Full Text DA-98-001
 
NEUROBIOLOGICAL SUBSTRATES OF COGNITIVE FUNCTIONING IN DRUG ADDICTION
 
NIH GUIDE, Volume 25, Number 38, November 8, 1996
 
RFA:  DA-98-001
 
P.T. 34

Keywords: 
  Addiction 
  Drugs/Drug Abuse 

 
National Institute on Drug Abuse
 
Letter of Intent Receipt Date:  May 13, 1997
Application Receipt Date:  June 13, 1997
 
PURPOSE
 
The National Institute on Drug Abuse (NIDA) invites applications for
research projects on the neural substrates of the addictive process
relating to cognitive brain functions.  Powerful new approaches are
now available for exploring brain mechanisms underlying cognitive
functions as well as the addictive process and/or its consequence.
The purpose of this initiative is to encourage the use of these
approaches to broaden our understanding of the relation of drug abuse
and addiction with brain mechanisms underlying cognition.  The
results obtained from these studies should ultimately guide the
development of improved drug abuse prevention and treatment
strategies by identifying the brain circuits and neurobiological
mechanisms specifically affected in addiction disorders.
 
This Request for Applications (RFA) will support individual research
project grants and mentored career development awards. Research
proposals for projects exploring the physiological, chemical, and
structural modifications in the brain associated with cognitive
functioning in drug addiction will be considered.
 
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 RFA,
Neurobiological Substrates of Cognitive Functions in Drug Abuse
Disorders, is related to the priority area of alcohol and other
drugs.  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 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.
Foreign institutions are not eligible for FIRST Independent Research
Support and Transition (FIRST) (R29) awards.
 
MECHANISM OF SUPPORT
 
This RFA will use the National Institutes of Health (NIH) research
project grant (R01), exploratory/developmental grant (R21), small
grant (R03), and FIRST Award (R29), as well as Mentored Research
Scientist Development Award (K01) and Mentored Clinical Scientist
Development Award (K08) mechanisms.  Most investigator-initiated
research is supported by the research project grant (R01) mechanism.
Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  The total
project period for an application submitted in response to this RFA
may not exceed 5 years.  The anticipated award date is around April
1, 1998.
 
The R29, K01, and K08 applications submitted in response to this RFA
should use the Just-In-Time (JIT) submission procedures.  These
procedures were published in the NIH Guide, Volume 25, Number 10,
March 29, 1996 with additional instructions published in Volume 25,
Number 16, May 17, 1996.  Copies of these two NIH Guide notices are
available from the contact person listed under INQUIRIES and on the
NIH (www.nih.gov) or NIDA (www.nida.nih.gov) Home Pages.
 
The exploratory/developmental grants (R21), small grants (R03), FIRST
Awards (R29), the mentored research scientist development awards
(K01) and the mentored clinical scientist development awards (K08)
have special requirements and criteria.  Applicants intending to
apply utilizing these mechanisms, are
urged to contact the program person listed in INQUIRIES for further
information.
 
This RFA is an one-time solicitation.  Future unsolicited competing
continuation applications will compete with all
investigator-initiated applications and will be reviewed according to
the customary peer-review procedures.
 
FUNDS AVAILABLE
 
It is anticipated that approximately $1.5 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. However, it is anticipated that
approximately six to eight new awards, ranging in size from $100,000
to $300,000 will be made under this RFA.
 
RESEARCH OBJECTIVES
 
Background
 
Much progress has been made in our understanding of the neural
substrates underlying cognitive functions.  Still, little is known
about the relationship between cognitive processes that are strong,
mediating factors in the drug addiction process (such as craving,
decision-making, euphoria, expectancy of output, impulsivity, learned
associations, reward seeking, and risk assessment) and their precise
neural substrates.  For example, which neural circuits become
modified and are important in the drug addiction process?  How do the
affected neural activities in these drug abuse- and
addiction-associated systems influence normal neural functions in
circuits that are thought to mediate higher brain functions such as
arousal, attention, learning, memory, or even consciousness?
 
Recent data have begun to indicate that several brain loci typically
associated with memory are activated during craving; however, the
relationship between drug-related neural events and those subserving
different types of learning, memory, and/or emotion in these brain
loci remains to be elucidated.  Further, the relationship of these
drug cue-associated alterations to signal processing in other brain
loci mediating specific cognitive functions is also not well
understood.  Similarities and differences among brain activation
patterns, neurochemical events, and structural modifications
resulting from the use of different drugs or from drug use under
different emotional states and/or vigilance levels need to be
investigated.
 
New methodological approaches in basic and clinical neurobiology now
provide researchers the capability to investigate how drugs of abuse
affect the brain and its function, and at the same time allow for the
direct assessment of resultant alterations in cognitive functioning.
This RFA provides the unique opportunity for a synergistic
interaction between the areas of cognitive and addiction neuroscience
in an effort to broaden significantly the understanding of the
neurobiological basis of drug use and addiction.  The principal goal
of the research to be supported by this RFA is to integrate
neurobiological research of addiction with advances in cognitive
neuroscience.  The following examples serve as a guide only and are
not meant to constitute an exhaustive list of the types of research
questions that are appropriate under this initiative.
 
o  Circuits within the brain subserving cognitive processes are
likely to be involved in the development and progression of addictive
disorders.  Which specific brain loci and circuits are affected
during each of the different stages of the addiction process?  What
are the similarities and/or differences in the brain activity
patterns identified in association with drug use behavior compared to
the activity patterns that are associated with normal cognitive
processes?  What neurochemical and/or structural substrates are
associated with these changes in activity within brain areas involved
in cognitive processing?
 
o  Drug abuse and addiction affect normal cognitive functions. Are
the spatial and temporal distributions of normal brain activities
affected by drugs of abuse?  Do drugs of abuse alter neural circuits
such as those involved in risk assessment, decision-making, or
impulsivity?  Are drug-related changes in cognitive brain activities
more marked during certain phases of the drug addiction process?  Do
these changes depend on the continued presence of the drug?
 
o  Clinical studies have begun to identify activity changes in brain
loci associated with shifts in vigilance levels.  To understand more
fully how drug use might impact on learning, memory, and related
cognitive processes, it is important to establish the relationship of
drug-induced altered states with the neural correlates of
wakefulness, drowsiness, and sleep in human and in non-human, primate
subjects.  The influence of factors such as motivation, attention,
emotional state, relaxation, imagery, etc. on the overall
drug-related brain activity level changes is also of interest.  Are
the activation levels of various brain regions (the mesencephalic
reticular formation and the intralaminar thalamus, for example)
coordinated during drug use?  What is the impact of factors such as
emotional state on drug-related activation level changes?
 
o  Drugs such as PCP and LSD (and other hallucinogens) are known to
produce flashbacks, or a recurrence of symptoms like those produced
by the drug long after the drug use experience.  What neural circuits
are involved in this phenomenon?  Marijuana can induce flashbacks in
LSD users.  What is the mechanism by which marijuana can induce
flashbacks in LSD users?
 
o  What can drugs of abuse tell us about normal memory functioning?
Can they provide clues about enhancing memory or reversing the memory
loss associated with dementing disorders such as Alzheimer's disease
or with AIDS?  For example, novel marijuana receptor antagonists have
recently been developed. What are the effects of these compounds on
cognition?  The opiate antagonist naloxone has also been shown to
improve memory performance in several species under a variety of
testing conditions.  Are there other drugs that can be identified
that could lead to therapeutic advances in treating memory loss?
 
o  Cholingeric and glutamatergic pathways in the cortex, limbic
system, basal ganglia, and thalamus are involved in many aspects of
learning, memory, arousal, attention, and sleep, yet little is known
about the actions of drugs of abuse on these systems. Certain drugs
of abuse such as marijuana and PCP have profound effects on memory
and attention and both are thought to impact these two
neurotransmitter systems, though a direct relationship has yet to be
shown.
 
o  Several factors influence individual vulnerabilities to the
addictive process in humans, including emotional states and genetic
makeup.  Are differences in function within brain circuits underlying
cognitive processes related to individual vulnerabilities to the
addictive process?
 
o  Prenatal and/or postnatal exposure to drugs of abuse may influence
the development of cognitive brain processes.  Are
children/adolescents exposed to drugs of abuse different in their
cognitive functioning from children/adolescents unexposed to drugs of
abuse?  Are there any special characteristics in the brain activation
patterns associated with drug-seeking behaviors in age groups at high
risk for drug taking, such as adolescents in their late teens?
 
o  Sex differences may influence susceptibility to addiction
disorders.  Are there differences between males and females in
drug-induced activation patterns in cognitive neural circuits?
 
o  Disruption of cognitive functions is often an early symptom of HIV
infection.  Are the cognitive abnormalities associated with HIV
infection in drug users different from the cognitive abnormalities
associated with HIV infection in non-drug users? What are the
physiological, chemical, and structural modifications in the brain
associated with the cognitive disruptions of AIDS dementia in the
context of drug use?
 
All applications must address issues of project feasibility,
implementation of the study, study design, sampling procedure,
instrumentation and management, data collection, tracking of
subjects, follow-up, and data analysis, as appropriate.
 
Investigators are encouraged to offer HIV testing and counseling in
accordance with current guidelines to subjects identified during the
course of the research as being at risk for HIV acquisition or
transmission.
 
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
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, 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.
 
LETTER OF INTENT
 
Prospective applicants are encouraged to discuss their research plans
with the program staff listed under INQUIRIES. Potential applicantss
are asked to submit, by May 13, 1997, a letter of intent that
includes a descriptive title of the proposed research, 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 the RFA in response to which the application
is to be submitted.  Although a letter of intent is not required, is
not binding, and does not enter into the review of a subsequent
application, the information that it contains allows NIDA staff to
estimate the potential review workload and 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
Parklawn Building, Room 10-42
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-2620
FAX:  (301) 443-0538
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; and from the Grants
Information Office, Office of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC
7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email:
asknih@odrockm1.od.nih.gov.
 
The RFA label available in the PHS 398 application form must be
affixed to the bottom of the face page of the application.  Failure
to use this 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 on
line 2 of the face page of the application form and the YES box must
be marked.
 
FIRST (R29) award applications must include at least three sealed
letters of reference attached to the face page of the original
application.  FIRST (R29) award application submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
 
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
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for courier/overnight mail service)
 
At the time of submission, two additional copies of the application
must be sent to:
 
Director, Office of Extramural Program Review
National Institute on Drug Abuse
Park law Building, Room 10-42
5600 Fishers Lane
Rockville, MD  20857
 
Applications must be received by June 13, 1997.  If an application is
received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not
accept any application in response to this 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 Schedule
 
Letter of Intent Receipt Date:  May 13, 1997
Application Receipt Date:       June 13, 1997
Peer Review Meeting:            October/November 1997
Council Review Meeting:         January 1998
 
REVIEW CONSIDERATIONS
 
Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness by the NIDA.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, DRG staff may contact the
applicant 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 and technical merit by an appropriate peer
review group convened by NIDA in accordance with the review criteria
stated below.
 
REVIEW CRITERIA
 
o  relevance of proposed research to the goals and objectives of this
RFA;
 
o  scientific, technical, or medical significance and impact of the
proposed research;
 
o  creativity, originality, and the degree of synergy of scientific
issues pertaining to the areas of cognitive and addiction
neuroscience in the proposed research;
 
o  appropriateness and adequacy of the experimental approach and
methodology proposed to conduct the research;
 
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
appropriateness of their methodological training and their
demonstrated research skill;
 
o  availability of the resources necessary to perform the research;
 
o  appropriateness of the proposed budget and duration in
relationship to the proposed research;
 
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
 
Award criteria that will be used to make award decisions include:
scientific and technical merit of the proposal as determined by peer
review, availability of funds, program needs and balance, and
adequacy of provisions for the protection of human and animal
subjects.
 
INQUIRIES
 
Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
For inquiries on programmatic issues pertaining to human studies,
contact:
 
Chiiko Asanuma, Ph.D.
Division of Clinical and Services Research
National Institute on Drug Abuse
Parklawn Building, Room 10A-46
Rockville, MD  20857
Telephone:  (301) 443-4877
FAX:  (301) 443-2317
email:  cs2j@nih.gov
 
For inquiries on programmatic issues pertaining to animal studies,
contact:
 
Thomas Aigner, Ph.D.
Division of Basic Research
National Institute on Drug Abuse
5600 Fishers Lane, Room 10A-19
Rockville, MD  20857
Telephone:  (301) 443-6975
FAX:  (301) 594-6443
Email:  ta17r@nih.gov
 
For inquiries on fiscal matters, contact:
 
Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
Parklawn Building, Room 8A-54
Rockville, MD  20857
Telephone:  (301) 443-6710
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 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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