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 Grants.gov 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
 (http://www.nida.nih.gov)

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 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

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 http://www.health.gov/healthypeople/.

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 (www.nida.nih.gov/funding.html).

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 http://grants.nih.gov/grants/funding/modular/modular.htm.

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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html.  A 
complete copy of the updated Guidelines is available at  
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm.  
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: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

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: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

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:
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

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 http://grants.nih.gov/grants/funding/phs398/phs398.html must 
be used in applying for these grants and will be accepted at the 
standard application deadlines (http://grants.nih.gov/grants/dates.htm) 
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 301/435-0714, Email: GrantsInfo@nih.gov.

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 
http://grants.nih.gov/grants/guide/notice-files/not98-030.html.

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 
http://grants.nih.gov/grants/funding/phs398/phs398.html 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 
http://grants.nih.gov/grants/funding/modular/modular.htm.  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:  jp183r@nih.gov

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:  gf6s@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 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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