NEUROBIOLOGICAL MECHANISMS OF ADOLESCENT ALCOHOL ABUSE

Release Date:  November 25, 1998

RFA:  AA-99-003

P.T.

National Institute on Alcohol Abuse and Alcoholism

Letter of Intent Receipt Date:  February 23, 1999
Application Receipt Date:  March 23, 1999

PURPOSE

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is seeking
research grant proposals to conduct basic research, using animal models and non-
invasive imaging techniques in humans, to identify the neurobiological,
physiological, genetic, and environmental factors that lead to adolescent alcohol
abuse and dependence.  According to the 1997 Monitoring the Future Study, 54
percent of 8th graders, 72 percent of 10th graders, and 82 percent of 12th
graders have used alcohol in their lifetime. (1) Of greater concern is the
widespread occurrence of heavy drinking (five or more drinks in a row during the
past two weeks).  Among high school seniors this statistic was 31.3 percent. 
Furthermore, recent research has shown that individuals who start drinking at
ages 14 or younger have lifetime rates of dependence of 40 percent or more
compared to roughly 10 percent among those who started drinking at ages 20 and
over.  Despite these high rates of alcohol use and associated risks among
secondary school students, relatively few studies to date define the
neurobiological and physiological mechanisms of high alcohol intakes or the
effects of excessive drinking in adolescents.

The focus of this Request for Applications (RFA) is to stimulate research on the
neurobiological mechanisms and risk factors for alcoholism during late childhood
through adolescence.  A second emphasis of this RFA is on the relative
contribution and/or interaction of neurobiological, genetic, environmental, and
social factors (e.g., family history, stress, peer influences) in the development
of adolescent alcohol abuse. In addition, evaluation of the effects of alcohol
ingestion during postnatal development, particularly 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.  While a multidisciplinary
approach is encouraged, a basic neuroscience component must be included for a
proposal to be responsive to this RFA.  Use of nonhuman primate models is
encouraged because of their extended adolescent period.

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 activity
for setting priority areas.  This RFA, Neurobiological Mechanisms of Adolescent
Alcohol Abuse, is related to the priority area of alcohol abuse reduction and
alcoholism prevention.  Potential applicants may obtain a copy of "Healthy People
2000" (Full Report:  Stock No. 170-011-00474-0 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

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.

MECHANISM OF SUPPORT

Research support may be obtained through applications for a research project
grant (R01), exploratory/developmental Grant (R21), and small grant (R03). 
Applicants for R01s may request support for up to 5 years.  In FY 1998, the
average total cost per year for new and competing renewal R01s funded by the
Division of Basic Research was approximately $190,000.  Currently, small grants
(R03) and exploratory/developmental grants (R21) are limited to 2 years for up
to $50,000 per year and $70,000 per year, respectively, for direct costs. 
Exploratory/developmental grants and small grants cannot be renewed, but grantees
may apply for R01 support to continue research on the same topics.  Applicants
that anticipate submitting a small grant (R03) or exploratory/developmental grant
(R21), should contact the Program Contact listed under INQUIRIES for additional
information on these mechanisms.

Applications requesting direct costs of $500,000 or more in any one year must
obtain written agreement from the NIAAA that the application will be accepted for
consideration of award, in accordance with NIH policy, which is available at
http://grants.nih.gov/grants/guide/notice-files/not98-030.html.

Applicants may also submit applications for Investigator-Initiated Interactive
Research Project Grants (IRPG).  Interactive Research Project Grants require the
coordinated submission of related research project grants (R01) 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 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 or from the NIAAA Web site
http://www.niaaa.nih.gov/.

FUNDS AVAILABLE

It is estimated that up to $3.0 million will be available to fund approximately
15 grants under this RFA.  This level of support is dependent on the receipt of
a sufficient number of applications of high scientific merit.  The award of
grants pursuant to this RFA is contingent upon the availability of funds for this
purpose.  The earliest possible award date is September 30, 1999.

RESEARCH OBJECTIVES

Background

Alcohol remains the most commonly abused substance among adolescents.  Males have
consistently reported more frequent and heavier use than females, but this
difference has been gradually diminishing over the last decade.  This is
particularly important since females require less alcohol to achieve blood
alcohol concentrations equivalent to males.  Thus, females may be at enhanced
risk for the medical consequences of alcohol abuse including liver disease, brain
damage, and associated behavioral deficits.  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.

To date, relatively few studies define the neurobiological mechanisms and
consequences of excessive drinking in adolescents.  One reason for the paucity
of research in this area is the difficulty of studying the neurobiological and
physiological mechanisms of alcohol abuse or dependence in human adolescents, in
part, due to ethical and legal considerations, that prohibit administering
alcohol to youths.  Because of limitations in the types of studies that can be
conducted with human adolescents, animal models need to be developed to study
neural mechanisms of adolescent alcohol abuse and alcoholism.  One approach,
which is the most cost effective, is to use rodents.  However, the adolescent
period in laboratory rodents, defined as the age around the time of sexual
maturation, is very brief (for males about three weeks to a month and for females
about two weeks). (2)  Thus, behavioral paradigms that require extensive training
such as self-administration and drug discrimination may need to be modified, or
new paradigms  developed to accommodate the shorter developmental time period. 
An alternative approach, and one that is also encouraged, is the use of primate
models because of their extended adolescent period (age 2-4 years) and complex
social systems.

1.  Characteristics of Normal Adolescent Development

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. (2)  In
addition, hormonal levels change dramatically during adolescence as a result of
the onset of puberty.  After a prolonged period of suppression during the
childhood/juvenile period, there is reactivation of the hormonal regulatory
systems that control reproduction. (3)  This reinstatement stimulates the release
of gonadal hormones (e.g., testosterone in males and estrogen in females). 
Pulsatile release of growth hormones also increases during the growth spurt of
adolescence.

Corresponding to the shifts in brain and hormonal status are significant
transitions in cognitive, psychological, and social development.  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.  Sensation seeking and risk taking behaviors also increase in
adolescence relative to other ages, which is consistent with the need to
establish new social relationships, explore novel domains, and achieve parental
independence.  Thus, environmental influences during adolescence, including
alcohol consumption per se, 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 neurobiologic, genetic,
psychosocial and environmental factors could lead to earlier and more effective
prevention and treatment strategies.

2.  Neural and Behavioral Changes Unique to Adolescence

Evidence from human and animal studies indicates that unique neuroanatomical,
neurochemical and behavioral changes are occurring during postnatal development,
including adolescence. The prefrontal cortex (PFC), an area thought to mediate
higher cognitive abilities, undergoes major changes during adolescence in humans
and other animals. (4)  Absolute volume of the PFC declines during adolescence,
and connectivity of the PFC and other cortical regions are substantially refined
through preferential synapse elimination.  Dopaminergic and cholinergic inputs
to the PFC also increase during adolescence relative to other developmental
stages.  In addition, several neurochemical markers in the cortico-mesolimbic
dopamine system experience reorganization during adolescence, suggesting possible
shifts in the relative balance of dopamine activity.  For example, D1 and D2
receptors show greater overproduction and decline at puberty in the striatum than
in the nucleus accumbens. (5) Basal dopamine synthesis and turnover increase in
the striatum and nucleus accumbens during adolescence, whereas they decrease in
the PFC. (6)  Finally, maturational changes occur in other brain regions and
neurotransmitters systems during adolescence.

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. (7) 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
the stimulatory effects of catecholaminergic agonists, but more sensitive to the
dopamine antagonist haloperidol, a pattern suggestive of functional immaturity
of dopamine autoreceptors, or postsynaptic dopamine receptors, in mesolimbic
brain regions.  Dopamine is one of many neurotransmitters in the cortico-
mesolimbic reward system that have been implicated in the alcohol addiction
process.  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.

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.

3.  Current Research on Neurobiological and Behavioral Mechanisms of Adolescent
Drinking

Predisposition to Alcoholism:  Neurobehavioral research in human adolescents has
largely been limited to studies of vulnerability in 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.
(8)  More important, the neurophysiological abnormalities may be most pronounced
during the prepubertal and late adolescent years.  This latter finding
underscores the importance of considering developmental stages, particularly
adolescence, when trying to identify early risk markers for alcoholism.

Animal studies have found functional differences in the dopamine system (as
activated by amphetamine) between the selectively bred alcohol-preferring and
nonpreferring lines of rats as early as 28 days of age. (9)  Given that the
divergent drinking characteristics of these lines are also evident at this age,
it is possible that hyposensitivity of the dopamine system may be a potential
biological marker for susceptibility to alcohol abuse.

Ontogeny of Response and Tolerance to Alcohol.  Adolescent animals consume higher
absolute levels of alcohol than older animals, and that they may be able to
tolerate higher levels of ethanol intakes due to their relative insensitivity to
the sedating and motor impairing effects of ethanol. (10)  The relative
insensitivity of young rats to ethanol is seen not only with ethanol induced
sleep time and motor performance, but also with ethanol-induced hypothermia. This
ethanol-induced invulnerability, which occurs despite slower rates of ethanol
metabolism in younger animals, is due to a lower initial brain sensitivity to
ethanol, and to accentuated development of acute and chronic tolerance early in
life. (11)  The neurobiological mechanisms for the ontogenetic differences in
alcohol sensitivity need to be explored.

Behavioral and Physiological Consequences of Early Drinking.  While decreased
sensitivity to the sedative effects of alcohol may enable greater intakes in
adolescents (see above), this increased exposure to alcohol could have harmful
effects.  Investigators have found that inhibition by ethanol of hippocampal
NMDA-mediated synaptic potentials and long-term potentiation was greater in
adolescents than adults. (12) Behaviorally, adolescent rats showed greater
impairment on acquisition of a spatial memory task after ethanol exposure.  A
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. (2) Furthermore,
chronic ethanol treatment may lead to increased N-methyl-D-aspartate (NMDA)-
mediated neurotoxicity, which could be exacerbated by repeated withdrawals such
as during binge drinking. (2)  Consistent with this hypothesis is the possibility
that severity of alcohol and drug withdrawal symptoms may be a powerful marker
of protracted neuropsychological impairments in detoxified late adolescents and
young adults.  Since the immature brain is more susceptible to NMDA neurotoxicity
and since teenagers are more likely to engage in weekend binge drinking, it would
be important to study the effects of chronic binge patterns of ethanol exposure
on brain structure and function in human adolescents and on neurochemical and
cognitive functioning in animal models.

Stress, Hormones, Adolescence, and Alcohol Abuse.  Late childhood and adolescence
are periods of extreme flux in terms of both sexual and psychosocial development. 
The stress response system (hypothalamic-pituitary-adrenal axis) develops between
5 and 9 years of age, resulting in increased secretion of many adrenal steroids
(cortisol, androstenedione, dehydroepiandosterone).  This is followed by
increased activity of gonadotropins and then sex steroids (estradiol in females
and testosterone in males).  Increased life stressors associated with sexual and
social maturation together with hormonally-induced mood and behavior changes
could contribute to increased consumption of alcohol during the adolescent
period. (13).

In adult humans and animals, the relationship among stress, drinking, and
underlying neuroendocrine or neurochemical mechanisms is complex. (14) In
adolescents, a few studies using non-human primates have shown that under
conditions of social separation stress, subjects double their rates of alcohol
consumption.  In these studies, individual differences in stress-induced drinking
are attributed to anxiety-like behaviors (Type I alcoholism) mediated by
ontogenetic changes in cortisol and corticotropin levels or to poor impulse
control and impaired social competence associated with reduced serotonin
functioning (a trait-like marker present in infancy)(Type II alcoholism). (15)

With respect to sex steroid hormones, recent evidence from adult nonhuman
primates indicates that sensitivity to the subjective effects of ethanol changes
during different phases of the menstrual cycle due to alterations in endogenous
levels of ovarian-derived hormones. (16)  Given that adolescence is a time when
hormonal systems are still developing in humans and animals  and may be
fluctuating wildly, research on the interaction among life stressors, affective
states, and hormonal changes may be critical to understanding the onset and
continuation of adolescent drinking.

Early Exposure as a Predictor of Later Alcohol Abuse.  As mentioned above, early
exposure to alcohol at or before 14 years has been shown to be a powerful
predictor of later alcohol abuse and dependence.  There are two possible
explanations for this effect. First, early alcohol use may simply be a marker,
not a causative factor, of later alcohol abuse.  Second, it is possible that
alcohol exposure during adolescence may actually alter neurodevelopmental
processes in such a way that the likelihood of later abuse is increased. 
However, there have been relatively few reports using animal models to study the
effects of  pre- or post-weaning exposure to alcohol (including adolescence) on
later alcohol consumption, and the results have been conflicting.  More studies
are needed to explore whether there is a causal relationship between early
chronic exposure to alcohol and later alcohol problems, as well as the underlying
mechanisms for this effect.

Research Areas of Interest

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 be important
to identify neurobiologic and behavioral risk factors for alcoholism, and the
neural consequences of heavy drinking during adolescence.  For example, recent
developments in noninvasive imaging, such as functional MRI, offer opportunities
to study neurobiological markers for alcoholism as well as alcohol-induced brain
and cognitive deficits among human adolescents.  Animal models 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 studies of the relationship between environmental factors
such as stress in enhancing the likelihood of early alcohol exposure and later
intake.  The advent of PET and SPECT neuroimaging technologies and radioactive
ligands that label dopamine, opiate, and benzodiazepine receptors could allow
investigations of the functional ontogeny of various neurotransmitter systems in
adolescent primates, as well as the effects of early alcohol exposure on
development of these systems, and the relationship of these changes to future
drinking and social functioning.

Additional areas needing further research include, but are not limited to:

o  Modification and/or development of animal paradigms (in conjunction with a
neuroscience component) to study alcohol's hedonic effects, modes of initiation,
reinforcement, drug discrimination, sensitization, tolerance and dependence
during the juvenile through adolescent period.

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

o  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 that could impact on problem drinking behavior.

o  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 effects.

o  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 among hormonal changes,
affective state, and stress on drinking during adolescence.

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

o  Use of noninvasive neuroimaging (fMRI, MRS, PET, SPECT), neurophysiological
(EEG, ERP, MEG), and neuropsychological/ cognitive measures in adolescent
humans/primates to study risk markers for alcoholism, ontogeny of neuroanatomical
and neurochemical brain mechanisms of craving and intoxication, and to assess
progression of damage and recovery of function following abstinence.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

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
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).

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.

NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN
RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.  This
policy applies to all initial (Type 1) applications submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by February 23, 1999, 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 and 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 to avoid
conflict of interest in the review.

The letter of intent is to be sent to:

Office of Scientific Affairs
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Room 409, MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4375
FAX:  (301) 443-6077

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants.  These forms are available at most institutional offices of
sponsored research and from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone 301/435-0714, Email:  grantsinfo@nih.gov

The RFA label available in the PHS 398 (rev. 4/98) 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 2 of the face page of the application form and the
YES box must be marked.  The Abstract Page must clearly indicate the nature of
the required neurobiological component.  Page limits and limits on size of type
are strictly enforced.  Non-conforming applications will be returned without
being reviewed.

Submit a signed, typewritten original of the application, including the checklist
and three signed photo copies in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

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

Office of Scientific Affairs
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Room 409, MSC 7003
Bethesda, MD  20892-7003
Rockville, MD  20852 (for express/courier service)

Applications must be received by March 23, 1999.  If an application is received
after that date, it will be returned to the applicant without review.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the Center for
Scientific Review (CSR) and for responsiveness by the NIAAA, including the
required neurobiological component.  Incomplete applications will be returned to
the applicant without further consideration.  If the application is not
responsive to the RFA, CSR staff may 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 NIAAA in accordance with the review criteria stated below.  As part of the
initial merit review, a process will be used by the initial review group in which
applications receive a written critique and undergo a process in which only those
applications deemed to a 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 National Advisory Council on
Alcohol Abuse and Alcoholism.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written comments, reviewers will be asked to discuss the following aspects of the
application in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application.  Note that the application does not need to be
strong in all categories to be judged likely to have major scientific impact and
thus deserve a high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is essential
to move a field forward.

Significance:  Does the study address the goals of the RFA?  If the aims of the
study are achieved, how will scientific knowledge be advanced?  Will the study
advance the concepts or methods that drive this field?

Approach:  Are the conceptual framework, design, methods, and analyses adequately
developed, well-integrated, and appropriate to the aims of the project?  Does the
applicant acknowledge potential problem areas and consider alternative designs?

Feasibility:  Can the design be implemented (including recruitment of subjects,
cooperation of relevant organizations, and/or collection of necessary data)?

Innovation:  Does the project employ novel concepts, approaches, theories, or
methods?

Investigator:  Are the principal investigator and key research personnel
appropriately trained and well suited to carry out this work?

Environment:  Does the scientific environment in which the work will be done
contribute to the probability of success?  Does the proposed research take
advantage of the unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?

Budget: Is the requested budget and estimation of time to completion of the study
appropriate for the proposed research?

In addition, plans for the recruitment and retention of subjects will be
evaluated as well as the adequacy of plans to include both genders and minorities
and their subgroups and children as appropriate for the scientific goals of the
research.

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

AWARD CRITERIA

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

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

Direct inquiries regarding programmatic issues to:

Ellen D. Witt, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402
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
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-0915
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.

REFERENCES

1.  Johnston, J.D., O'Malley, P.M., Bachman, J.G. (1998)  National Survey Results
on Drug Use from the Monitoring the Future Study, 1975-1997,Vol I, Secondary
School Students. NIH Pub. No. 98-4345.

2.  Witt, E.D. (1994) Mechanisms of adolescent alcohol abuse and alcoholism: A
case for developing animal models.  Behavioral and Neural Biology, 62, 168-177.

3.  Reiter, E.O., Kulin, H.E. (1992) Neuroendocrine regulation of puberty. In E.
R. McAnarney, R. E. Kreipe, D. P. Orr, & G. D. Comerci (Eds.), Textbook of
adolescent medicine  (pp. 99-106).  Philadelphia:  W. B. Saunders Company.

4.  Lewis, D.A. (1997) Development of the prefrontal cortex during adolescence: 
insights into vulnerable neural circuits in schizophrenia. 
Neuropsychopharmacology, 16, 385-98.

5.  Teicher, M.H., Andersen, S.L., Hostetter Jr., J.C. (1995) Evidence for
dopamine receptor pruning between adolescence and adulthood in striatum but not
nucleus accumbens.  Developmental Brain Research, 89, 167-72.

6.  Andersen, S.L., Dumont, N.L., Teicher, M.H. (1997) Developmental differences
in dopamine synthesis inhibition by (+)-7-OH-DPAT. Naunyn-Schmeideberg's Archives
of Pharmacology, 356, 173-181.

7.  Spear, L. T., Brake, S. C. (1983)  Periadolescence:  age-dependent behavior
and psychopharmacological responsivity in the rat.  Developmental Psychobiology,
16, 83-109.

8.  Hill, S.Y., Steinhauer, S. R.  (1993)  Assessment of prepubertal and
postpubertal boys and girls at risk for developing alcoholism with P300 from a
visual discrimination task.  Journal of Studies on Alcohol, 54, 350-358.

9.  McKinzie, D.L., McBride, W.J., Murphy, J.M., Lumeng, L., Li, T.K. ( in press)
Rat lines selectively bred for alcohol preference: a potential animal model of
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10.  Silveri, M. M., Spear, L.P. (1998)  Decreased sensitivity to the hypnotic
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11.  Swartzwelder, H.S., Richardson, R.C., Markwiese-Foerch, B., Wilson, W.A.,
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12.  Swartzwelder, H.S., Wilson, W.A., Tayyeb, M.I. (1995) Age-dependent
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13.  Tschann, J.M., Adler, N.E., Irwin Jr., C.E., Millstein, S.G., Turner, R.A.,
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14.  Hunt, W.A., Zakhari, S. (Eds) (1995) National Institute on Alcohol Abuse and
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16.  Grant, K.A., Azarov, A., Shively, C.A., Purdy, R.H. (1997) Discriminative
stimulus effects of ethanol and 3-hydroxy-5-pregnan-20-one in relation to
menstrual cycle phase in cynomolgus monkeys (Macaca fascicularis). 
Psychopharmacology, 130, 59-68.


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