Full Text AA-95-005

ROLE OF TOBACCO DEPENDENCE IN ALCOHOLISM TREATMENT

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

RFA:  AA-95-005

P.T. 34

Keywords: 
  Alcohol/Alcoholism 
  Addiction 
  Smoking Behavior 
  Treatment, Medical+ 


National Institute On Alcohol Abuse And Alcoholism

Letter of Intent Receipt Date:  October 18, 1995
Application Receipt Date:  November 21, 1995

PURPOSE

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is
seeking research applications to study the alcohol tobacco
interaction in its implications for alcoholism treatment.  The
objective of this RFA is to encourage research that will lead to
improved strategies for treating alcohol and nicotine dependence in
patients receiving care for problem drinking.  Such research may
identify and test relevant clinical intervention strategies; identify
interactions between the two substances that have implications for
relapse prevention, or further understanding of the alcoholism
treatment process by investigating reinforcement mechanisms
underlying conjoint abuse of the two substances.

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 Request
for Applications (RFA), 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, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
Foreign applicants are not eligible for First Independent Research
Support and Transition (FIRST) (R29) Awards.

MECHANISM OF SUPPORT

Research support may be requested through applications for a regular
research project grant (R01), FIRST Award (R29),
exploratory/developmental grant (R21), and small grant (R03).  An
applicant for an R01 may request support for up to five years.  In FY
1995, the average total cost per year for new R01s funded by the
NIAAA was approximately $200,000.  Because the nature and scope of
the research proposed in response to this RFA may vary, it is
anticipated that the size of an award will vary also.

FIRST Award applications must be for five years.  Total direct costs
for the five-year period may not exceed $350,000 or $100,000 in any
one budget period.  Small grants (R03) and exploratory/developmental
grants (R21) are limited to two years for up to $50,000/year and
$70,000/year, respectively, for direct costs.  FIRST Awards, small
grants and exploratory/developmental grants cannot be renewed, but
grantees may apply for R01 support to continue research on the same
topics.

Potential applicants for FIRST Awards (R29), small grants (R03), and
exploratory/developmental grants (R21) should obtain copies of the
specific announcement for these programs from the National
Clearinghouse for Alcohol and Drug Information, P.O. Box 2345,
Rockville, MD 20852, telephone (301) 468-2600 or 1-800-729-6686.
Investigators submitting applications that exceed $500,000 for direct
costs in any one year must contact program staff prior to submitting
an application.

Applicants may also submit applications for Investigator-Initiated
Interactive Research Project Grants (IRPG) (refer to PA-94-086, Vol.
23, No. 28, July 29, 1994).  Interactive Research Project Grants
require the coordinated submission of related research project grants
(R01) and, to a limited extent, FIRST Award (R29) applications from
investigators who wish to collaborate on research, but do not require
extensive shared physical resources.  These applications must share a
common theme and describe the objectives and scientific importance of
the interchange of, for example, ideas, data, and materials among the
collaborating investigators.  A minimum of two independent
investigators with related research objectives may submit concurrent,
collaborative, cross-referenced individual R01 and R29 applications.
Applicants may be from one or several institutions.  Further
information on these and other grant mechanisms may be obtained from
the program staff listed under INQUIRIES.

FUNDS AVAILABLE

It is estimated that $2 million in total costs will be available to
support approximately 8 to 10 grants under this RFA.  This level of
support is dependent on the receipt of a sufficient number of
applications of high scientific merit.  Although this program is
provided for in the financial plan of NIAAA, the award of grants
pursuant to this RFA is also contingent upon the availability of
funds.  The earliest possible award date is July 1, 1996.

RESEARCH OBJECTIVES

Background

Behavioral Research

During the past decade many lines of converging data have suggested
that alcohol and tobacco consumption are correlated.  For example,
smokers consume two times as much alcohol per capita as do non-
smokers (Carmody et al., 1985) and their risk of excessive drinking
is also twice that of non-smokers, a relationship that holds across a
broad range of demographic variables (Henningfield et al., 1990;
Johnson and Jennison, 1992).  Alcoholism itself is estimated as 10 to
14 times more prevalent among those who smoke than those who do not
(DiFranza and Guerrera, 1990).  In addition, heavy drinking tends to
be associated with heavy smoking with 85 percent of currently
drinking alcoholics smoking daily.  Although smoking has
substantially declined in the United States to approximately 30
percent of adults it has diminished very little among alcoholics.

Co-occurrence of smoking and excessive drinking has important
treatment implications.  For example, previous or current problems
with alcohol and alcohol treatment bodes negatively for success in
smoking cessation (Bobo et al., 1987; DiFranza and Guerrera, 1990;
Sandor, 1991).  On the other hand, smoking cessation prior to formal
alcoholism treatment (Miller et al., 1983) appears to improve
subsequent drinking outcome.  Conversely, reducing drinking appears
to improve the prospects for successful smoking cessation (Burling et
al., 1982).  Curiously, participation in a stop-smoking program
conducted during the course of alcoholism treatment was found to
enhance maintenance of sobriety, even though the intervention had
little impact on smoking behavior itself (Burling et al., 1991).

Discontinuation of smoking and long-term abstinence from drinking are
also associated.  Alcoholics who maintain sobriety longer have been
reported as more successful in smoking cessation  (Bobo et al., 1987;
Hughes, 1993).  Similarly, relapse to drinking may prompt smoking
relapse (Shiffman et al., 1985; Sees and Clark, 1993).

Several pharmacologic and behavioral mechanisms have been proposed to
explain the association between smoking and drinking.  At a
pharmacologic level some degree of cross-tolerance seems to occur
between nicotine and alcohol as sympathetic nervous system agents,
each of which has both depressant and stimulant effects.  Second,
conjoint use of the two substances may also be due to accelerated
metabolism of one substance following ingestion of the other.  Third,
nicotine and alcohol may somewhat counteract the aversive effects of
each other, while potentiating reinforcing effects.

Basic Science

Administration of both alcohol and nicotine together to laboratory
animals alters the responses to either drug when administered alone.
For example, prior exposure to a low dose of nicotine increases
alcohol consumption, whereas a high dose decreases consumption
(Gauvin, Morre and Holloway, 1993).  Animals respond more for lateral
hypothalamic stimulation after nicotine treatment and less after
ethanol treatment, compared to controls (Schaefer and Michael, 1992).
However, when both agents are given together, responding is higher
than after nicotine alone suggesting that alcohol is enhancing the
reinforcing properties of nicotine.  In discriminative stimulus
studies, nicotine enhances the alcohol-like effects of nicotine in
alcohol-preferring rats compared to non-preferring rats (Gordon,
Meehan and Schecter, 1993).

Further evidence of interactions between alcohol and nicotine derives
from comparative sensitivity and cross-tolerance studies suggesting
that the sensitivities to alcohol and nicotine are related.  Mice
selectively bred for alcohol sensitivity are also more sensitive to
nicotine compared to alcohol-insensitive mice.  In addition, alcohol-
sensitive mice rendered tolerant to alcohol are also tolerant to
nicotine (de Fiebre and Collins, 1993; Luo, Marks and Collins, 1994
and Majchrzak and Dilsaver, 1992) and nicotine-tolerant, alcohol-
sensitive mice display cross-tolerance to alcohol (Collins et al.,
1993).  These effects are not observed in alcohol-insensitive mice.
In other studies, nicotine can antagonize the motor incoordinating
effect of alcohol (Dar and Bowman, 1994), whereas a nicotinic
receptor antagonist partially blocks increased locomotor activity
induced by alcohol (Blomqvist, Soderpalm and Engel, 1992).

To better understand the treatment implications of alcohol and
tobacco co-dependence, it is necessary to determine the mechanism of
interaction of these two agents and how the actions are modified when
both drugs are co-administered.  Several lines of evidence suggest
that although alcohol and nicotine have different molecular
structures, they have actions in common.  For example, both
substances stimulate the release of dopamine in the nucleus
accumbens, (Imperato and Di Chiara, 1986a, 1986b) an area of the
brain involved with the reinforcing properties of drugs.  A role for
dopamine is also suggested by the observation that blockade of
dopamine receptors increases both alcohol and nicotine intake
(Gauvin, et al, 1993; Dawe et al, 1995) .

Acetaldehyde is a pyrolysis product of tobacco and has been suggested
to play a role in the reinforcing effects of alcohol.  The rapid
transport of acetaldehyde in an unmetabolized and undiluted form from
the lungs through the heart to the brain may enhance the reinforcing
properties of smoking.

Areas of Research Interest

The following list of topics is intended only to illustrate NIAAA
interests; topics not specified should not be viewed as excluded from
consideration.  The primary objective of the RFA is to enhance the
efficacy of treatment for nicotine addicted, alcohol dependent
patients.  To that end, research studies are solicited in the
following areas.

Research is needed to determine the conditions under which tobacco
use serves as a salient risk factor for alcohol relapse.

Research suggests several hypothesized mechanisms for the linkage in
conjoint alcohol-tobacco use.  Studies are needed to more clearly
specify these putative mechanisms and understand their interactions.

Studies are needed that identify the optimal sequencing of alcohol
and smoking cessation in treatment programs.

Studies are needed that investigate the use of new/existing
pharmacologic agents as adjuncts to alcohol and smoking cessation and
in the maintenance of abstinence.

Our understanding of treatment issues would be advanced by the
identification of the cellular and molecular mechanisms that underlie
initiation, maintenance and relapse in conjoint alcohol and tobacco
consumption.  Studies that seek to advance the transfer of basic
research findings toward treatment intervention applications are
expressly encouraged.

Research is needed that elucidates factors that underlie the joint
vulnerability to alcohol and nicotine dependence.

Research is needed to develop common assessment methodologies for
alcohol and tobacco dependence that will lead to improved treatment
efficacy.

Research is needed to determine the extent to which alcohol acts
through nicotinic receptors and other receptors and whether chronic
nicotine exposure can alter those actions.

Research is needed using gene knockout technology against the
nicotinic receptor, examine the interactions of alcohol and nicotine.

Studies are needed that clarify the nature of the discriminative
stimuli for alcohol and nicotine and how these stimuli interact.

Studies are needed to determine whether conditioned cues associated
with smoking enhance alcohol reinforcement.

Studies are needed that assess the role of acetaldehyde in alcohol-
nicotine interactions.

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, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in affect since 1990.  The new policy contains some
provisions that are substantially different from the 1990 policies.

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

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

LETTER OF INTENT

Prospective applicants are asked to submit, by October 18, 1995, 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 of 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 avoid conflict of
interest in the review.

The letter of intent is to be sent to:

RFA:  AA-95-005
Office of Scientific Affairs
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 409
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
FAX:  (301) 443-6077

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 6701 Rockledge Drive, Room 3032, MSC 7762, Bethesda, MD
20892, telephone 301-710-0267; and from the NIAAA program
administrators listed under INQUIRIES.

The RFA label available in the PHS 398 (rev. 5/95) 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 2a of the face page of the application form and the YES box must
be marked.  Page limits and limits on size of type are strictly
enforced.  Applications for the FIRST award (R29) must include at
least three sealed letters of reference attached to the face page of
the original application.  FIRST award (R29) applications submitted
without the required number reference letters will be considered
incomplete and will be returned without review.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, photocopies in one package to:

DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express mail)

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

Mark Green, Ph.D.
Office of Scientific Affairs
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 409
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003  (20852 for express mail)

Applications must be received by November 21, 1995.  If an
application is received after that date, it will be returned to the
applicant without review.  The Division of Research Grants (DRG) 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 DRG 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 be prepared as a revised application and include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by DRG
and for responsiveness by the NIAAA.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, DRG staff will 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 Institute in accordance with the review criteria stated below.

As part of the initial merit review, a process (triage) may be used
by the initial review group in which applications will be determined
to be competitive or non-competitive based on their scientific merit
relative to other applications received in response to the RFA.
Applications judged to be competitive will be discussed and be
assigned a priority score.  Applications determined to be non-
competitive will be withdrawn from further consideration and the
Principal Investigator and the official signing for the applicant
organization will be notified.  The second level of review will be
provided by the appropriate National Advisory Council or Board.

Review Criteria

Criteria to be used in the scientific and technical merit review of
alcohol research grant applications will include the following:

1.  The scientific, technical, or medical significance and
originality of the proposed research.

2.  The appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research.

3.  The adequacy of the qualifications (including level of education
and training) and relevant research experience of the principal
investigator and key research personnel.

4.  The availability of adequate facilities, general environment for
the conduct of the proposed research, other resources, and
collaborative arrangements necessary for the research.

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

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

7.  Where applicable, the adequacy of procedures to protect or
minimize effects on human and animal subjects and the environment.

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 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 treatment aspects of proposed research to:

Joanne Fertig, Ph.D.
Division of Clinical and Prevention Research
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 402
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-0796
FAX:  (301) 443-8744
Email:  jfertig@willco.niaaa.nih.gov

Direct inquiries regarding the neuroscience and behavioral aspects of
proposed research to:

Walter Hunt, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 402
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4223
FAX:  (301) 594-0673
Email:  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 MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4703
FAX:  (301) 443-3891
Email:  jweeda@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 and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routing education,
library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS
mission to protect and advance the physical and mental health of the
american people.

.

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