NONHUMAN PRIMATE MODELS OF NEUROBIOLOGICAL MECHANISMS OF ADOLESCENT ALCOHOL 
ABUSE AND ALCOHOLISM

Release Date:  October 4, 2001

RFA:  RFA-AA-02-006

National Institute on Alcohol Abuse and Alcoholism
 (http://www.niaaa.nih.gov/)

Letter of Intent Receipt Date:  January 21, 2002
Application Receipt Date:       February 19, 2002

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  MODULAR 
INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS 
THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED 
IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

PURPOSE

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) invites 
applications using nonhuman primate models to focus on the following areas:  
1) neurobiological mechanisms and risk factors for alcoholism during late 
childhood through adolescence; 2) the relative contribution and/or 
interaction of genetic, environmental, and social factors (e.g., stress, peer 
influences) with neurobiological mechanisms in the development of adolescent 
alcohol abuse; 3) evaluation of the immediate and long-term consequences of 
heavy drinking during adolescence on cognitive/brain functioning; and 4) the 
contribution of early alcohol exposure (juvenile and adolescent periods) to 
excessive drinking and abnormal cognitive and social functioning during 
subsequent developmental stages. It is the intent of this Request for 
Applications (RFA) to foster interdisciplinary research (e.g., behavior, 
neuroanatomy, neurophysiology, neuropharmacology, neuroimaging). Therefore, 
good integration among components with diverse scientific disciplines is 
essential.  NIAAA strongly encourages investigators with expertise in primate 
developmental biology and behavior to seek collaborations with established 
alcohol researchers in order to elucidate the neurobiological mechanisms of 
adolescent alcohol abuse and alcoholism.  A high priority will be given to 
applications that include integrated research.

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a PHS-
led national activity for setting priority areas.  This Request for 
Applications (RFA), Title of RFA, is related to one or more of the priority 
areas.  Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople/.

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.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research project 
grant (R01) and the NIAAA exploratory/developmental (R21) award mechanism.  
Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant.  The total project period for a 
research project grant (R01) application submitted in response to this RFA 
may not exceed 5 years. Exploratory/developmental grants (R21) are limited to 
3 years for up to $100,000/year for direct costs. (See Program Announcement 
PA- 99-131, “NIAAA Exploratory/Developmental Grant Program,” 
http://grants.nih.gov/grants/guide/pa-files/PA-99-131.html, for a complete 
description of the R21 mechanism.)

Applicants are also encouraged to submit applications for Investigator-
Initiated Interactive Research Project Grants (IRPG) which is available at 
http://grants.nih.gov/grants/guide/pa-files/PA-96-001.html.  The IRPG 
mechanism requires 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. 

This RFA is a one-time solicitation.  Future unsolicited competing 
continuation applications will compete with all investigator-initiated 
applications and be reviewed according to the customary peer review 
procedures.  The anticipated award date is September 29, 2002.

FUNDS AVAILABLE

The NIAAA intends to commit approximately $2.5 million in FY 2002 to fund 
approximately 6 to 8 new and/or competitive continuation grants in response 
to this RFA.  Because the nature and scope of the research proposed may vary, 
it is anticipated that the size of each award will also vary. Although the 
financial plans of the NIAAA provide support for this program, awards 
pursuant to this RFA are contingent upon the availability of funds and the 
receipt of a sufficient number of meritorious applications. At this time, it 
is not known if this RFA will be reissued.

RESEARCH OBJECTIVES

Background

Although NIAAA recently launched a basic research initiative on adolescence, 
relatively few studies to date define the neurobiological mechanisms and 
consequences of heavy drinking in adolescents. One reason for the paucity of 
research in this area is the difficulty of studying the neurobiological and 
physiological (e.g., endocrine, heart rate, neurophysiology) mechanisms of 
alcohol abuse or dependence in human adolescents, in part, due to ethical and 
legal considerations, that prohibit administering alcohol to youths.  Most of 
the controlled laboratory studies on the neurobiological and behavioral 
mechanisms of adolescent drinking have been conducted in rodents.  However, 
there are several reasons that nonhuman primate models may be more 
advantageous for evaluating the etiology and consequences of adolescent 
alcoholism and for investigating cross-generational phenomena. First, 
nonhuman primates are genetically more similar to humans than rodents, with 
some species sharing between 90 to 99% of their DNA with humans. Because of 
the significant genetic overlap, many of the physiologic systems in nonhuman 
primates are highly similar to humans in terms of patterns of development and 
vulnerability to environmental influences including alcohol exposure (1). 
Second, the adolescent period in laboratory rodents is very brief (for males, 
about three weeks to a month and for females, about two weeks). Behavioral 
paradigms and social/environmental manipulations used in adult rodent studies 
may require weeks or even months of training, periods that extend well beyond 
the rodent adolescent window.  Nonhuman primate models are a better approach 
because of their extended adolescent period (2-4 years or longer in some 
species) and complex behavioral repertoires and social systems.  Furthermore, 
because of their protracted lifespan, it is possible to perform more 
extensive and elaborate studies on alcohol exposure during the adolescent 
period and determine the long-term consequences of this early exposure.  For 
these reasons, NIAAA proposes an initiative to focus on neurobiological 
mechanisms of adolescent alcohol abuse and dependence, neurobiological and 
physiological risk factors for development of alcoholism, and consequences of 
excessive drinking in adolescents using nonhuman primate models.

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. The first change 
indicative of puberty is the secretion of adrenal androgens and neuroactive 
steroids. 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 relative in adolescence 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, nonhuman primate, and rodent 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.  At the same time that loss of excitatory input to the PFC is 
occurring through synpatic pruning, dopaminergic and cholinergic inputs to 
the PFC 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 between the PFC and 
subcortical structures in the mesolimbic system.  For example, D1 and D2 
receptors show overproduction and decline at puberty in the striatum and 
nucleus accumbens.(5)  Basal dopamine synthesis and turnover in the striatum 
and nucleus accumbens are lower in early adolescence than in late 
adolescence, whereas the converse is true in PFC.  Finally, maturational 
changes occur in other limbic regions (hippocampus and amygdala) and 
neurotransmitters systems during adolescence (6).   

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.  Periadolescent 
animals are more "hyperactive" as measured by tests of exploratory behavior 
and social play, and have difficulty with complex discrimination learning 
tasks (7).  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. 

Nonhuman primates also undergo major social and behavioral changes during 
adolescence that distinguish this stage of development. While females remain 
in their natal troop at the onset of puberty, males typically leave their 
troop and join all-male gangs before entering a new troop.  This adolescent 
emigration period is especially risky for males, since they engage in 
substantial amounts of aggressive behavior with peers and competitive adults.  
They are also subjected to predation and possible malnourishment as they 
explore new environments and emigrate to new territory (1,6). Data exists 
regarding behavioral changes and synaptic pruning of various neurotransmitter 
receptors in primate cortex during adolescence.  However, less normative data 
is available on other neurochemical and pharmacological aspects of nonhuman 
primate neurodevelopment and their interaction with cognitive and social 
development.  

Given the relatively prolonged adolescent period in nonhuman primates, an 
understanding of the ontogeny of psychopharmacological responsiveness in 
neurotransmitter systems related to mechanisms of alcohol reinforcement, or 
alcohol's subjective effects using primate models could be extremely 
important in understanding the development of alcoholism 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.  Recently, it was found that high risk 
children of alcoholics show reduced right amygdala volumes, an area 
responsible for emotional processing (8).  More important, the 
neurophysiological and neuroanatomical 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 
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.

Rhesus monkeys with low serotonin metabolite (5-HIAA) levels in cerebrospinal 
fluid and greater availability of serotonin transporters are more aggressive 
and exhibit less intoxication on initial exposure to alcohol (10).  This 
pattern of behavioral and biochemical markers is similar to those 
predisposing to early onset alcoholism in humans, and may be related to early 
developmental stress (see below).  It would be important to determine the 
relationship among environmental factors, genetic backgrounds, and 
neurobiological and behavioral markers in predisposing to alcoholism using 
primate models.

Ontogeny of Response and Tolerance to Alcohol: Adolescent rats consume higher 
absolute levels of alcohol than older animals, possibly due to their relative 
insensitivity to the sedating and motor impairing effects of ethanol (6).  
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 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.  Although research in nonhuman primates suggests 
that low sensitivity to alcohol may be present in this species as well, more 
research is needed on neurobiological mechanisms for the ontogenetic 
differences in alcohol sensitivity.

Behavioral and Physiological Consequences of Early Drinking:  While decreased 
sensitivity to the sedative effects of alcohol may enable greater intakes in 
adolescents, 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 is greater in 
adolescents than adults (11).  Behaviorally, adolescent rats show greater 
impairment on acquisition of a spatial memory task after ethanol exposure, 
and binge alcohol exposure in rats during adolescence produces long-lasting 
changes in memory function (12).  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. 
Consistent with this  hypothesis is the finding that severity of alcohol and 
drug withdrawal symptoms may be a powerful marker of neuropsychological 
impairments in detoxified late adolescents and young adults (13).  
Furthermore, a recent study found reduced hippocampal volumes in adolescents 
with a history of alcohol abuse/dependence disorder (14).  Juvenile animals 
exposed to heavy binge-like episodes of ethanol develop damage in the frontal 
olfactory cortex and limbic system structures, including the hippocampus 
(15).  The immature brain is more susceptible to NMDA neurotoxicity and since 
teenagers are more likely to engage in weekend binge drinking, it is 
important to study the effects of chronic binge patterns of ethanol exposure 
on brain structure, neurochemistry, and cognitive functioning.  Primate 
models may be a better choice for studying the long-term consequences of 
alcohol exposure because of the prolonged adolescent period, which allows 
extensive manipulation of different types and length of exposure. This 
coupled with the new neuroanatomical and neuroimaging techniques offers a 
unique opportunity to study the brain changes associated with adolescent 
drinking.       

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, 
dehydroepiando-sterone).  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 (16).

In adult humans and animals, the relationship among stress, drinking, and 
underlying neuroendocrine or neurochemical mechanisms is complex.  In 
adolescents, a few studies using nonhuman primates have shown that under 
conditions of social separation stress, subjects double their rates of 
alcohol consumption (17,18).  In these studies, individual differences in 
stress-induced drinking are attributed to anxiety-like behaviors 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).

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 (19).  Given that adolescence 
is a time when hormonal systems are still developing in humans and animals, 
and may be fluctuating, 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.  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 early 
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. Primates, because of their extended adolescent period, offer a 
good opportunity to study this early exposure effect. 

Research Areas of Interest

More basic research is needed using nonhuman primate models to elucidate the 
neurobiological mechanisms of alcoholism and the effects of alcohol ingestion 
throughout the juvenile/adolescent period.  Nonhuman primate models would be 
important to identify neurobiologic and behavioral risk factors for 
alcoholism, the neural consequences of heavy drinking during adolescence, as 
well as to determine the role of environmental factors such as stress in 
enhancing the likelihood of early alcohol exposure and later intake. Primate 
models will be important for investigating the neurochemical, 
neuropharmacological, and behavioral mechanisms underlying the variable 
response to alcohol during ontogeny with respect to alcohol sensitivity, 
reinforcement, and discrimination.  The complex social groups of advanced 
nonhuman primates containing well-established relationships and 
multigenerational lineage are conducive to interdisciplinary studies 
incorporating genetic, neurobiological, and environmental factors.  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 Use of PET and SPECT neuroimaging in combination with behavioral measures 
to identify risk markers for alcoholism, the ontogeny of neuroanatomical and 
neurochemical circuits of intoxication and reinforcement, and to assess 
progression of alcohol damage and recovery of function during abstinence.

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

o Studies of the role of prefrontal cortex in alcohol-seeking behavior and 
alcohol consumption during the adolescent period.  Use of prefrontal 
anatomy/circuitry, physiology, and pharmacology to study alcohol-induced 
changes rewiring of synaptic connections and in cognitive functioning at 
multiple levels of analysis from cellular responses to behavioral 
functioning. 

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 Studies to examine the interaction among premorbid temperament/ 
personality, cognitive functioning, neurobiological, environmental, and 
genetic factors in the development of addictive behaviors in adolescents.

SPECIAL REQUIREMENTS

This RFA is intended to publicize NIAAA’s interest in the use of primate 
models of development in the study of neurobiological mechanisms of 
adolescent drinking.  Investigators wishing to obtain support for such 
research who lack expertise in alcohol research should seek collaboration 
with investigators experienced in alcohol research, insofar as such 
experience will prove essential for proper study design and data analysis.  
Investigators desiring to establish such collaborations are encouraged to 
contact the individual mentioned under INQUIRIES, below.  Awardees will be 
expected to attend one joint meeting every two years in or near Washington, 
DC, in order to review progress, and should include sufficient funds in their 
budgets to support such attendance. 

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT

The Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at:
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. 

LETTER OF INTENT

Prospective applicants are asked to submit 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 IC staff to 
estimate the potential review workload and plan the review.

The letter of intent is to be sent to:

RFA-AA-02-006
Extramural Project Review Branch 
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) 
Telephone: (301) 443-4375  FAX: (301) 443-6077 

by the letter of intent receipt date listed.
 
APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 5/2001) 
at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable PDF format.  Beginning January 10, 2002, however, the 
NIH will return applications that are not submitted on the 5/2001 version.  
For further assistance contact GrantsInfo, Telephone 301/435-0714, Email: 
GrantsInfo@nih.gov.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS 

The modular grant concept establishes specific modules in which direct costs may 
be requested as well as a maximum level for requested budgets.  Only limited 
budgetary information is required under this approach.  The just-in-time concept 
allows applicants to submit certain information only when there is a possibility 
for an award.  It is anticipated that these changes will reduce the 
administrative burden for the applicants, reviewers and NIH staff.  The research 
grant application form PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in 
applying for these grants, with modular budget instructions provided in Section 
C of the application instructions.

The RFA label available in the PHS 398 (rev. 5/2001) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  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 RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed, photocopies, 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 be 
sent to:

Chief, Extramural Project Review Branch
National Institute on Alcohol Abuse and Alcoholism
Willco Bldg, Suite 409
6000 Executive Blvd, MSC 7003
Bethesda, MD  20892-7003

Applications must be received by the application receipt date listed in the 
heading of this RFA.  If an application is received after that date, it will 
be returned to the applicant without review.

The Center for Scientific Review (CSR) 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 
CSR 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 
include an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIAAA. 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, 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 NIAAA National Advisory Council or Board.

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.

(1) Significance:  Does this study address an important problem? If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

(2) 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 tactics?

(3) Innovation:  Does the project employ novel concepts, approaches or 
method? Are the aims original and innovative?  Does the project challenge 
existing paradigms or develop new methodologies or technologies?

(4) Investigator:  Is the investigator appropriately trained and well suited 
to carry out this work?  Is the work proposed appropriate to the experience 
level of the principal investigator and other researchers (if any)?  Will the 
team of investigators and collaborators receive sufficient participation or 
guidance from individuals with expertise in nonhuman primate/developmental 
neurobiology/alcohol research. 

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

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

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

o  The adequacy of the proposed plan to share data, if appropriate.)

Schedule

Letter of Intent Receipt Date:    January 21, 2002
Application Receipt Date:         February 19, 2002
Peer Review Date:                 April-May 2002
Council Review:                   August 2002
Earliest Anticipated Start Date:  September 29, 2002

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Ellen D. Witt, Ph.D.
Neuroscience and Behavioral Research Branch
National Institute on Alcohol Abuse and Alcoholism
Willco Bldg., Suite 402
6000 Executive Blvd., 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:

Ms. Judy Simons
Grants Management Branch 
National Institute on Alcohol Abuse and Alcoholism 
6000 Executive Blvd, Suite 504, MCS 7003 
Bethesda, MD 20892-7003 
Telephone: (301) 443-2434
FAX (301) 443-3891 
Email: jsimons@willco.niaaa.nih.gov 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 authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92.  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.  Suomi, S.J., Rasmussen, K.L., Higley, J.D.  (1992) Primate models of 
behavioral and physiologic change in adolescence. In  E. R. McAnarney, R. E. 
Kreipe, D. P. Orr, & G. D. Comerci (Eds.), Textbook of adolescent medicine  
(pp. 135-139).  Philadelphia:  W. B. Saunders Company.

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.  Spear, L.P. (2000) The adolescent brain and age-related behavioral 
manifestations.  Neuroscience and Biobehavioral Reviews, 24, 417-463.

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., DeBellis, M.D., Keshavan, M.S.,et. al. (2001) Right amygdala 
volume in adolescent and young adult offspring from families at high risk for 
developing alcoholism.  Biological Psychiatry, 49, 894-905.

9.  McKinzie, D.L., McBride, W.J., Murphy, J.M., et.al. (1999)  Rat lines 
selectively bred for alcohol preference: a potential animal model of 
adolescent alcohol drinking.  In J.H. Hannigan, N.E. Spear, L.P. Spear, & C. 
Goodlett (Eds.), Alcohol and Alcoholism: Effects on Brain and Development, 
Mahwah, NJ: Erlbaum, pp. 135-160.

10.  Heinz, A., Higley, J.D., Gorey, J.G., et al. (1998) In vivo association 
between alcohol intoxication, aggression, and serotonin transporter 
availability in nonhuman primates.  American Journal of Psychiatry, 155, 023-
1028.

11.  Swartzwelder, H.S., Wilson, W.A., Tayyeb, M.I. (1995) Age-dependent 
inhibition of long-term potentiation by ethanol in immature versus mature 
hippocampus.  Alcoholism:  Clinical and Experimental Research, 19, 1480-85.

12.  White, A.M., Ghia, AJ., Levin, E.D., Swartzwelder, H.S. (2000) Binge 
pattern ethanol exposure in adolescent and adult rats: differetial impact on 
subsequent responsiveness to ethanol.  Alcoholism: Clinical and Experimental 
Research, 24, 1251-1256.

13.  Brown, S.A., Tapert, S.F., Granholm, E., Dellis, D.C. (2000) 
Neurocognitive functioning of adolescents: effects of protracted alcohol use.  
Alcoholism: Clinical and Experimental Research, 24, 164-171.

14.  DeBellis, M.D., Clark, D.B., Beers, S. R., et al., (2000) Hippocampal 
volume in adolescent-onset alcohol use disorders.  American Journal of 
Psychiatry, 157, 737-744.

15.  Crews, F.T., Braun, c.J., Hoplight, B., et al. (2000) Binge ethanol 
consumption causes differential brain damage in young adolescent rats 
compared with adult rats.  Alcoholism: Clinical and Experimental Research, 
24, 1712-1723.

16.  Tschann, J.M., Adler, N.E., Irwin Jr., C.E., et al. (1994) Initiation of 
substance use early in adolescence: The roles of pubertal timing and 
emotional distress.  Health Psychology, 13, 326-33.

17.  Higley, J.D., Linnoila, M. (1997) A nonhuman primate model of excessive 
alcohol intake:  Personality and neurobiological parallels of Type I- and 
Type II-like alcoholism.  In M. Galanter (Ed), Recent Developments in 
Alcoholism, Volume 13, Alcoholism and Violence.  New York: Plenum Press, pp. 
191-219.

18.  Fahlke, C., Lorenz, J.G., Long, J., et al. (2000) Rearing experiences 
and stress-induced plasma cortisol as early risk factors for excessive 
alcohol consumption in nonhuman primates.  Alcoholism: Clinical and 
Experimental Research, 24, 644-650.

19.  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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