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
http://odphp.osophs.dhhs.gov/pubs/hp2000.
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
http://grants.nih.gov/grants/funding/modular/modular.htm 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
(http://grants.nih.gov/grants/guide/notice-files/not94-100.html).
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 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: GrantsInfo@nih.gov. Alternatively, applications can be
downloaded from the NIH website at:
http://grants.nih.gov/grants/funding/phs398/phs398.html. 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
http://grants.nih.gov/grants/guide/notice-files/not98-030.html).
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 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 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:
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, 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: ta17r@nih.gov
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: jt58t@nih.gov
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: gf6s@nih.gov
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: tl25u@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 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.
http://www.nida.nih.gov/MeetSum/Nicotine/Nicotineagenda.html. Nicotine and
Tobacco Research: Special Issue (in press).
Weekly TOC for this Announcement
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