Full Text AA-95-002


NIH GUIDE, Volume 23, Number 43, December 9, 1994

RFA:  AA-95-002

P.T. 34

  Behavioral/Experimental Psychology 

National Institute on Alcohol Abuse and Alcoholism

Letter of Intent Receipt Date:  June 1, 1995
Application Receipt Date:  July 19, 1995


The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is
seeking research applications to map quantitative trait loci (QTL)
influencing rat and mouse behavioral traits that 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), QTL Mapping of Alcohol-Related Behavioral
Traits in Rodents, 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, DC 20402-9325 (telephone 202-783-3238).


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 applicants are not eligible for First Independent Research
Support and Transition (FIRST) (R29) Awards.


Research support may be obtained through applications for a regular
research grant (R01) or FIRST (R29) Award.  Applicants for R01s may
request support for up to five years.  In FY 1994, the average total
cost per year for new R01s funded by the 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 five years.  Total direct costs
for the five-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 (IRPG) (refer to PA-94-086, Vol.
23, No. 28, July 29, 1994).  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 under INQUIRIES.


It is estimated that up to $1.1 million in total costs 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,


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, however, remain 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 syntony 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

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

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" trials.

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.,

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

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, DC, 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 of 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 NIAAA
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.
Office of Scientific Affairs
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 409
6000 Executive Boulevard MSC 7003
Bethesda, MD  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, MD 20892,
telephone 301-710-0267; 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 reviewed.

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
Westwood Building, Room 240
Bethesda, MD  20892**

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

Mark Green, Ph.D.
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 409
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003

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 NIAAA.  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

Review Criteria

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.  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.

7.  Where applicable, the adequacy of procedures to protect or
minimize effects on animal 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, MD  20892-7003
Telephone:  (301) 443-4223
FAX:  (301) 594-0673
Email:  rkarp@willco.niaaa.nih.gov

Direct inquiries regarding behavioral aspects of proposed research

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, MD  20892-7003
Telephone:  (301) 443-4223
FAX:  (301) 594-0673
Email:  ewitt@willco.niaaa.nih.gov

Direct inquiries regarding fiscal matters to:

Joseph Weeda
Office of Planning and Resource Management
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 504
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4703
FAX:  (301) 443-3891
Email:  jweeda@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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