Full Text PA-96-057
 
QTL MAPPING OF ALCOHOL-RELATED BEHAVIORAL TRAITS IN RODENTS
 
NIH GUIDE, Volume 25, Number 18, June 7, 1996
 
PA NUMBER:  PA-96-057
 
P.T. 34

Keywords: 
  Alcohol/Alcoholism 
  Behavioral/Experimental Psychology 
  0755044 

 
National Institute on Alcohol Abuse and Alcoholism
 
PURPOSE
 
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is
seeking research grant 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.
 
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 Program
Announcement, 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 202-512-1800).
 
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) Awards (R29).  Regular research grant
applications (R01) from foreign institutions are limited to three
years.
 
MECHANISM OF SUPPORT
 
Research support may be obtained through applications for a research
project grant (R01) or First Independent Research Support and
Transition (FIRST) Award (R29).  Applicants may also submit
Investigator-Initiated Interactive Research Project Grants (IRPG)
under this program announcement.  Interactive Research Project Grants
require the coordinated submission of related regular research
project grant applications and, to a limited extent, FIRST Award
applications from investigators who wish to collaborate on research,
but do not require extensive shared physical resources.  Further
information on the IRPG mechanism is available in program
announcement PA-96-001, NIH Guide for Grants and Contracts, Vol. 24,
No. 35, October 6, 1995.
 
RESEARCH OBJECTIVES
 
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 (Zeng, 1994; Jansen and Stam, 1994;
Crabbe, et al., 1994a).  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 (Dietrich, et al., 1995), along with the development of
new and more powerful methods of data analysis (Zeng, 1994; Jansen
and Stam, 1994), 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)
(Crabbe, et al., 1994a). 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.  Variation in novelty seeking has
recently been associated with variants of the gene encoding the
dopamine D4 receptor (Benjamin, et al., 1996).  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., 1994a).  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, 1995), 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.,
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
(Jacob, et al., 1995) and has already proven suitable for QTL mapping
(Brown, et al., 1996; Galli, et al., 1996; Gauguier, et al., 1996).
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.
While recombinant inbred (RI) strains have been used extensively to
map QTL influencing behavioral traits (Crabbe et al., 1994a),
applicants should consider carefully whether the small size of most
extant batteries of RI strains (<25 strains) affords sufficient
statistical power to detect QTL of modest to moderate effect size.
 
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
study.
 
SPECIAL REQUIREMENTS
 
This program announcement is intended to publicize NIAAA's interest
in 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
obtain support for such research 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.  Investigators desiring to
establish such collaborations are encouraged to contact one of the
individuals mentioned under INQUIRIES, below.  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.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained 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
301/435-0715, Email: asknih@odrockm1.od.nih.gov.  The title and
number of the program announcement must be typed in section 2 on the
face page of the application.
 
Applications for the FIRST award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
 
The completed original application and five legible copies must be
sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817-7710 (for express/courier service)
 
REVIEW CONSIDERATIONS
 
Applications that are complete will be evaluated for scientific and
technical merit by an appropriate peer review group convened in
accordance with the standard NIH peer review procedures.  As part of
the initial merit review, all applications will receive a written
critique and undergo a process in which only those applications
deemed to have the highest scientific merit, generally the top half
of the applications under review, will be discussed, assigned a
priority score, and receive a second level review by the appropriate
national advisory council.
 
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.  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).
 
AWARD CRITERIA
 
Applicatons will compete for available funds with all other approved
applications.  The following will be considered in making funding
decisions:  quality of the proposed project as etermined by peer
review, availability of funds, and program priority.
 
Applications assigned to 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 application as
determined by peer review, NIAAA programmatic needs and balance, and
the availability of funds.  Priority will be given to applications
analyzing behavioral and neurochemical traits not yet subject to QTL
analysis. Applicants desiring further information about funding
priorities are encouraged to contact one of the persons listed under
INQUIRIES.
 
INQUIRIES
 
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
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, MD  20892-7003
Telephone:  (301) 443-4223
FAX:  (301) 594-0673
Email:  ewitt@willco.niaaa.nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Linda Hilley
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:  lhilley@willco.niaaa.nih.gov
 
AUTHORITY AND REGULATIONS
 
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 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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.

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