ROLE OF LIMBIC SYSTEM AND BRAIN ONTOGENY IN DRUG ABUSE

Release Date:  February 25, 1998

PA NUMBER:  PA-98-032

P.T.

National Institute on Drug Abuse

PURPOSE

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 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This PA, Role of Limbic System and Brain
Ontogeny in Drug Abuse, is related to the priority areas of tobacco, alcohol and
other drugs, and maternal and infant health.  Potential applicants may obtain a
copy of "Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0 or Summary
Report: Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone: 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic, 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 research project grant (R01) and
exploratory/developmental grant (R21).

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 $90,000 per year.  Specific information on this
research mechanism can be obtained from NIDA s homepage
(www.nida.nih.gov/funding.html)

Because the nature and scope of the research proposed in response to this program
announcement may vary, it is anticipated that the size of an award will also
vary.

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, and limbic area are specified from neural ectoderm
including regionalization of gene transcription, cell-cell interaction, and
secreted signals that influence these processes are sought.

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 is encouraged.

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, 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 glia cell fate is specified by cell-cell
interaction, growth factor, cytokines, hormones, and by neurotransmitters in the
midbrain, nucleus accumbens, striatum, and limbic regions.

o  How drugs of abuse modulate the molecular mechanisms 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, 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, and
limbic areas.

o  How drugs of abuse modulate or alter fundamental mechanisms 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, 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, 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, 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
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is 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 were published in the Federal Register of March 28, 1994 (FR 59
14508-14513), and in the NIH Guide for Grants and Contracts, Volume 23, Number
11, March 18, 1994.

Investigators also may obtain copies of the policy from the program staff listed
under INQUIRIES.  Program staff may also provide additional relevant information
concerning the policy.

NATIONAL ADVISORY COUNCIL ON DRUG ABUSE RECOMMENDED GUIDELINES FOR THE
ADMINISTRATION OF DRUGS TO HUMAN SUBJECTS

The National Advisory Council on Drug Abuse recognizes the importance of research
involving the administration of drugs to human subjects and has developed
guidelines relevant to such research.  Potential applicants are encouraged to
obtain and review these recommendations before submitting an application that
will administer compounds to human subjects.  The guidelines are available on the
NIDA Home Page at http://165.112.78.61/ HSGuide.html or may be obtained by
calling 301-443-2755.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
5/95) 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 Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, Email: 
[email protected].  The title and number of the program announcement must be
typed in Section 2 on the face page of the application.

The completed original application and five legible copies must be sent or
delivered 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 that are complete will be evaluated for scientific and technical
merit by an appropriate peer review group convened in accordance with the
standard 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 following criteria apply to both the R01 and R21 mechanisms.

The goals of NIH-supported research are to advance the 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:

- The adequacy of plans to include both genders, minorities, and their subgroups,
as appropriate for the scientific goals of the research.  Plans for the
recruitment and retention of subjects will also be evaluated.

- The reasonableness of the proposed budget and duration in relation to the
proposed research.

- 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.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications assigned to that institute.  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 Basic Research
National Institute on Drug Abuse
5600 Fishers Lane, 10A19
Rockville, MD 20857
Telephone:  301-443-6300
FAX:  301-594-6043
Email:  [email protected]

Direct inquiries regarding fiscal matters to:

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
5600 Fishers Lane
Rockville, MD 20857
Telephone:  301-443-6710
FAX:  301-594-6847
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.279.  Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241
and 285), and administered under PHS grants policies and Federal Regulations 42
CFR 52 and 45 CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency review.

The Public Health Service (PHS) strongly encourages all grant 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.

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