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RFA: Genetics of Alcohol-Related Behavio

Karp, Robert RKARP at willco.niaaa.nih.gov
Wed Dec 14 14:35:54 EST 1994

     Attached is a new RFA from NIAAA on mapping of genes influencing complex 
alcohol-related behavior in rodents.  The intent of this RFA is to encourage 
collaboration between behavioral scientists studying complex behavioral 
traits in rodents which might model human traits predisposing to alcoholism, 
and molecular geneticists with experience in mapping quantitative trait loci 
(QTL).  Potential applicants desiring further information about this RFA are 
urged to contact me at the address below.

               Robert W. Karp
               Program Director, Genetics
               rkarp at willco.niaaa.nih.gov


                             PUBLIC HEALTH SERVICE
                         NATIONAL INSTITUTES OF HEALTH

                           REQUEST FOR APPLICATIONS

                                 RFA AA-95-002


                                 DECEMBER 1994


The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is seeking
research proposals to map quantitative trait loci (QTL) influencing rat and mouse
behavioral traits which model human behavioral traits predisposing to alcoholism. 
Mapping of such QTL will permit subsequent testing of human homologues of
these genes for linkage to alcoholism in human pedigrees.  Such a test will help to
establish which animal behavioral traits are most relevant to human alcoholism. 
Mapping of the QTL will also serve as a prologue to the isolation of the relevant
genes and the identification of the products they encode.  This approach can
provide a novel route to elucidating the physiological mechanisms for
predisposition to alcoholism and to developing intervention strategies to diminish
harmful effects of alcohol.


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) is related to
the priority areas of alcohol abuse reduction and alcoholism treatment.  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, D.C.
20402-9325 (Telephone:  202-783-3238).


Applications may be submitted by domestic or foreign, public or private, nonprofit
or for-profit organizations, such as universities, colleges, hospitals, research
institutes and organizations, units of State or local governments, and eligible
agencies of the Federal Government.  Women and minority investigators are
encouraged to apply.  Foreign applicants are not eligible for First Independent
Research Support and Transition (FIRST) Awards (R29).


Research support may be obtained through applications for a regular research grant
(R01) or First Independent Research Support and Transition (FIRST) Award (R29). 
Applicants for R01s may request support for up to 5 years.  In FY 1992, the
average total cost per year for new R01s funded by NIAAA was approximately
$200,000.  Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the size of an award will vary also.  

FIRST Award applications must be for 5 years.  Total direct costs for the 5-year
period may not exceed $350,000 or $100,000 in any one budget period.  FIRST
Awards cannot be renewed, but grantees may apply for R01 support to continue
research on the same topics.  Potential applicants for FIRST Awards should obtain
copies of the FIRST program announcement (revised February 1994) from the
National Clearinghouse for Alcohol and Drug Information, P.O. Box 2345,
Rockville, Maryland 20852, telephone:  301-468-2600 or 1-800-729-6686. 
Program project grant applications (P01) will not be accepted for this RFA.

Applicants may submit applications for Investigator-Initiated Interactive Research
Project Grants.  Interactive Research Project Grants require the coordinated
submission of related research project grant (R01) and, to a limited extent FIRST
Award (R29) applications from investigators who wish to collaborate on research,
but do not require extensive shared physical resources.  These applications must
share a common theme and describe the objectives and scientific importance of
the interchange of, for example, ideas, data, and materials among the collaborating
investigators.  A minimum of two independent investigators with related research
objectives may submit concurrent, collaborative, cross-referenced individual R01
and R29 applications.  Applicants may be from one or several institutions.  Further
information on these and other grant mechanisms may be obtained from the
program staff listed in the Inquiries section of this RFA.


It is estimated that up to $1.1 million will be available for approximately six grants
under this RFA in FY 1996.  This level of support is dependent on the receipt of
sufficient number of applications of high scientific merit.  The funds set aside for
this RFA are intended to support all aspects of projects funded, except for
genotyping of the animals generated during the course of the research, which will
be supported by a separately awarded contract (see SPECIAL REQUIREMENTS,
below).  Although this program is provided for in the financial plan of NIAAA, the
award of grants pursuant to this RFA is also contingent upon the availability of
funds for this purpose.  The earliest possible award date is March 1, 1996.


Genetic Basis of Alcoholism

Alcoholism has been recognized for over a century as a familially transmitted
condition.  Over the past 25 years, considerable evidence from family, twin, and
adoption studies supports important roles for both genes and environment in its
etiology in both men (Cloninger, et al., 1981; Merikangas, 1990; McGue, et al.
1992) and women (Kendler, et al. 1992).  The specific etiological factors
underlying susceptibility to alcoholism remain, however, unknown.  Ongoing
efforts to discover genes linked to alcoholism in human pedigrees are challenged by
the heterogeneous, polygenic nature of alcoholism, along with the incompletely
understood role of the environment in its etiology (Aston and Hill, 1990).  These
efforts could be greatly bolstered by a strategy taking advantage of powerful
genetic methods permitting identification of genes influencing ethanol-related
behavior in experimental animals (Lander and Botstein, 1989; Gora-Maslak, et al.,
1991).  Human homologues of these genes could then be tested directly for
linkage to alcoholism in human pedigrees.

The recent large increase in the density of markers on the mouse genetic map
(Copeland, et al., 1993), along with the development of new and more powerful
methods of data analysis (Lander and Botstein, 1989), have now made it possible
to map individual quantitative trait loci (QTL), the genes contributing jointly to the
determination of genetically complex traits (such as behavior) (Gora-Maslak, et al.,
1991).  Since mapped genes can be isolated and their encoded products
characterized, QTL mapping offers a powerful reductionistic approach for
dissecting the complex physiological bases of alcohol-related behavior.  A detailed
human-mouse synteny map can accurately predict the map location of potential
human homologues of mouse genes (Nadeau, et al., 1992), so that these predicted
loci can then be tested for linkage to alcoholism in human alcoholic pedigrees. 
This strategy would permit the direct application of knowledge gained from an
animal behavior genetic study, for which behavioral measures are precisely defined
and powerful genetic techniques can be brought to bear, to a human genetic study
of alcoholism.  A finding of linkage would, moreover, provide additional evidence
for the relevance of the animal behavior under study to human alcoholism.  

Human Behavioral Indicators of Predisposition to Alcoholism

Because family history of alcoholism is a significant risk factor for alcoholism
(Cotton, 1979), researchers have examined psychological, biological, and
behavioral characteristics that distinguish children of alcoholics from children of
non-alcoholics as a means of identifying indicators of vulnerability to alcoholism. 
The most prominent theories of vulnerability to alcoholism have centered on
temperament, baseline sensitivity, and acute tolerance to alcohol.

Temperament models of vulnerability to alcoholism propose that deviations in
dispositional traits mediate transmission of alcoholism (Tarter, 1991; Cloninger,
1987).  According to Tarter, who used Rowe and Plomin's (1977) six dimensions
of temperament, children at high risk for developing alcoholism have traits such as
high behavioral activity, low attention span and persistence, low soothability, high
emotionality, and low sociability.  These disturbances of temperament in children
of alcoholics are attributed to neurological dysfunction in the prefrontal, limbic, and
midbrain areas.  This theory is supported by observations of a number of
differences between children of alcoholics and children of nonalcoholics, including
increased incidence of psychopathology (attention deficit hyperactivity disorder,
childhood conduct disorder, anxiety disorders and depression, antisocial personality
disorder), behavioral disturbances (impulsiveness, aggression, emotionality),
neuropsychological deficits (abstraction/ conceptualization, verbal ability), and
neurophysiological variations (reduced amplitude of the P3 component of event-
related potentials) (see Tarter, 1991; Sher, 1991 for reviews).

In a similar vein, Cloninger's model of Type 1 and Type 2 alcoholism (Cloninger,
1987) is based on temperamental differences (novelty seeking, harm avoidance,
reward dependence), which are related to selective neurological substrates and
predispose an individual to certain types of alcoholism.  For example, Type 2
alcoholics are high in novelty seeking, associated with impulsiveness, distractibility,
and positively motivated drinking.  Type 1 alcoholics, on the other hand, are high
in harm avoidance and reward dependence associated with anxiety, shyness,
emotional dependence, and negatively motivated drinking (i.e., escape from
dysphoric feelings).

The sensitivity hypothesis of vulnerability to alcoholism, first elaborated by
Schuckit and his colleagues in the early 1980s, postulated that children of
alcoholics are less sensitive to the subjective intoxicating effects of alcohol, and
therefore, are susceptible to drinking excessively (Schuckit, 1980, 1984). 
However, subsequent studies designed to test this hypothesis demonstrated
opposite effects, i.e., children of alcoholics were more sensitive to the reinforcing
effects of alcohol as measured by muscle relaxing, stress-dampening,
electroencephalographic and mood effects (see Sher, 1991 for review).  A recent
interpretation proposed by Newlin and Thomson (1990) may resolve this conflict. 
Compared to sons of nonalcoholic fathers, sons of alcoholic fathers show greater
acute sensitivity to the reinforcing effects of alcohol (euphoria, muscle relaxation,
stress-response dampening) on the ascending limb of the blood alcohol curve, and
less sensitivity (greater acute tolerance) to the aversive effects of alcohol (nausea,
dysphoria) on the descending limb of the blood alcohol curve.

Measuring Animal Behaviors Related to Human Traits Predicting Alcoholism

Investigators are now mapping QTL influencing various ethanol-related behaviors in
mice, including preference for drinking, sensitivity to sedation, locomotor
activation, hypothermia, and withdrawal severity (for review, see Crabbe, et al.,
1994).  More recently, they have begun mapping genes influencing more complex
behaviors, such as acute functional tolerance to ataxia (Crabbe, et al., 1994a) and
hypothermia (Crabbe, et al., 1994b), conditioned place preference (a measure of
reinforcement) (Cunningham and Malott, 1994), and conditioned taste aversion (a
measure of aversive effects) (Risinger and Cunningham, 1994).  Aspects of more
complex rodent behaviors could conceivably be homologous to human traits
predisposing to alcoholism.  Some of the corresponding assays could, in principle,
be adapted for QTL mapping.  Examples are given below.  (These examples are for
illustrative purposes only, and are not intended to exclude other behavioral tests
from this RFA.)

Tests that assess intrinsic traits of temperament or personality predisposing
humans to alcoholism, such as impulsiveness, novelty seeking, aggression,
hyperactivity, emotionality, anxiety, and stress reactivity, can be administered to
rodents.  Impulsiveness in individuals at risk for alcoholism has been attributed to
prefrontal-limbic brain dysfunction (Tarter, 1991) and is comparable to difficulties
in response inhibition observed in rodents with prefrontal lesions (see Kolb, 1984
for review).  Evidence of impaired response inhibition in rodents has been
measured by reversal learning tasks (i.e., the animal first learns to respond to a
particular stimulus or location for a reward, and then must reverse its response to a
different place or stimulus), tests of response extinction (a previously rewarded
response is no longer rewarded), or go/no go tasks (reward is presented for
responding to a stimulus on "go" trials, and for not responding on "no go" trials)
(Kolb, 1984; Sakurai and Sugimoto, 1985).   Animals with deficits in response
inhibition have difficulty shifting responses on reversal tasks, continue responding
when rewards are no longer presented, and fail to suppress responding on "no go"

Research on alcohol and aggression in humans and animals has focused on
whether alcohol consumption increases violent/aggressive behavior toward family
members, peers, or rivals (see Miczek, et al., 1993 for review).  However, whether
a history of antisocial personality or aggressive behavior predisposes a person to
excessive alcohol consumption has received little study.  Measures of aggressive
behavior in rodents that might reflect aspects of human antisocial behavior include
social interaction/social conflict paradigms, such as isolation-induced aggression
between male pairs, resident-intruder encounters, and possibly frustration-induced
aggression (omission of reward) (Cairns, et al., 1983; Miczek, et al., 1993; Brain,
et al., 1993).

Measures of other traits potentially serving as markers of human alcoholism, such
as anxiety, emotionality, activity level, and novelty-seeking, could be applied to
rodents.  Novelty or "sensation-seeking" can be measured by nose-poke or hole
board behavior in which the animal places its nose or head into a board with
equally spaced holes.  Activity level can easily be measured with activity wheels or
by the number of boxes crossed in an open field.  Hole board behavior and
exploratory open field activity, along with number of defecations and rearings in
the open field, have also been used to quantitate levels of anxiety and
emotionality.  Other experimental paradigms for measuring anxiety include conflict
paradigms, acoustic startle response, and elevated plus-maze (see Crawley, 1985;
Shepard, 1986; Heilig, et al., 1994; Stout and Weiss, 1994 for reviews of all of
these paradigms).

A further related behavior is stress reactivity, which could be measured by
responses to various stressors (social stress, isolation, early weaning), such as
changes in vocalization pattern, disruption of circadian rhythms, or autonomic
responses such as changes in blood pressure or heart rate (see Pohorecky, 1990;
Brown, et al., 1991 for reviews).

Acute behavioral tolerance to a single challenge dose of alcohol can be
demonstrated in animals by comparing the extent of functional impairment at a
given blood alcohol concentration on the ascending limb of the blood alcohol curve
with the extent of impairment when the same alcohol concentration is reached on
the descending limb.  The development of acute tolerance within a single session
to alcohol's effects such as motor impairment, hypothermia, and operant
responding has been shown by several studies (LeBlanc, et al., 1975; Crabbe, et
al., 1994b; Le, et al., 1992; Hiltunen and Jarbe, 1992).

Finally, because frequency and amount of alcohol consumed are significant
discriminators of alcoholic subtypes (Babor, et al., 1992; Morley and Skinner,
1986), measures of temporal patterns of alcohol consumption in rodents may be
informative behavioral markers.  Using operant techniques, distinctive temporal
patterns of alcohol consumption have been demonstrated in the selectively bred
alcohol-preferring and -nonpreferring rats (Schwarz-Stevens, et al., 1991).  Such
techniques could possibly be adapted to permit QTL mapping.

Methodological Considerations

Most QTL mapping of behavioral traits has been done in mice because of the well-
developed genetic map available for this species.  However, the rat genome map is
now undergoing rapid development (Yamada, et al., 1994; Serikawa et al., 1992)
and has already proven suitable for QTL mapping (Lindpaintner, 1992).  Because
many interesting behavioral paradigms have been developed in rats to study
ethanol-related behaviors, NIAAA encourages investigators studying rat behavior to
respond to this RFA.

While the choice of animal strains for study is an important feature of experimental
design, applicants are encouraged to consider using any of a wide variety of
strains, rather than confining their attention only to those already used extensively
in alcohol research.  Applicants are also encouraged to consider using  existing
batteries of recombinant inbred (RI) and recombinant congenic (RC) strains.

Applicants are encouraged (when cost and experimental considerations permit) to
test more than one behavioral paradigm on the same group of animals.  Applicants
may also wish to consider neurochemical measurements (e.g., receptor binding
studies, in situ hybridization, other histological measurements) on the same group
of animals.  Such studies offer the prospect of a rigorous determination of genetic
correlations among multiple behaviors and neurochemical parameters, as well as
mapping of the genes responsible for those correlations.  

Some behavioral paradigms of great potential interest may be so complex as to
preclude measurements on the hundreds of animals required for QTL mapping. 
Investigators working with such paradigms are strongly encouraged to attempt
modifying them so as to permit measurements on hundreds of animals, without
degrading their informativeness about the principal aspect of the behavior under


This RFA is intended to support the genetic analysis of animal behaviors not
previously analyzed, in the hope that these behaviors may usefully model human
traits related to predisposition to alcoholism.  Investigators wishing to respond to
this RFA who lack expertise in genetic analysis should seek collaboration with
investigators experienced in QTL mapping, insofar as such experience will prove
essential for proper study design and data analysis.  

To support as economically as possible the large amount of genotyping required for
this research, NIAAA will award a separate contract for genotyping of animals
generated by the research supported under this RFA.  Awardees under this RFA
who desire NIAAA funding for the genotyping of the animals they generate are
expected to use the services provided under this contract.  Awardees will be
expected to attend one joint meeting per year in or near Washington, D.C., in order
to review progress, and should request sufficient funds in their budgets to support
such attendance.


Prospective applicants are asked to submit, by June 1, 1995, 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 or title of the RFA in response to
which the application may 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 Institute staff to estimate the
potential review workload and avoid conflict of interest in the review.

The letter of intent is to be sent to:

      Mark Green, Ph.D.
      Chief, Extramural Project Review Branch
      Office of Scientific Affairs
      National Institute on Alcohol Abuse and Alcoholism
      Willco Building, Suite 409
      6000 Executive Blvd. MSC 7003
      Bethesda, Maryland  20892-7003
      Telephone:  301-443-4375
      FAX:  301-443-6077


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; from the Office of Grants Information, Division of Research
Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449,
Bethesda, Maryland 20892, telephone 301-594-7248; and from the NIAAA
program administrators named below under Inquiries.

The RFA label available in the PHS (rev. 9/91) 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 2a of the face page of the application form and the YES box must
be marked.  Page limits and limits on size of type are strictly enforced.  Applicants
for FIRST Awards (R29) are reminded that such applications must include three
letters of reference.  Non-conforming applications will be returned without being

Submit a signed, typewritten original of the application, including the Checklist,
and three signed, photocopies in one package to:

      Division of Research Grants, NIH
      Westwood Building, Room 240
      5333 Westbard Avenue
      Bethesda, Maryland  20892*

* (If using express mail or overnight carrier, the zip code is

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

      Mark Green, Ph.D.
      Chief, Extramural Project Review Branch
      National Institute on Alcohol Abuse and Alcoholism
      6000 Executive Boulevard, Suite 409  MSC 7003
      Bethesda, Maryland  20892-7003
      Telephone:  301-443-4375
      FAX:  301-443-6077

Applications must be received by July 19, 1995.  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 be prepared as a revised application and include an introduction
addressing the previous critique.


Upon receipt, applications will be reviewed for completeness by DRG and for 
responsiveness by the Institute.  Incomplete applications will be returned to the
applicant without further consideration.  If the application is not responsive to the
RFA, DRG staff will 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 the Institute in accordance with the
review criteria stated below.

As part of the initial merit review, a process (triage) may 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 the RFA.  Applications judged to be competitive will be discussed and
be assigned a priority score.  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.  The second level of review
will be provided by the National Advisory Council on Alcohol Abuse and


Criteria to be used in the scientific and technical merit review of alcohol research
grant applications will include the following:

      1.    The scientific, technical, or medical significance and originality of the
            proposed research.

      2.    The appropriateness and adequacy of the experimental approach and
            methodology proposed to carry out the research.

      3.    The adequacy of the qualifications (including level of education and
            training) and relevant research experience of the principal investigator
            and key research personnel.

      4.    The availability of adequate facilities, general environment for the
            conduct of the proposed research, other resources, and collaborative
            arrangements necessary for the research.

      5.    The reasonableness of budget estimates and duration in relation to the
            proposed research.

      6.    Where applicable, the adequacy of procedures to protect or minimize
            effects on animal and human subjects and the environment.

The review criteria for FIRST Awards (R29) are contained in the FIRST program
announcement (revised February 1994).


Applications recommended for approval by the National Advisory Council on
Alcohol Abuse and Alcoholism will be considered for funding on the basis of the
overall scientific and technical merit of the proposal as determined by peer review,
NIAAA programmatic needs and balance, and the availability of funds.


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

Direct inquiries regarding genetic aspects of proposed research to:

      Robert W. Karp, Ph.D.
      Division of Basic Research
      National Institute on Alcohol Abuse and Alcoholism
      Willco Building, Suite 402
      6000 Executive Boulevard MSC 7003
      Bethesda, Maryland  20892-7003
      Telephone:  301-443-4223            
      FAX:  301-594-0673
      Internet:  rkarp at willco.niaaa.nih.gov

Direct inquiries regarding behavioral aspects of proposed research to:

      Ellen Witt, Ph.D.
      Division of Basic Research
      National Institute on Alcohol Abuse and Alcoholism
      Willco Building, Suite 402
      6000 Executive Boulevard MSC 7003
      Bethesda, Maryland  20892-7003
      Telephone:  301-443-4223            
      FAX:  301-594-0673
      Internet:  ewitt at willco.niaaa.nih.gov

Direct inquiries regarding fiscal matters to:

      Joseph Weeda
      Chief, Grants Management Branch
      Office of Planning and Resource Management
      National Institute on Alcohol Abuse and Alcoholism
      Willco Building, Suite 504
      6000 Executive Boulevard MSC 7003
      Bethesda, Maryland  20892-7003
      Telephone:  301-443-4703            
      FAX:  301-443-3891       
      Internet:  jweeda at willco.niaaa.nih.gov


This program is described in the Catalog of Federal Domestic Assistance, No.
93.273.  Awards are made under the authorization of the Public Health Service
Act, Sections 301 and 464H, and administered under the PHS policies and Federal
Regulations at Title 42 CFR Part 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 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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