NEUROBIOLOGY OF ETHANOL-RELATED BEHAVIORS

NIH GUIDE, Volume 23, Number 24, June 24, 1994



PA NUMBER:  PA-94-077



P.T. 34



Keywords:

  Alcohol/Alcoholism 

  Neurophysiology 

  Addiction 

  0705048 



National Institute on Alcohol Abuse and Alcoholism



PURPOSE



Understanding how ethanol consumption can alter behavior is an

important goal of the National Institute on Alcohol Abuse and

Alcoholism (NIAAA).  Consequently, NIAAA is seeking research grant

applications using state-of-the-art neuroscience and behavioral

techniques to elucidate the cellular and molecular mechanisms

underlying the acute and chronic actions of ethanol on the brain that

mediate ethanol-induced behaviors.  Animal and human studies are needed

in which ethanol-induced behaviors, including ethanol-seeking behavior,

motor incoordination, cognitive deficits, and aggression are coupled to

changes in neurotransmitters and neuromodulators in the brain.

Especially encouraged are applications that directly address specific

mechanisms underlying medical and behavioral problems associated with

excessive alcohol use, with a goal of developing prototypic therapeutic

approaches.



HEALTHY PEOPLE 2000



The Public Health Service (PHS) is committed to achieving the health

promotion and disease prevention objectives of "Healthy People 2000,"

a PHS-led national activity for setting priority areas.  This program

announcement, Neurobiology of Ethanol-Related Behaviors, is related to

the priority areas of alcohol abuse reduction and alcoholism treatment.

Potential applicants may obtain a copy of "Healthy People 2000" (Full

Report:  Stock No. 017-001-00474-0, or Summary Report:  Stock No.

017-001-00473-1) through the Superintendent of Documents, Government

Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).



ELIGIBILITY



Applications may be submitted by domestic and foreign, public and

private, non-profit and for-profit organizations, such as universities,

colleges, hospitals, research institutes and organizations, units of

State and local governments, and eligible agencies of the Federal

government.  Women and minority investigators are encouraged to apply.

Only domestic institutions are eligible for First Independent Research

Support and Transition (FIRST) Awards (R29).  U.S. citizenship,

however, is not required.



MECHANISM OF SUPPORT



Research support may be obtained through applications for regular

research project grants (R01), FIRST awards (R29),

exploratory/developmental grants (R21), and small grants (R03).

Applicants for R01s may request support for up to five years.  Small

grants and exploratory/developmental grants are limited to two years

for up to $50,000 per year and $70,000 per year, respectively, for

direct costs.  FIRST Award applications must be for five years.  Total

direct costs for the five-year period may not exceed $350,000, or

$100,000 in any one budget period.  FIRST awards,

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 FIRST awards, Exploratory/Developmental

Grants, and Small Grants may 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.  Although program project

grants (P01) will be considered for funding, due to budget constraints

and NIAAA requirements for program balance, applications for P01s in

the program areas of NIAAA are not generally encouraged.  Applications

for program projects should not be submitted without prior clearance by

NIAAA program staff.



While NIAAA desires to stimulate research in this area, the amount of

funding available will depend on appropriated funds, quality of

research grant applications, and program priorities at the time of the

award.  In FY 1993, 29 new and competing renewal grants related to this

program area were funded by NIAAA for approximately $4.3 million in

total costs.



RESEARCH OBJECTIVES



Abuse of alcoholic beverages is responsible for numerous medical and

social problems, including alcoholism per se and brain-related

toxicity.  As noted in the Eighth Special Report to the U.S. Congress

on Alcohol and Health, ethanol related mortality accounts for more than

five percent of all deaths in the United States.  This rate of

mortality ranks behind only cardiovascular and cancer mortality.



In addition to ethanol addiction, important adverse behavioral

consequences resulting from ethanol consumption are vehicular and

occupational accidents and violence and aggression.  Vehicular

accidents result largely from cognitive and motor impairments that

reduce performance and efficiency in such activities as driving a car

or operating machinery.  Violence and aggression after ethanol

consumption are often expressed as homicide, suicide, rape, spousal

battering, and child abuse.  Depression and low self-esteem in ethanol

abusers may contribute to antisocial behavior and suicide.

Inappropriate sexual responses are often related to ethanol intake and

may be expressed as sex crimes, including incest, date rape, and sexual

abuse of children and the elderly.



Since the presence of ethanol in the brain and chronic exposure can

alter biological mechanisms mediating behavior, the NIAAA requests

applications that address those mechanisms underlying undesirable

ethanol-induced behaviors.



Over the past 20 years, numerous reports have provided substantial

evidence suggesting that acute and chronic ethanol administration

alters various neurotransmitters and neuromodulators in the brain,

leading to alterations in behavior.  For example, dopamine and

serotonin as well as opiates, aminobutyric acid (GABA), and possibly

other neurotransmitters and hormones have been implicated in the

reinforcing effect of ethanol.  GABA and N-methyl-D-aspartate receptors

have also been associated with the intoxicating properties of acute

ethanol exposure and ethanol withdrawal.  Interfering with these

neurotransmitter-mediated events shows promise as a potential

therapeutic strategy for treating the various behavioral complications

of alcohol abuse and alcoholism.



Further research, taking into account genetic attributes, ethanol

effects, and environmental factors, can help to ascertain whether or

not ethanol-induced alterations in neurotransmitters and

neuromodulators specifically cause changes in behaviors relevant to

excessive ingestion of ethanol and/or to specific medical or social

problems associated with alcohol abuse.  Such studies will help

identify potential targets for later therapeutic strategies to help

reduce these problems.



Examples of areas needing further research include, but are limited to:



o  Development and application of appropriate animal protocols of

ethanol-induced behavior changes, coupling in vivo measures of

neurotransmitter release or neuroimaging techniques to behavioral

paradigms that address relevant medical and social situations related

to alcohol abuse and alcoholism.



o  Careful correlative studies assessing changes in specific

neurotransmitters and neuromodulators in specific areas of the brain

with appropriate behavioral end points directly relevant to the medical

and social problems outlined above.  Most relevant are studies using

oral ethanol administration that relate blood ethanol concentrations to

the behaviors monitored.



o  Use of innovative techniques, such as microdialysis, voltammetry, or

single electrode recordings, in specific brain regions in freely

behaving animals performing behavioral tasks relevant to the problems

discussed above.



o  Use of genetically defined animals to further clarify the

relationships between ethanol-related behavior and genetic differences

in neurotransmitter systems.



o  Development of new techniques or innovative use of existing

techniques for humans, such as PET and SPECT imaging that will allow

simultaneous monitoring of neurotransmitter changes of individuals

performing behavioral tasks relevant to the problems discussed above

during ethanol intake.



o  Specific pharmacological manipulations of various transmitter

systems to determine the extent to which ethanol-induced changes in

relevant behaviors can be altered and to determine whether such

alterations might have potential clinical relevance in ameliorating

abnormal behaviors induced by ethanol consumption.



STUDY POPULATIONS



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 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) which have been in effect

since 1990.  The new policy contains some new 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 reprinted in the NIH GUIDE

FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11.



Investigators may obtain copies from these sources or from the program

staff or contact person listed below.  Program staff may also provide

additional relevant information concerning the policy.



APPLICATION PROCEDURES



Applications are to be submitted on the grant application form PHS 398

(revised 9/91) and will be accepted at the standard application

deadlines as indicated in the application kit.



Application kits are available from most institutional offices of

sponsored research and from the Office of Grants Information, Division

of Research Grants, Westwood Building, Room 449, National Institutes of

Health, Bethesda, MD 20892, telephone 301-710-0267.  The number and

title of this program announcement must be typed in item number 2a on

the face page of the application.



FIRST applications must include at least three sealed letters of

reference attached to the face page of the original application.  FIRST

applications submitted without the required number of reference letters

will be considered incomplete and will be returned without review.



The completed original and five permanent, legible copies of the PHS

398 form must be sent or delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



REVIEW CONSIDERATIONS



Applications received under this program announcement will be assigned

to an appropriate Initial Review Group (IRG) in accordance with

established PHS Referral Guidelines.  The IRG, consisting primarily of

non-Federal scientific and technical experts, will review the

applications for scientific and technical merit in accordance with

standard NIH review procedures.  Notification of the review

recommendations will be sent to the applicant after the initial review.

Applications will receive a second-level review by an appropriate

National Advisory Council, whose review may be based on policy

considerations as well as scientific merit.  Only applications

recommended by the Council may be considered for funding.  Small Grants

(R03) do not receive a second level review.



Review Criteria



Criteria for scientific/technical merit review of applications for

regular research grants (R01) are:



1.  The overall scientific and technical merit and significance of the

proposed research.



2.  The appropriateness and adequacy of the experimental design,

including the adequacy of the methodology proposed for collection and

analysis of data.



3.  The adequacy of the qualifications and relevant research experience

of the principal investigator and key research personnel.



4.  The adequacy of facilities and general environments necessary for

the conduct of the proposed research, other resources, and any

collaborative arrangements necessary for the research.



5.  The appropriateness of budget estimates for the proposed research

activities.



6.  Where applicable, the adequacy of procedures to protect human and

animal subjects and the environment.



7.  Conformance of the application to the NIH policy on inclusion of

women and minorities in study populations.



The review criteria for Small Grants (R03), Exploratory/ Developmental

Grants (R21), and FIRST Awards (R29) are contained in their program

announcements.



AWARD CRITERIA



Applications recommended by a National Advisory Council will be

considered for funding on the basis of overall scientific and technical

merit of the research as determined by peer review, program needs and

balance, and availability of funds.



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.



Direct inquiries regarding programmatic issues to:



Walter A. Hunt, Ph.D.

Division of Basic Research

National Institute on Alcohol Abuse and Alcoholism

Willco Building, Suite 402

6000 Executive Boulevard

Rockville, MD  20892-7003

Telephone:  (301) 443-4225

FAX:  (301) 594-0673

Internet:  WHunt@WILLCO.NIAAA.NIH.GOV



Direct inquiries regarding fiscal matters to:



Joseph Weeda

Office of Planning and Resource Management

National Institute on Alcohol Abuse and Alcoholism

Willco Building, Suite 504

6000 Executive Boulevard

Rockville, MD  20892-7003

Telephone:  (301) 443-4703

FAX:  (301) 443-3891



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,

"Grants for Research Projects;" Title 45 CFR Parts 74 and 92,

"Administration of Grants;" and 45 CFR Part 46, "Protections of Human

Subjects."  This program is not subject to the intergovernmental review

requirements of Executive Order 12372 or Health Systems Agency review.



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