Full Text DA-93-001


NIH GUIDE, Volume 21, Number 31, August 28, 1992

RFA:   DA-93-001
      (previously DA-93-01)

P.T. 34

  Drugs/Drug Abuse 

National Institute on Drug Abuse


The Medications Development Division of the National Institute on Drug
Abuse (NIDA) invites the submission of research applications to develop
innovative preclinical (nonhuman) methods for the identification of
potential treatment agents for the entire spectrum of cocaine abuse,
from pre-addiction through abstinence, relapse, and recovery.  The
methods may be based on behavioral, neurophysiological, neurochemical,
or other approaches as long as a strong case is made that they will be
relevant to human cocaine abuse and its pharmacologic treatment.  These
methods should be novel, or they should expand other underdeveloped or
unrecognized methods as tools for evaluating pharmacotherapies for drug
abuse disorders.


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), Development of Innovative Methods to Identify
Medications for Treating Cocaine Abuse, is related to the priority area
of health promotion (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 20492-9325 (telephone 202-783-3238).


Applications may be submitted by foreign and domestic, non-profit and
for-profit, public and private organizations such as universities,
colleges, hospitals, laboratories, research institutions, units of
State and local governments, and eligible agencies of the Federal
Government.  Applications from minority individuals and women are
encouraged.  Foreign applicants are not eligible for First Independent
Research Support and Transition (FIRST) Awards (R29).


Support mechanisms include Research Projects (R01) and the FIRST award
(R29).  Most investigator-initiated research is supported by
independent research grants (R01).  A research grant is awarded to an
institution on behalf of a Principal Investigator (PI) who has designed
and will direct a specific project or set of projects.  For information
on the special requirements of the FIRST awards, please contact the
program staff listed at the end of the announcement.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all investigator-initiated
applications and be reviewed according to the customary peer review


Applications submitted in response to this announcement will compete
for approximately $1,000,000 that has been made available for this
purpose in Fiscal Year 1993.  It is expected that approximately four to
five grants will be supported.  This level of support is dependent on
the receipt of a sufficient number of applications of high scientific
merit.  Although this program is provided for in the financial plans of
the NIDA, awards pursuant to this RFA are contingent upon the
availability of funds for this purpose.



Several behavioral models of drug abuse have been useful in studying
important variables in the laboratory.  Perhaps the most widely
recognized of these is the self-administration model in which an animal
presses a lever to inject an abused drug intravenously.  This
methodology has been an invaluable research tool in many ways,
especially in the preclinical evaluation of the abuse potential of

The drug discrimination model is a second method that has proven
useful.  In this method, an animal is trained, on the basis of internal
(interoceptive) cues, to make one response when a particular drug is
injected and to make a different response when a different drug (or
placebo) is injected.  This procedure has proved valuable in assessing
the subjective effects (e.g., the "high") of cocaine, as well as the
likelihood that an unknown compound produces a similar interoceptive

Little is known about the predisposing factors involved in drug-seeking
behavior in humans or in the animal models that are used to study this
human trait.  Furthermore, these models (when they are available) are
limited in that they may apply only to a particular phase of cocaine
abuse.  For example, the self-administration model may be predictive of
the drug-seeking portion of addictive behavior.  But having an animal
in a cage pressing a lever for a drug reinforcement may not be
predictive of an individual on a street corner considering whether or
not to take cocaine.  Furthermore, there are no models of pre-addictive
use in which the individual administers cocaine frequently but
nondependently.  This lack of a preclinical method restricts the study
of the variables that may cause escalation to drug dependence.  Thus,
it is difficult to identify a new medication that may be useful in this
early phase of drug abuse.

Just as there are no models of pre-addiction to study factors that may
engender the acquisition of drug abuse, there are no validated methods
to represent the recovery phase following treatment in which the addict
is striving not to avoid relapse to drug use.  This lack of suitable
methods restricts the study of variables that contribute to relapse.
Even though clinicians who treat drug abuse maintain that relapse
prevention is the most important and the most difficult phase of drug
abuse treatment, there is no model for "slips" or relapses.

The presently available methodology (self-administration, cocaine
discrimination) has not proven useful in identifying and developing new
chemical entities that are useful in the clinics to combat cocaine
abuse.  The lack of a set of laboratory methods to study the phases of
cocaine abuse from pre-addiction through recovery limits the
identification and development of new medications that may be useful in
treating cocaine abuse.  For the identification and development of a
wider range of medications, the selection and development of new
methods relevant to a broader spectrum of drug abuse, especially
cocaine abuse, will be an important advance.

Methods to study compounds that may be potentially useful in combatting
drug abuse via brain reward mechanisms have not been adequately
developed.  The areas of the brain that probably mediate reward
(nucleus accumbens, striatum, prefrontal cortex) have been identified.
It appears that, in terms of modern neurophysiological and
electrophysiological methodologies, research has not focused on the
discovery of potential pharmacotherapies.  One such example is the in
vivo microdialysis technique, in which extracellular levels of
neurotransmitters can be monitored in brain areas of freely moving
animals.  Thus, the development and application of neurophysiological
methods to identify useful treatment agents are needed.

Areas of Interest

The areas of research interest that may be funded include those that
are innovative, that develop new methods of drug discovery for cocaine
abuse pharmacotherapies, and that will advance the development of a new
medication for the treatment of cocaine abuse.  In general, these may

o  an innovative behavioral model of craving that does not employ the
standard self-administration paradigms;

o  models of behavioral toxicity that look at attenuation of important
adverse effects of cocaine through a new approach;

o  techniques to study post-addictive behavior as experimental models
of recovery and possible relapse;

o  neurophysiological techniques which utilize the putative underlying
mechanisms of cocaine abuse to identify new medications; and

o  electrophysiological methods which will identify and develop new
pharmacotherapeutic agents.

These areas of research interest are not intended to be all-inclusive.
However, experimental animal models to develop therapeutic
interventions for cocaine abuse are extremely limited.  Therefore, a
major research effort is required to design creative approaches to
expand the current methods and models to those that have not been
explored.  Well-known models of drug abuse to study cocaine are of
interest only insofar as their application constitutes an innovative
approach.  It is anticipated that no single method will be definitive.
It is anticipated that both behavioral and non-behavioral techniques
will be identified and developed.


This RFA is targeted for preclinical studies in intact non-human
species, including rodents and monkeys, as well as cell preparations
from non-human sources.  The PHS Policy on Humane Care and Use of
Laboratory Animals by Awardee Institutions requires that applicant
organizations establish and maintain appropriate policies and
procedures to ensure that humane care and use of live vertebrates
involved in research, research training, and biological testing
activities supported by PHS.  All institutions are required to comply,
as applicable, with the Animal Welfare Act as amended (7 USC 2131 et
sec.).  These documents are available from the Office for Protection
from Research Risks (OPRR), National Institutes of Health, Bethesda, MD

An applicant organization proposing to use vertebrate animals in
PHS-funded studies must file an Animal Welfare Assurance Form with
OPRR.  As part of the Assurance, which commits the applicant
organization to comply with PHS policy, the applicant organization must
appoint an Institutional Animal Care and Use Committee (IACUC) which is
required to review and approve those sections of application for PHS
support that involve vertebrate animals.  IACUC approval should be
submitted at the time of application for studies that involve animal

If animal subjects will be involved at sites other than the applicant
organization, the applicant must identify, within the application, the
assurance status of each participant and must arrange the appropriate
certifications and verifications.


Applicants are to use the grant application form PHS 398 (rev. 9/91).
The number and abbreviated title of this RFA, DA-93-01, "METHODS TO
item number 2a on the face page of the PHS 398 application form.

Applicants must affix the RFA label available in the 398 application to
the bottom of the face page.  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.

Application kits containing the necessary forms and instructions for
regular research grants may be obtained from business offices or
offices of sponsored research at most universities, colleges, medical
schools, and other major research facilities.  If such a source is not
available, the following office may be contacted for the necessary
application material:

Division of Research Grants
Office of Grants Inquiries
Westwood Building, Room 449
Bethesda, MD  20892
Telephone:  (301) 496-7441

Submit a signed, typewritten original of the application, including the
Checklist, and four photocopies, and for R29 applicants, three letters
of reference, in one package, to:

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

At the time of submission, one additional copy of the application
should also be sent to:

Heinz Sorer, Ph.D.
Medications Development Division
National Institute on Drug Abuse
Parklawn Building, Room 11A-55
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-6270

Applications must be received by the special receipt date of December
11, 1992.  Applications received after date will be returned to the
applicant without review.  The receipt and review schedule follows:

                  Initial           Advisory Council   Earliest Award
Receipt Date      Review                 Review             Date

Dec 11, 1992      Feb/Mar 1993      May 1993           Jun 1993

The Division of Research Grants (DRG) will not accept any application
in response to this announcement that is essentially the same as one
currently pending initial review.  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 conform to
the requirements for revised applications in the Form PHS 398


The Division of Research Grants serves as a central point of receipt of
applications for most discretionary PHS grant programs.  Applications
received under this announcement will be assigned to an initial review
group in the NIDA.  The review group, consisting primarily of
non-Federal scientific and technical experts, will review the
applications for scientific and technical merit.  Notification of the
review recommendations will be sent to the applicant after this initial
review.  Applications will receive a second-level review by the
National Advisory Drug Abuse Council whose review may be based on
policy considerations as well as scientific merit.  Only applications
recommended for further consideration by the Council may be considered
for funding.


Criteria for scientific/technical merit review of the applications will
include the following:

o  Relevance of objectives to the goal of this program as stated in
this RFA including:

a) Is the method innovative?
b) Is the method workable as either a screening technique or as an
evaluation technique?
c) Will the method identify potential treatment agents?

o  Adequacy of the research design and methodology;

o  Applicability of the project to clinical situations covering
specific aspects of the addictive process from pre-addiction through
craving, abstinence, relapse, and recovery;

o  Potential contribution to the development of medications to treat
cocaine abuse;

o  Demonstrated scientific expertise of the PI and other key personnel;

o  Availability of adequate facilities, other resources, and
collaborative arrangements necessary for the research; and

o  Appropriateness of budget estimates for the proposed research


Award criteria include:

o  Availability of funds;

o  Potential contribution to the medications development program;

o  Overall scientific and technical merit as determined by peer review;

o  Needs and balances of the medications development portfolio;

o  Relevance to program goals and objectives, as stated in this RFA

o  Preference in funding under this RFA will be given to applications
for innovative methods to identify medications for treating cocaine
abuse.  Applications relevant to abused drugs other than cocaine may be
submitted and considered under the NIDAs general program announcement.


Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify and issues or questions from potential
applicants is encouraged.

Direct inquiries regarding programmatic issues to:

Heinz Sorer, Ph.D.
Medications Development Division
National Institute on Drug Abuse
Parklawn Building, Room 11A-55
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-6270

Direct inquiries regarding fiscal matters to:

Shirley A. Denney
Chief, Grants Management Branch
National Institute on Drug Abuse
5600 Fishers Lane, Room 8A-55
Rockville, MD  20857
Telephone:  (301) 443-6710


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, Section 301 and 515 (42 USC 241 and 290cc)
and administered under PHS grants policies and Federal Regulations 42
CFR 92 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.


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