Full Text DA-95-003

HUMAN BASIC AND CLINICAL NEUROSCIENCE OF DRUG ADDICTION

NIH GUIDE, Volume 24, Number 4, February 3, 1995

RFA:  DA-95-003

P.T. 34

Keywords: 
  Neuroscience 
  Drugs/Drug Abuse 
  Addiction 


National Institute on Drug Abuse

Letter of Intent Receipt Date:  April 3, 1995
Application Receipt Date:  May 9, 1995

PURPOSE

A generation of neuroscientific research utilizing animal models has
provided the identification of receptors for every major abused drug
and many of their endogenous ligands.  A variety of models have been
developed to explain the fundamental behavioral and biological
mechanisms of addiction, e.g., brain reward, tolerance, and
dependence.  These discoveries and models, coupled with the rapid
advances in noninvasive brain imaging methodology, now make it
feasible to study drug addiction and the human brain to determine the
etiology and the biomedical and biobehavioral consequences of drug
abuse, as well as the effects of treatment of this disorder.  The
National Institute on Drug Abuse (NIDA) proposes to initiate a major
program using noninvasive technologies or autopsy materials to study
the human brain and the etiology and consequences of drug abuse and
to translate this information into novel prevention, diagnostic, and
treatment strategies.  Research applications proposing to use current
or to develop new noninvasive techniques to assess neuroanatomical,
neurochemical, or other functional differences or changes in human
brain that contribute to vulnerability to drug abuse, are a
consequence of drug use, or result from pharmacological or non-
pharmacological treatment are therefore invited.  Investigators
interested in research of this type with respect to AIDS etiology,
consequences, and treatment in connection with drug abuse and
addiction are particularly encouraged to apply.

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 Request
for Applications (RFA), Human Basic and Clinical Neuroscience of Drug
Addiction, 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 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic, for-profit and
nonprofit organizations, public and private such as colleges,
universities, hospitals, laboratories, units of State and local
government, and eligible agencies of the Federal government.  Foreign
institutions are not eligible for First Independent Research Support
and Transition (FIRST) (R29) awards.  Racial/ethnic minority
individuals, women and persons with disabilities are encouraged to
apply as Principal Investigators.

MECHANISM OF SUPPORT

This RFA will use the NIH research project grant (R01),
exploratory/developmental research award (R21), FIRST (R29) award,
and small grant (R03).  Investigators may also respond to this RFA
under the Interactive Research Project Grant Program (IRPG), which
utilizes the R01 and R29 mechanisms. If an IPRG is proposed, it must
consist of a minimum of two independent applications (see PA-94-086,
NIH Guide for Grants and Contracts, Vol. 23, No. 28, July 29, 1994).
However, if the IRPG mechanism is used under this RFA, the receipt
date of this RFA takes precedence over the IRPG special receipt date.
Research grants are awarded to institutions on behalf of Principal
Investigators who have designed and will direct a specific project or
set of projects.

FUNDS AVAILABLE

It is anticipated that approximately $3 million will be available to
support projects submitted under this RFA.  Because the nature and
scope of the research proposed in response to this RFA may vary, the
size of an award will vary also.  It is anticipated that
approximately 8 to 10 new awards will be made under this RFA.

RESEARCH OBJECTIVES

This program is intended to support research on basic and clinical
human neuroscience of addiction.  Research using animals is not
excluded, but their use in projects submitted under this RFA must be
specifically justified.  Effort is to be made to use
state-of-the-science approaches.  Individual research project grants
funded under this RFA may conduct research that uses various imaging
or other innovative technologies, living neural tissue, or postmortem
tissue to:

1.  elucidate in humans the basic mechanisms of action of drugs of
abuse, including interaction with other drugs and with mental or
physical conditions, such as psychiatric disorders or AIDS;

2.  examine the neurobiological factors, including those related to
AIDS, that contribute to vulnerability to drug abuse;

3.  examine the central nervous system (CNS) status of patients
during diagnosis and treatment for drug dependency disorders; HIV
infected persons or persons with AIDS may be special populations for
such studies.

1.  Basic Human Neuroscience

Investigators are invited to study the effects of substance abuse on
the structure and function of the human brain using various imaging
and other technologies (e.g., ligand PET scanning, functional
magnetic resonance imaging, magnetic source imaging,
electroencephalography, magnetic resonance spectroscopy), autopsy
material, or other methods (e.g., neural tissue transplantation,
neuron cultures, analytical neurochemistry).  The main goals of the
basic research supported through this initiative are to:  (1)
identify in humans the neuronal systems involved in mediating the
pleasurable or reinforcing experiences associated with substance
abuse (the human brain reward system), and (2) characterize in humans
the neurochemical, neuroanatomical, and neurophysiological changes
that underlie states of drug tolerance and dependence, as well as to
characterize the reversible and irreversible brain changes that
result from drug abuse.

Investigators are further encouraged to verify in man observations
made in animal studies that drug abuse produces long-lasting changes
in neurochemical markers and morphological features of specific sets
of neurons.  The effects of different types of drugs of abuse on
neurochemical markers could be assayed in postmortem human brain
tissue samples.  Such studies should measure fundamental neuronal and
glial structure and function including morphology, activity of
enzymes involved in neurotransmitter synthesis and degradation,
receptor densities and distribution, second messenger systems, and
measurements of gene expression.  Changes in these due to drug-
related HIV infection are also subjects of interest.

Of particular interest are studies that will take advantage of the
opportunity to correlate directly the changes in the patterns of
biologic activity in the human brain with the subjective experiences
of the individual exposed to drugs of abuse.  This research should
help elucidate the precise neural mechanisms affected by drugs of
abuse as well as reveal how drug-induced alterations might lead to
and maintain drug-seeking behavior and addiction.  Also important are
studies assessing brain function during various stages of withdrawal
and abstinence, which should provide important information about the
neural substrates involved in drug craving.

Studies are also encouraged that would refine current imaging
techniques or develop new ones, elucidating the basic mechanisms and
correlations that relate images to neuronal activity, for example,
establishing the mathematical relationships between blood flow,
metabolism, and cellular activity, or providing greater levels of
refinement for viewing anatomical structures; e.g., applications of
magnetic resonance microscopy which attempt to provide resolution at
the cellular level.  Again, alterations due to drug-related HIV
infection are suitable topics for this request for applications.

Research in the chemistry necessary to human brain imaging is also
encouraged, for example, the synthesis of novel imaging reagents for
use in humans.  Another area of interest is the application of
imaging technologies to pharmacokinetics.

2.  Vulnerability and Etiological Investigations

In humans, neurobiological factors that relate to high vulnerability
to abuse drugs or to high vulnerability to suffer the adverse health
consequences of drug abuse are not currently defined.  NIDA is also
interested in research on neurobiological aspects of drug abuse that
might be unique to special groups, such as women and youth.  In this
connection, NIDA also encourages applications that focus specifically
on HIV positive populations or individuals at risk for acquiring
AIDS.  Applications for support under this RFA will use original
approaches to apply the latest in imaging and other innovative
techniques to the examination of neurobiological factors underlying
the etiology of and vulnerability to drug abuse in humans.

Such projects might use noninvasive techniques to:

a.  Examine factors contributing to the biomedical etiology of drug
abuse; for example, studies evaluating genetic, developmental, and
environmental factors in drug addiction, including nutritional and
environmental toxic elements; or examining the neurobiological
relationship between early use of tobacco and alcohol and later
development of cocaine and heroin addictions.

b.  Identify the type and distribution of the biomedical consequences
of abusing drugs because of as-yet-unidentified neurobiological
predispositions.

c.  Assess the prevalence, distribution, and epidemiology of
biobehavioral risk factors underlying the vulnerability to abuse
drugs.  This might include investigations of the role of various
stressors in vulnerability to drug addiction (e.g., links between
post traumatic stress disorders and drug seeking behaviors or between
HIV infection and drug addiction).

d.  Modify and further develop existing technologies and
methodologies for studying the neurobiological risk factors of drug
abuse.

Projects should develop new information about how individual
differences in genetics, neurobiological profiles, or psychological
behaviors predict drug abuse or, alternatively, protect from drug
abuse.

3.  Clinical and Treatment Neuroscience

Clinical and treatment-oriented neurobiological researchers are
encouraged to submit applications that utilize state-of-the-art brain
imaging, analytical neurochemistry, electrophysiology,
neuropsychological assessment, genetic analysis, and other technology
to elucidate the CNS status of patients during various stages of
diagnosis and treatment of drug dependency disorders.  For example,
studies might examine neurotransmitter metabolites appearing in blood
and cerebrospinal fluid as neurochemical markers for diagnosis, as
correlates of mood and behavior, and as predictors of clinical
outcome.  This example also encompasses metabolic changes in response
to various treatment interventions, pharmacological, behavioral, and
psychosocial.  It is important to describe the changes that occur in
the endogenous opioid system, neuroendocrine system, and other
neuronal systems in patients throughout all stages of the addictive
process, including protracted abstinence, response to treatment,
recovery, and long-term cognitive, perceptual, motor, or other
deficits resulting from drug abuse.  HIV-positive subjects or AIDS
patients might be special populations in such applications.

Studies evaluating the relationship between drug seeking behavior and
preexisting neurological deficits, particularly hypofrontality and
attention deficit hyperactivity disorders, or the comorbidity of drug
use and of other mental disorders, especially depression,
schizophrenia, anti-social personality, or AIDS-related dementia, are
also encouraged.  Research investigating the relationship between
drug abuse and development of various neurological disorders such as
Parkinson's disease, Alzheimer's disease, etc., is also of interest.

Since many drug addicts are polydrug abusers, studies to investigate
the neurological, neurochemical, pharmacological, pathological, and
psychological consequences of interactions among abused drugs, such
as cocaine, heroin, alcohol, nicotine, marijuana, anabolic steroids,
and inhalants, are also encouraged.

SPECIAL REQUIREMENTS

The exploratory/developmental grant (R21) and small grant (R03)
applications are limited to two years, are non-renewable, and are
limited in direct cost amount per year (R03, $50,000; R21, $90,000).
The R03 mechanism is intended for new, inexperienced investigators
and both are intended for established investigators exploring new
areas or departing from their usual research topics.  There are
special requirements for these mechanisms.  An applicant intending to
apply for them under this RFA should contact the program person
listed under INQUIRIES for further information.

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 new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990. The new policy contains some new
provisions that are substantially different from the 1990 policies.

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
reprinted in the NIH Guide for Grants and Contracts of March 18,
1994, Volume 23, Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed below.  Program staff may also
provide additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by April 3, 1995, a
letter of intent that includes a descriptive title of the proposed
research, the proposed mechanism of support, the name, address, and
telephone number of the Principal Investigator, the identities of
other key personnel and participating institution, and the number and
title of this RFA.  Although a letter of intent is not required, is
not binding, and does not enter into the review of subsequent
applications, the information that it contains allows NIDA staff to
estimate the potential review workload and to avoid conflict of
interest in the review.

The letter of intent is to be sent to:

Director
Office of Extramural Program Review, NIDA
5600 Fishers Lane, Room 10-42
Rockville, MD  20857
Telephone:  (301) 443-2755
FAX:  (301) 443-0538

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research, and may be obtained from
the Office of Grants Information, Division of Research Grants,
National Institutes of Health, Westwood Building, Room 240, Bethesda,
MD 20892, telephone 301-435-0714.

FIRST award (R29) applications must include at least three sealed
letters of reference attached to the face page of the original
application.  FIRST award applications submitted without the required
number of reference letters will be considered incomplete and will be
returned without review.

The RFA label in the PHS 398 must be affixed to the bottom of the
original face page.  Failure to use the RFA label could result in
delayed processing of the application such that it may not reach the
review committee in time for review.  In addition, the RFA title and
number must be typed in Item 2a on 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 three signed photocopies in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to:

Director
Office of Extramural Program Review
National Institute on Drug Abuse
5600 Fishers Lane, Room 10-42
Rockville, MD  20857

Applications must be received by May 9, 1995.  If an application is
received after that date will be held for the next regular receipt
date and reviewed under standard circumstances.  However, it will not
be considered as a response to this RFA.  The Division of Research
Grants (DRG) will not accept any application in response to the RFA
that is essentially the same as one currently pending initial review,
unless the applicant withdraws the pending application.  The DRG will
not accept any application that is essentially the same as one
already reviewed.  This does not preclude the submission of
substantial revisions of applications already reviewed, but such
applications must include an introduction addressing the previous
critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the
Division of Research Grants (DRG) and responsiveness by NIDA.
Incomplete applications will be returned to the applicant without
further consideration.  If the application is not responsive to the
RFA, the applicant may be contacted to determine whether to return
the application to the applicant or submit it for review in
competition with unsolicited applications at the next review cycle.

Applications that are complete and responsive to the RFA will be
evaluated for scientific/technical merit by an appropriate peer
review group convened by NIDA in accordance with the review criteria
stated below.  As part of the initial merit review, a triage will be
used by the initial review group in which applications will be
determined to be competitive or non-competitive based on their
scientific merit relative to other applications received in response
to this RFA.  Applications determined to be non-competitive will be
withdrawn from further consideration and the Principal Investigator
and the official signing for the applicant organization will be
notified.

Review Criteria

o  scientific, technical or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research; and

o  Adequacy of plans to include both genders and 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 initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.

AWARD CRITERIA

The anticipated date of award is September 30, 1995.  Applications
recommended for further consideration by the NIDA Advisory Council
will be considered for funding on the basis of overall scientific and
technical merit of the application as determined by peer review,
appropriateness of budget estimates, program needs and balance,
policy considerations, adequacy of provisions for the protection of
human subjects, and availability of funds.  Special award criteria
apply to R03 and R21 mechanisms.  Applicants should contact the
program person listed under INQUIRIES.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Harold W. Gordon, Ph.D. or Arthur Horton, Ph.D.
Division of Clinical and Services Research
National Institute on Drug Abuse
5600 Fishers Lane, Room 10A-38
Rockville, MD  20857
Telephone:  (301) 443-4877
Email:  hgordon@aoada.ssw.dhhs.gov

Direct inquiries regarding fiscal or grants management issues to:

Chief, Grants Management Branch
National Institute on Drug Abuse
5600 Fishers Lane, Room 8A-54
Rockville, MD  20857
Telephone:  (301) 443-6710
Email:  gfleming@aoada.ssw.dhhs.gov

The National Institute of Mental Health is not participating in this
RFA, but continues to fund research in the area of basic human
neuroscience through the unsolicited grant application process.  For
more information contact:

Dr. Israel Lederhendler
Systems Neuroscience Program
National Institute of Mental Health
5600 Fishers Lane, Room 11-102
Rockville, MD  20857
Telephone:  (301) 443-1576
FAX:  (301) 443-4822

AUTHORITY AND REGULATIONS

This program is described in the Catalogue of Federal Domestic
Assistance No. 93.279.  Awards are made under authorization of the
Public Health Service Act, Section 301, and administered under PHS
grants 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."  Title
42 CFR Part 2, "Confidentiality of Alcohol and Drug Abuse Patient
Records" may also be applicable to these awards.  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 recipients to provide a smoke-
free workplace and promote the non-use of all tobacco products.  This
is consistent with the PHS mission to protect and advance the
physical and mental health of the American people.

.

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