Full Text DA-94-003

HUMAN BASIC AND CLINICAL NEUROSCIENCE OF DRUG ADDICTION

NIH GUIDE, Volume 23, Number 3, January 21, 1994

RFA:  DA-94-003

P.T. 34

Keywords: 
  Addiction 
  Neuroscience 
  Neurophysiology 
  Etiology 
  Brain 


National Institute on Drug Abuse

Letter of Intent Receipt Date:  March 12, 1994
Application Receipt Date:  April 12, 1994

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 has 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 grant applications 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.  These
applications may establish integrated, multidisciplinary imaging
programs in which basic and clinical studies are conducted in humans,
or the applications may request support for smaller studies.

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
non-profit, public and private organizations, e.g., colleges,
universities, hospitals, laboratories, units of State and local
government, and eligible agencies of the Federal government.
Applications from minority individuals and women are encouraged.
Foreign institutions are not eligible for the program project (P01)
or center grant (P50) awards.

MECHANISMS OF SUPPORT

Support mechanisms include research project grants (R01), program
projects (P01), center grants (P50), and small grants (R03).
Investigators may also respond to this RFA under the Interactive
Research Project Grant Program (IRPG), which utilizes the R01
mechanism.  If an investigator wishes to respond under an IRPG,
additional requirements must be met as described in PA-93-078.
However, if the IRPG mechanism is used under this RFA, this RFA
deadline receipt date takes precedent over the IRPG special receipt
date.  Most investigator-initiated research is supported by research
project grants (R01).  Research grants are awarded to institutions on
behalf of Principal Investigators who have designed and will direct a
specific project or set of projects.  Research project grants can be
renewed at intervals or supplemented through the formal submission
and review process described below. Investigator(s) may apply for a
renewal (competing continuation) of R01 grants by submitting an
application for further support, including a report of progress and
including specific plans for future work.  Applications for competing
supplements to expand the scope of already-awarded grants that
utilize the R01, P01, or P50 mechanism to include human neuroscience
may be submitted.

FUNDS AVAILABLE

It is anticipated that approximately $10 million will be available to
support the first year of the human neuroscience research program.
Because the nature and scope of the research proposed in response to
this RFA may vary, the size of an award will vary also.  However, it
is anticipated that approximately 20 new awards will be made under
this announcement.

RESEARCH OBJECTIVES

This research program is intended to support (1) individual research
project grants on basic and clinical human neuroscience and (2) the
establishment of human neuroscience research centers (HNRCs) to
conduct interdisciplinary research on the human neuroscience of drug
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.

Human neuroscience research within an HNRC should involve the
systematic development and integration of knowledge derived from a
variety of sources, and should utilize a number of designs.  The
proposed research must be organized around a central theme.  The
theme of the HNRC should clearly relate to investigating the human
neuroscience of drug addiction.

Both individual research project grants and HNRCs 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 mental conditions;

(2) examine the neurobiological factors that contribute to
vulnerability to drug abuse;

(3) examine the CNS status of patients during diagnosis and treatment
for drug dependency disorders.

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
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.

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 that attempt to provide resolution at
the cellular level.

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, youths, and
minority populations.  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:  (l) 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; (2) identify the type and distribution of the
biomedical consequences of abusing drugs because of
as-yet-unidentified neurobiological predispositions; (3) assess the
prevalence, distribution, and epidemiology of biobehavioral risk
factors underlying the vulnerability to abuse drugs.  This might
include investigations of the role of stress in vulnerability to drug
addiction (e.g., links between post traumatic stress disorders and
drug seeking behaviors); and (4) 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 proposals 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.

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, and anti-social personality, are also encouraged.
Research investigating the relationship between drug abuse and
development of various neurological disorders such as Parkinson
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,
inhalants, etc., are also encouraged.

SPECIAL REQUIREMENTS

There are special requirements for the center grant (P50), program
project (P01), and small grant (R03) applications.  If an applicant
intends to apply under this RFA utilizing either of those support
mechanisms, they may contact the program person listed under
INQUIRIES for further information.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
both genders in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder, or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale for exclusion or inadequate representation
should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objective of
the study.  This information should be included in the form PHS 398
in Sections 1-4 of the Research Plan AND summarized in Section 5,
Human Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However,
NIH recognizes that it may not be feasible or appropriate in all
research projects to include representation of the full array of the
United States racial/ethnic minority populations (i.e., American
Indian or Alaskan Natives, Asians or Pacific Islanders, Blacks,
Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply. Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by March 12, 1994, 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 institutions, 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 is 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
National Institute on Drug Abuse
5600 Fishers Lane, Room 10-42
Rockville, MD  20857
Telephone:  (301) 443-2755

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.

The RFA label in the application form PHS 398 must be affixed to the
bottom of the original face page.  Failure to use the RFA label and
to follow instructions 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 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 April 12, 1994, and will be reviewed
according to the following review schedule:

Application Receipt Date:  April 12, 1994
Initial Review:            July 1994
Advisory Council Review:   September 1994
Earliest Award Date:       September 1994

R01, P01, R03, or IRPG applications received after the receipt date
will be held for the next regular receipt date and reviewed under
standard circumstances.  However, they will not be considered as a
response to this RFA.  P50 applications received after the above
receipt date will be returned to the applicant without review.

REVIEW CONSIDERATIONS

The Division of Research Grants, NIH, serves as a central point for
receipt of applications for most discretionary DHHS grant programs.
Applications received under this RFA will be assigned to a special
review group convened by NIDA.  The review group, consisting of
experts in basic and clinical human neuroscience research, as
warranted by the applications, will review the applications for
scientific and technical merit in accordance with the standard NIH
peer review procedures.  Pre-review site visits will not be made, and
applications will not be deferred for site visit; therefore,
applications must be complete when submitted.  Notification of the
review recommendations will be sent to the applicant after the
initial review.

Those applications that are complete and responsive will be evaluated
in accordance with the appropriate criteria for scientific/technical
merit by a peer review group convened by NIDA.  Applications may be
triaged by an NIDA-convened peer review group according to scientific
merit relative to other applications received in response to this
RFA.  Those applications judged to be competitive will be evaluated
further for scientific/technical merit by the usual peer review
procedures.  Following this review, the applications will be given a
secondary review by the National Institute on Drug Abuse Advisory
Council unless not recommended for further consideration by the
initial review group.

AWARD CRITERIA

The anticipated date of award is September 30, 1994.

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.  Where appropriate, funding for the HNRC applications will
also be considered on the basis of demonstrated capacity to recruit
evaluable patients and submit acceptable data in appropriate time
frames to permit optimal analysis of results.

INQUIRIES

Written and telephone 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:

Christine R. Hartel, Ph.D.
National Institute on Drug Abuse
5600 Fishers Lane, Room 10A-31
Rockville, MD  20857
Telephone:  (301) 443-1887

Direct inquiries regarding fiscal or grants management issues to:

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
5600 Fishers Lane, Room 8A-54
Rockville, MD  20857
Telephone:  (301) 443-6710

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.

.

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