Release Date:  January 19, 2000

PA NUMBER:  PA-00-045

National Institute on Drug Abuse



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.


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 


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 


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.



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 

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 

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-

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 

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.  


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 


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 

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. 


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


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.


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.

the PHS 398.  It is not required and will not be accepted with 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:
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 
BETHESDA, MD 20892-7710 
BETHESDA, MD 20817 (for express/courier service) 


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 

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 

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.


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 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

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

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

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


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.


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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