtained when tobacco products are used. Additional examples of neurobiological research related to tobacco use or nicotine dependence are studies designed to: Investigate the role of the cholinergic system in abstinence symptoms. Determine if smoking or nicotine use is associated with and/or reduces the neurobiological markers associated with stress. Determine the neurobiological mechanism underlying nicotine’s stimulant effects, and/or investigate whether there is a relationship between the stimulant and putative stress-reducing effects of nicotine. Examine the relative roles of the autonomic nervous system versus the central nervous system in tobacco dependence or in cigarette craving. Determine whether the environmental cues that contribute to the desire for a cigarette are mediated by the same central circuits that are activated by other drugs of abuse. Investigate mechanisms, such as allelic differences in nicotine receptors or brain metabolic enzymes, that could account for individual differences in vulnerability or resistance to developing dependence to nicotine. Develop better ligands to monitor nicotine receptors in the central nervous system for imaging studies in humans and animals. II. Behavioral Sciences Research Behavioral and cognitive studies are needed to study the antecedents and consequences of nicotine use and the nature of the nicotine addiction process. Antecedents include both genetic and environmental risk factors for nicotine use. Studies of antecedents and consequences should take into consideration how these vary across gender, age, and ethnicity. Smokers exhibit many difficulties quitting the use of tobacco products. There are anecdotal reports that smoking withdrawal symptoms are as severe as those of any hard drug. Therefore, studies are needed to examine how nicotine craving compares to that for other drugs and to determine how the interoceptive (subjective) effects of nicotine contribute to cigarette craving or smoking behavior itself. Additional research topics on the cognitive and behavioral aspects of smoking/nicotine dependence are studies that seek to: Develop new animal models that correlate well with the human pattern of tobacco use, and use such models to investigate the acquisition of nicotine self-administration, its escalation, and relapse following abstinence. Determine the role of stimuli paired with smoking (including sensory stimuli from the act of smoking) in the rewarding effects of cigarettes, the control of smoking behavior, and in the relapse to tobacco use. (Similar studies on other modes of tobacco delivery would also be of interest.) Examine whether non-nicotine constituents in tobacco or tobacco smoke contribute to addiction. Develop and examine new pharmacotherapies and/or environmental manipulations that may prove useful in reducing or preventing smoking behavior or other modes of nicotine self-administration. Determine the factors that produce vulnerability to initiate smoking/tobacco use or to become addicted to nicotine, and also the factors that protect an individual against tobacco use or addiction, particularly as a function of age or developmental stage. Determine the role of exposure to other stimulants (e.g., methylphenidate, caffeine) in the propensity to use nicotine. Conversely, determine nicotine’s effect on responses to other abused drugs, including the propensity to self- administer. Determine the role of mental or other neurological disorders, such as depression, anxiety, schizophrenia, Parkinson’s or Alzheimer’s disease, in the acquisition of nicotine addiction, maintenance, withdrawal, and relapse to tobacco use. Determine the effects of prenatal exposure to nicotine, alone and in combination with other abused drugs, including, for example, assessment of later vulnerability to nicotine and other drug abuse, stress, or psychiatric disorders. Similarly, examine the effects of nicotine exposure in infancy or childhood through second-hand smoke. Conduct basic sciences studies aimed at understanding why women exhibit poorer responses to nicotine replacement therapies and have higher relapse rates than men. For both neurobiological and behavioral investigations, applicants should take into account that neurobiological studies have revealed a variety of sex differences, for example, in nicotine pharmacokinetics, in the genetics of nicotine metabolism, and in the density of nicotinic acetylcholine receptors. Also, there is mounting evidence from behavioral studies indicating that the nature of nicotine addiction is different for males and females. Investigators are therefore urged to incorporate sex-differences into their research design for both human and animal studies. Studies have also shown that nicotine metabolism and some aspects of smoking behavior appear to differ between Whites and African Americans, while other aspects of tobacco use do not differ across races or ethnic groups, racial, ethnic, and cultural factors should be investigated where appropriate. 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 medical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided 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 NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research, which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994 ( 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 may also obtain copies from these policies from the Program Contact person listed under INQUIRIES who may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, Telephone: (301) 710-0267, E-mail: Alternatively, applications can be downloaded from the NIH website at: Follow the PHS 398 instructions for Preparing Your Application. The title and number of the PA must be typed on line 2 of the face page of the application form and the YES box must be marked. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. 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 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 APPLICATION INSTRUCTIONS FOR MODULAR GRANTS 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. 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 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. 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. 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. NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page (see 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 key 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 F&A) 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 key personnel, and the 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. 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 key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: - 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, and - List selected peer-reviewed publications, with full citations. 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. 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 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? In the context of the R21 mechanism, a strong rationale and conceptual framework are normally sufficient to establish the feasibility of the project in lieu of extensive preliminary data. (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 human, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Applications will compete for available funds with all other recommended applications assigned to the Institute. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, programmatic priorities, i.e., relevance to program goals and objectives as described in the Areas of Research Interest in the PA. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues on neurobiological studies should be directed to: Thomas G. Aigner, 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 FAX: (301) 594-6043 Email: Inquiries regarding programmatic issues on cognitive or behavioral studies should be directed to: Jaylan Turkkan, 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) 443-1263 FAX: (301)-594-6043 Email: Inquiries regarding fiscal matters should be directed to: Gary Fleming, J.D. 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: Inquiries regarding review matters should be directed 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: AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.279. Awards are made under authorization of Section 301 of the Public Health Service Act (42 USC 241 and 284) and administered under PHS policies and Federal Regulations at Title 42 CFR 52 Grants for Research Projects, Title 45 CFR Part 74 & 92, "Administration of Grants" and 45 CFR Part 46, Protection of Human Subjects. This program is not subject to the inter-governmental 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, 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. BIBLIOGRAPHY Substance Abuse and Mental Health Services Administration. Preliminary Results from the 1996 National Household Survey on Drug Abuse. SAMHSA, 1997. Reducing the Health Consequences of Smoking: Nicotine Addiction. A Report of the Surgeon General. Rockville, MD. DHHS Publication # (CDC) 88-8406. Washington, DC, United States Government Printing Office, 1988. Henningfield, JE, Cohen, C, and Slade, JD. Is nicotine more addictive than cocaine? Br. J. Addiction 86: 565-569, 1991. Addicted to Nicotine: A National Research Forum. Meeting summary, 1998. Nicotine and Tobacco Research: Special Issue (in press).

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