Full Text PA-95-089


NIH GUIDE, Volume 24, Number 33, September 22, 1995

PA NUMBER:  PA-95-089

P.T. 34

  Drugs/Drug Abuse 

National Institute on Drug Abuse


Rapid advances in brain imaging, neurophysiological assessment, and
genome analysis have made feasible the study of biological etiology
of drug abuse, dependency, and addiction.  New technology has also
facilitated assessment of the biomedical and biobehavioral
consequences, as well as the effects of treatment of drug abuse
disorders.  The National Institute on Drug Abuse (NIDA) is supporting
a major neuroscience initiative that targets newly developing
technologies designed for study of human subjects, autopsy material,
or, in appropriate circumstances, animal models.  The goal is to
better understand the etiology and neurobiological consequences of
drug abuse and addiction in order to design novel preventive,
diagnostic, and treatment strategies.  NIDA invites applications to
use current, or to develop new, noninvasive techniques to assess
neuroanatomical, neurophysiological, neurochemical, or functional
differences in human brain that (1) result from consequences of drug
use; (2) indicate individuals' vulnerabilities (or resistances) to
initiate and escalate drug use into abuse, dependence or addiction;
or (3) result from pharmacological or non- pharmacological treatment.
Applications are also encouraged to establish integrated,
multidisciplinary programs that include both basic research and
clinical studies.


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 program
announcement, 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 202-512-1800).


Applications may be submitted by foreign and domestic, for-profit and
non-profit, public and private organizations, such as colleges,
universities, hospitals, laboratories, units of State and local
government, and eligible agencies of the Federal Government.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.
Foreign institutions are not eligible for Program Project (P01)
grants or the First Independent Research Support and Transition
(FIRST) (R29) award.


Support mechanisms are the research project grant (R01), program
project grant (P01), FIRST Award (R29), exploratory/developmental
grant (R21) and small grant (R03).

Awards made under the R29, R03,or R21 mechanism may not be renewed,
but it is expected that projects supported by these mechanisms will
provide sufficient data to apply for support of a research project
grant (R01).  There are special requirements and review criteria for
the program project (P01), FIRST (R29), small grant (R03), and
exploratory/developmental (R21) grant applications.  The FIRST award
is intended for investigators at the beginning of their careers who
have not been previously designated a principal investigator on any
PHS research project (except R03).  The small grant award (R03) is
intended for new or established investigators beginning in a new
area. The exploratory/developmental grant (R21) is intended for
investigators to apply experience and sound methodology from other
scientific areas to drug addiction research.  If an applicant intends
to apply utilizing any of these mechanisms, he or she should contact
the program person listed under INQUIRIES for further information.


The objective of this program announcement is to initiate a major,
NIDA-wide research program that supports individual research grants
on the basic and clinical human neuroscience of drug abuse and
addiction.  Research using animals is not excluded, but animal use in
projects should be construed as preliminary steps leading directly to
follow-up research in humans.

Individual research project grants funded under this program
announcement may conduct research that uses various imaging or other
innovative technologies to:

(1) elucidate in humans the basic neurobiological mechanisms of
action of drugs of abuse, including interaction with other drugs and
mental conditions;

(2) examine the neurobiological factors that contribute to or
counteract vulnerability to drug abuse and addiction;

(3) evaluate the CNS status of patients during diagnosis, and the
changes of CNS status during and following treatment for drug
dependency disorders.

1.  Basic Human Neuroscience

The main goals of the basic research supported through this
initiative are: (1) to identify in humans the neuronal systems
involved in mediating the pleasurable or positive experiences
associated with substance abuse; (2) to characterize in humans the
neurochemical, neuroanatomical, and neurophysiological changes that
underlie states of drug tolerance, dependence, addiction, withdrawal,
and craving; and (3) to characterize the reversible and irreversible
brain changes that result from drug abuse and addiction.

Investigators are invited to study the effects of substance abuse on
the structure and function of the human brain using various
technologies (e.g., ligand PET scanning, functional magnetic
resonance imaging, magnetic source imaging, electroencephalography,
magnetic resonance spectroscopy) in living or autopsy tissue.

Investigators are encouraged to use in drug abuse research the
rapidly advancing imaging techniques that can elucidate the basic
mechanisms of neuronal activity associated with the biological action
of drugs.  Studies could establish the mathematical relationships
between blood flow, metabolism, and cellular activity, or studies
could provide greater levels of refinement for viewing anatomical
structures.  Research to improve technology in chemistry is necessary
to support advances in brain imaging.  For example, novel imaging
reagents could be synthesized for use in humans, or imaging
technologies could be applied to pharmacokinetics.

This initiative is also intended to encourage investigators to
verify, in humans, the key observations made in animal studies that
substance abuse produces long-lasting changes in neurochemical
markers and morphological features of specific populations of
neurons.  Such studies could 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.  The effects of drugs of abuse on
neurochemical markers could be assayed in postmortem human brain
tissue samples.

Of particular interest are studies that 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 suggest how
drug-induced alterations might lead to and maintain drug- seeking
behavior and addiction.  Also important are studies assessing brain
function during the withdrawal period and subsequent abstinence.
This information should be helpful in understanding the neural
substrates involved in drug craving as well as in assessing various
aspects of neural plasticity and recovery of function.

2.  Vulnerability and Etiological Investigations

In humans, neurobiological factors that underlie a vulnerability to
abused drugs or cause certain individuals to suffer adverse health
consequences after ingesting psychoactive substances are not
currently defined.  Projects could develop new information about how
individual differences in neurobiological profiles, genetics, or
psychological behaviors of an individual predict or, alternatively,
protect from, drug abuse and addiction.  Existing technologies and
methodologies for studying the neurobiological risk factors of drug
abuse and addiction could be modified and developed.

Investigators are strongly encouraged to make use of techniques to:
(l) examine factors contributing to the biomedical and biobehavioral
etiology of drug abuse and addiction;  (2) identify the type and
distribution of the biomedical consequences of abusing drugs because
of as-yet-unidentified neurobiological predispositions; and (3)
assess CNS activity associated with biobehavioral risk factors
underlying the vulnerability to abuse drugs.

To achieve these goals, studies could evaluate genetic,
developmental, and environmental factors, or the interaction of these
factors, in drug addiction, including nutritionally and
environmentally toxic elements, or, for a more specific example,
examine the neurobiological relationship between early use of
alcohol, tobacco, or marijuana and later development of cocaine and
heroin addictions.  These goals might include investigations of the
role of stress and/or childhood abuse (psychological, sexual, or
physical) in vulnerability to drug addiction (e.g., links between
post-traumatic stress disorders and drug-seeking behaviors).
Finally, NIDA is also interested in research on neurobiological
aspects of drug abuse and addiction that might be unique to special
groups, such as women, youths, and minority populations.  Studies are
strongly encouraged that employ designs that will permit direct
assessment of gender, age, ethnicity, or other differences in these
populations of drug abusers.

3.  Clinical and Treatment Neuroscience

Researchers are encouraged to submit applications that utilize
state-of-the-art brain imaging, analytical neurochemistry,
electrophysiology, genetic analysis, neuropsychological assessment,
and other technologies to elucidate CNS status of patients during
diagnosis and various stages of treatment of drug dependency
disorders.  For example, studies could examine neurotransmitter
metabolites appearing in blood and cerebrospinal fluid as
neurochemical markers for diagnosis, as correlates of mood and
behavior, or as predictors of clinical outcome. Furthermore, studies
are encouraged that assess metabolic changes in response to
pharmacological, behavioral, and psychosocial treatment
interventions.  It is important to describe the long-term cognitive,
perceptual, motor, or other deficits as well as 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, and response to

Studies are encouraged that evaluate the relationship between
drug-seeking behavior, craving, 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, and
anti-social personality.  Research investigating the relationship
between drug abuse/addiction and development and progression of
various neurological disorders, such as Parkinson's disease,
Alzheimer's disease, and AIDS-related neurological disease, is also
of interest.  New research is needed to investigate the interactive
neurobiological and sociological causes and/or consequences of drug
use/abuse with criminal, violent, or aggressive behavior.  Also,
since many drug addicts are polydrug abusers, studies to investigate
the neurological, neurochemical, pathological, pharmacological, and
psychological consequences of interactions among abused drugs, such
as cocaine, heroin, amphetamines, hallucinogens, alcohol, nicotine,
marijuana, anabolic steroids, and inhalants, are also encouraged.


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.


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 Office of Grants Information, Division of
Research Grants, National Institutes of Health, 6701 Rockledge Drive,
Room 1040 - MSC 7710, Bethesda, MD 20892-7710, (301/710-0267), email:
girg@drgpo.drg.nih.gov.  The title and number of this program
announcement must appear in Item 2 on the face page of the

FIRST applications must include at least three sealed letters of
reference attached to the Face Page of the original application.
FIRST applications submitted without the required number of reference
letters will be considered incomplete and will be returned without

Small Grant (R03) awards are limited in the number of pages in the
narrative description in the application, and in time and amount.
Exploratory/Developmental grant awards are also limited in time and

The completed original application and five legible copies must be
sent or delivered to:

6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD 20817-7710 (for courier/overnight service)


Applications that are complete will be evaluated for scientific and
technical merit by an appropriate peer 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 the applications under review, will be discussed, assigned a
priority score and receive a second level review by the appropriate
national advisory council or board.  Small grants receive a second
level review by NIH staff.

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 experience of the Principal Investigator and
staff, particularly, but not exclusively, in the area of the proposed

o  availability of the resources necessary to perform the research;

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

o  adequacy of the plans to include both genders and minorities and
their subgroups as appropriate for the scientific goals of the

Additional review criteria are used for program projects (P01), FIRST
Awards (R29), and exploratory/developmental grants (R21).

The initial review group will also examine the provisions for the
protection of human and animal subjects, and the safety of the
research environment.


Applications will compete for available funds with all other approved
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.


Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Joseph Frascella, Ph.D.
Division of Clinical and Services Research
National Institute on Drug Abuse
Parklawn Building, Room 10A-46
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-4877
FAX:  (301) 443-2317
Email:  jfrascel@aoada.ssw.dhhs.gov

Roger Brown, Ph.D.
Division of Basic Research
National Institute on Drug Abuse
Parklawn Building, Room 10A-19
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-6975
Email:  rbrown1@aoda.ssw.dhhs.gov

Direct inquiries regarding fiscal or grants management issues to:

Gary Fleming, J.D., M.AS,
Grants Management Branch
National Institute on Drug Abuse
Parklawn Building, Room 8A-54
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-6710
FAX:  (301) 594-6847
Email:  gfleming@aoada.ssw.dhhs.gov


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, 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 at Title 42 CFR 52,
"Grants for Research Projects," and 45 CFR Part 74, "Administration
of Grants".  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency

The 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 serves
are provided to children.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American


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