Full Text PA-95-073


NIH GUIDE, Volume 24, Number 24, June 30, 1995

PA NUMBER:  PA-95-073

P.T. 34


National Institute on Alcohol Abuse and Alcoholism


The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is
seeking research grant proposals to conduct basic research, using
animal models and state-of-the-art imaging techniques in humans, to
identify the neurobiological, physiological, and genetic factors that
lead to adolescent alcohol abuse and dependence.  Despite the fact
that alcohol use is high among secondary school students, relatively
few studies to date define the neurobiologic and physiologic
mechanisms of high alcohol intake or the effects of excessive
drinking in adolescents.  Studies of neurobiologic mechanisms and
risk factors for alcoholism during late childhood through adolescence
would increase our ability to predict which individuals will be most
likely to develop alcoholism early in life.  In addition, evaluation
of the effects of alcohol ingestion during postnatal development,
particularly during adolescence, would further our understanding of
alcohol's immediate consequences and the contribution of early
alcohol exposure to excessive drinking and abnormal cognitive and
social functioning during subsequent developmental stages.  Finally,
results obtained will help develop strategies for treatment and
prevention of adolescent alcohol abuse and alcoholism.


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, Mechanisms of Adolescent Alcohol Abuse and Alcoholism,
is related to the priority area of alcohol abuse and alcoholism.
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 foreign and domestic, 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).


Research support may be requested through applications for a regular
research project grant (R01), FIRST Award (R29),
exploratory/developmental grant (R21), and small grant (R03).
Applicants for R01s may request support for up to five years.  In FY
1994, the average total cost per year for new and competing renewal
R01s funded by the Division of Basic Research was approximately
$170,000.  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.  Small grants (R03) and
exploratory/ developmental grants (R21) are limited to two years for
up to $50,000 per year and $70,000 per year, respectively, for direct
costs.  FIRST Awards, exploratory/developmental grants, and small
grants cannot be renewed, but grantees may apply for R01 support to
continue research on the same topics.

Potential applicants for the FIRST Award (R29),
exploratory/developmental grant (R21), and small grant (R03) should
obtain copies of the specific announcements for these programs from
the National Clearinghouse for Alcohol and Drug Information, P.O. Box
2345, Rockville, MD 20847-2345, telephone 301-468-2600 or
1-800-729-6686.  Investigators submitting applications that exceed
$500,000 for direct costs in any one year should contact program
staff before submitting an application.

Applicants may also submit applications for Investigator-Initiated
Interactive Research Project Grants (IRPG) (PA-94-086, NIH Guide,
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.


Alcohol remains the most commonly abused substance among adolescents.
According to the National Adolescent Student Health Survey, 75.9
percent of 8th graders and 87.3 percent of 10th graders have used
alcohol in their lifetime (Windle, 1990).  Of greater significance is
the widespread occurrence of heavy drinking (defined as consuming
five or more drinks in a row during the past two weeks).  Among high
school seniors this statistic is 28 percent.  Males have consistently
reported more frequent and heavier use than females, but this
difference has been gradually diminishing over the last decade
(Johnston, et al., 1994).  This is particularly important since
females require less alcohol to achieve blood alcohol concentrations
equivalent to males (Frezza, et al, 1990).  Thus, if females begin
drinking heavily during adolescence and continue throughout life,
they may be at enhanced risk for the medical consequences of alcohol
abuse including liver disease (Norton, et al, 1987), brain damage
(Harper, et al., 1990), and associated behavioral deficits (Glenn &
Parsons, 1992).  Given the early onset of drinking and its frequency,
the consequences of alcohol's acute and chronic effects on
physiological growth and maturation, as well as its potential
deleterious effects on the development of social and interpersonal
competencies, are of major concern.

During the period of late childhood and adolescence, development of
neurobiologic systems is incomplete.  Although final brain size and
available neurons are largely fixed early in infancy, plasticity of
the brain continues during adolescence through the processes of
overproduction and elimination of synapses, progressive myelination,
variation in the evolution of neurotransmitter systems, and changes
in the rate of brain electrical and metabolic activity (Watkins and
Williams, 1992).  In addition, hormonal levels change dramatically
during adolescence as a result of the onset of puberty.
Corresponding to the shifts in brain and hormonal status are
significant transitions in cognitive, psychological, and social
development (Susman and Petersen, 1992).  Adolescence is marked by
the emergence of new thinking skills, reassessment of body image,
focus on peer relationships, and a desire to establish self identity
and distance from parents (Ingersoll, 1992).  Thus, environmental
influences during adolescence, including alcohol consumption, may
interact with unique neurobiological and physiological strengths and
weaknesses to predispose or protect an individual from alcohol abuse
and/or dependence.  A better understanding of alcohol's effects
during adolescence on the complicated interaction among genetic,
neurobiologic, psychosocial and environmental factors could lead to
earlier and more effective prevention and treatment strategies.

To date, relatively few studies define the neurobiological and
physiological effects of alcohol in adolescents, in part due to
ethical considerations that prohibit administering alcohol to youths.
Neurobehavioral research in human adolescents has been largely
limited to studies of children who are at high risk because of a
positive family history of alcoholism.  These investigations suggest
that there are neurocognitive and neurophysiological abnormalities in
children of recovering alcoholics that could be early indicators of
risk for alcoholism (Begleiter, et al, 1984; Hill, et al, 1990;
Porjesz and Begleiter, 1993; Whipple, et al, 1991).  More
importantly, the neurophysiological abnormalities are most pronounced
during the prepubertal and late adolescent years, are highly
dependent on the differential rates of nervous system development in
boys and girls, and may reflect maturational lag in children who are
at high risk for developing alcoholism (Hill and Steinhauer, 1993;
Steinhauer and Hill, 1993).  This latter finding underscores the
importance of considering developmental stages, particularly
adolescence, when trying to identify early risk markers for

Evidence from animal studies indicates that unique neurochemical and
behavioral changes are occurring during postnatal development,
including adolescence, that could mediate the response to alcohol
(see Witt, 1994, for review).  While the various neurotransmitter
systems develop at different rates, the ontogeny of several
neurotransmitter systems extends into the adolescent period.  For
example, in the rat, neurochemical markers of dopamine activity in
the striatum, such as levels of postsynaptic receptors and
presynaptic dopamine content, show a gradual increase until adult
levels are reached around puberty (Coyle and Harris, 1987; Noison and
Thomas, 1988).  Similarly, in animals and humans, presynaptic
cholinergic markers in the cortex do not reach adult levels until the
adolescent period (Coyle and Yamamura, 1976; Virgili, et al., 1990;
Court et al., 1993).

During the 7- to 10-day period just prior to the onset of puberty,
referred to as "periadolescence", both male and female rats are
behaviorally and pharmacologically distinct from younger and older
animals (Spear and Brake, 1983).  Periadolescent animals are more
"hyperactive" as measured by tests of exploratory behavior and social
play, and have difficulty with complex discrimination learning tasks.
Pharmacologically, periadolescent animals are less responsive
(hyposensitive) to drugs affecting the catecholaminergic system
(Spear, et al., 1980; Shalaby and Spear, 1980), which may be due to
functional immaturity of self-inhibitory presynaptic dopamine
autoreceptors in mesolimbic brain regions during the periadolescent
period (Spear et al., 1981).  However, whether periadolescent animals
drink more alcohol than early postpubertal or adult rats because of
an immature dopaminergic system, are more susceptible to alcohol
dependence, or fail to attain mature dopamine function following high
early intakes are important research questions that need to be
explored.  Dopamine is one of many neurotransmitter systems that have
been implicated in the alcohol addiction process.  An understanding
of the ontogeny of psychopharmacological responsiveness in
neurotransmitter systems related to mechanisms of alcohol
reinforcement, alcohol preference, or alcohol's subjective effects
could be extremely important in understanding the development of
alcohol addiction during adolescence.

Finally, animal studies of the ontogeny of alcohol's acute effects on
learning and memory have shown early age-dependent changes in
alcohol's effect on selective learning tasks (e.g., sensory
preconditioning) (Chen, et al., 1992).  However, more studies are
needed to look at ethanol's influence on age-related changes on other
cognitive measures and the neurochemical mechanisms underlying these
changes.  Similarly, few studies have investigated the effects of
chronic ethanol use on cognition and brain function.  A recent study
of alcohol-abusing teenagers found that both male and female
adolescent alcohol abusers were inferior in language skills, but only
females were impaired on tests of abstract reasoning and cognitive
flexibility (Moss, et al., 1994).  Furthermore, chronic ethanol
treatment may lead to increased N-methyl-D-aspartate (NMDA)-mediated
neurotoxicity (Crews & Chandler, 1993), which could be exacerbated by
repeated withdrawals such as during binge drinking (Hunt, 1993).
Since the immature brain is more susceptible to NMDA neurotoxicity
(Garthwaite & Garthwaite, 1986) and since teenagers are more likely
to engage in weekend binge drinking, it would be important to study
the effects of such patterns of ethanol exposure on neurochemical
parameters and cognitive functioning using adolescent animals models.

More basic research is needed in humans and animals to elucidate the
neurobiological mechanisms of alcoholism and the effects of alcohol
ingestion throughout the period of postnatal maturation.  Human
studies would also be important to identify neurobiologic and
behavioral risk factors for alcoholism during postnatal development,
particularly adolescence.  For example, with the advent of
noninvasive imaging techniques such as PET and SPECT as well as the
development of radioactive ligands to label dopamine and
benzodiazepine receptors, it may be possible to study the functioning
of various neurotransmitter systems in children at risk for
developing alcoholism and, more importantly to identify those who are
likely to become alcoholic during adolescence.  Animal studies will
be important for investigating the neurochemical,
neuropharmacological, and behavioral mechanisms underlying the
variable response to alcohol during ontogeny, examining the
consequences of acute and chronic alcohol ingestion on the immature
central nervous system, and for controlled studies of gene-
environment interactions as they relate to patterns of adolescent

Areas needing further research include, but are not limited to:

Development of animal paradigms to study modes of initiation of
alcohol-seeking behavior and alcohol's effects on reinforcement, drug
discrimination, sensitization, tolerance, and dependence during the
juvenile through adolescent period.

Ontogenetic studies to compare patterns of alcohol-related behavior
(e.g., alcohol reinforcement, sensitivity) as well as their
neurochemical, neuropharmacological, neurophysiological, and
neuroanatomical mechanisms during each stage of postnatal development
through adulthood.

Animal studies of the acute and chronic effects of alcohol on brain
and behavioral functioning during adolescence, and the effects of
early exposure on adult functioning.

Studies of recovery of neural and behavioral function following
alcohol consumption to determine if the adolescent brain is more or
less vulnerable than the adult brain to alcohol's acute and chronic

Studies of gender differences in alcohol's effect on normal hormonal
activation during puberty, mechanisms of alcohol's effect on
neuroendocrine-neurotransmitter interactions, and the relationship of
alcohol-induced hormonal/ neurotransmitter disturbances during
adolescence on the development of gender differences in behavior
(including mood, stress, peer relationships, sexual behavior,
aggression, cognitive functioning).

Human studies and animal studies using different genetically defined
strains to examine the interaction among premorbid
temperament/personality, cognitive functioning, neurobiological,
environmental, and genetic factors in the development of addictive
behaviors in adolescents.

Use of noninvasive neuroimaging (MRI, MRS, PET, SPECT),
neurophysiological (EEG, ERP, MEG), and neuropsychological/cognitive
measures in adolescent humans/animals to study brain mechanisms of
craving, intoxication, and withdrawal, and to assess progression of
damage and recovery of function following abstinence.


It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in affect since 1990.  The new policy contains some
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH
Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.


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.  Applications kits are
available at most institutional offices of sponsored research and may
be obtained from the Grants Information Office, Division of Research
Grants, National Institutes of Health, 6701 Rockledge Drive, Suite
3032, MSC 7762, Bethesda, MD 20892-7762, telephone 301-435-0714.  The
title and number of the program announcement must be typed in section
2a 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:

6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817-7710 (for express/courier service)


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 for scientific/technical merit review of applications for
regular research grants (R01) are as follows:

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  Adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be

The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.

The review criteria for Small Grants (R03), Exploratory/Developmental
Grants (R21), and FIRST Awards (R29) are contained in their program


Applications will compete for available funds with all other approved
applications assigned to the Institute.  The following will be
considered in making funding decisions: quality of the proposed
project as determined by peer review, availability of funds, and
program priority.


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

Direct inquires regarding programmatic issues 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) 443-6545
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) 443-0915
FAX:  (301) 443-3891
Email:  LHilley@willco.niaaa.nih.gov


This program is described in the Catalog of Federal Domestic
Assistance No. 93.273.  Awards are made under authorization of the
Public Health Service Act, Sections 301 and 464H, and administered
under 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 and contract 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 routing 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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Chen, W., Spear, L. P., & Spear, N. E.  (1992). Enhancement of
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juvenile rats.  Behavioral and Neural Biology, 57, 44-57.

Coyle, J. T. & Harris, J. C. (1987).  The development of
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Frezza, M., di Padova, C., Pozzato, G., Terpin, M., Barona, e., &
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Glenn, S. W. & Parsons, O. A. (1992).  Neuropsychological efficiency
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Harper, C. G., Smith, N. A., & Kril, J. J. (1990).  The effects of
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Hill, S. Y. and Steinhauer, S. R.  (1993).  Assessment of prepubertal
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Hunt, W. A. (1993).  Are binge drinkers more at risk for developing
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