NEUROSCIENCE RESEARCH ON DRUG ADDICTION

Release Date:  December 23, 1998

PA NUMBER:  PA-99-033

P.T.

National Institute on Drug Abuse

This PA replaces PA-94-005, which was published in the NIH Guide, Vol. 22, No.
39, October 29, 1993.

PURPOSE

The intent of this program announcement is to continue to encourage investigator
interest in the wide range of neuroscience research relevant to drug abuse, drug
dependence, and drug addiction supported by the National Institute on Drug
Abuse(NIDA).  The research relevant to this announcement does not involve human
subjects; for information about the neuroscience research program involving human
subjects, contact Dr. Joseph F. Frascella, 301-443-4877, [email protected].

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 PA, NEUROSCIENCE RESEARCH ON DRUG
ADDICTION, is related to the priority areas of tobacco, alcohol and other drugs,
and maternal and infant health.  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 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and nonprofit
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

Support mechanisms include:  Project Grants (R01), Small Grants (R03),
Exploratory Grants (R21), Program Projects (P01), and Research Centers (P30, P50
and P60).  Application for Research Centers must be in accordance with the NIDA
guidelines for Research Center applications.  Consultation with NIDA program
staff is encouraged prior to application.  Refer to the guidelines for the
specific eligibility requirements for the Small Grant Program (R03) and the
Exploratory Grant Program (R21).  Because the nature and scope of the research
proposed in this program announcement may vary, it is anticipated the size of an
award will vary also.

RESEARCH OBJECTIVES

The goals of the research areas outlined below are to understand the
neurobiological mechanisms underlying (1) drug abuse and addiction, (2) the
neurological and psychological consequences of drug abuse and addiction (e.g.,
neurotoxicity, altered cognition, drug psychoses, developmental deficits), and
(3) antecedents (vulnerability factors) and resistance factors to drug addiction
and relapse (e.g., stress, individual differences in responses to drugs of abuse,
resiliency, effects of treatment).  In addition, since the opiates (e.g., heroin,
hydromorphone) are prominent drugs of abuse and are also essential in the therapy
of severe pain, major research objectives outlined in this PA include efforts to
understand the neurobiological bases of pain and its alleviation by opiates and
alternative therapies.  The scientific understanding gained by this research is
anticipated ultimately to be applicable to improved treatment and prevention of
drug abuse and drug addiction, and their consequences.  The specific research
topics emphasized in this program announcement are:  (1) animal models to study
the neurobiology of addiction, (2) vulnerability to drug addiction, (3)
neuroadaptation and neurotoxicity, (4) developmental neurobiology, (5) drugs and
learning, memory, and cognition, (6) pain and analgesia, (7) drug effects on
sensory and perceptual systems, (8) drugs of abuse, sleep and circadian rhythms,
(9) neuropsychopharmacology of drugs of abuse, and (10) central nervous system
(CNS) interaction with other systems.

The following examples and topics are illustrative and not meant to encompass all
research responsive to this announcement.  The research opportunities outlined
below involve laboratory animal models, including non-human primates.  Inasmuch
as research has begun to show sex differences in many of the areas of research
outlined below (e.g., vulnerability, developmental neurobiology, learning, pain
and analgesia, aggression, etc.), investigators may wish to consider conducting
research with both male and female animals and to examine sex differences n
outcomes.

1.  Animal Models to Study the Neurobiology of Addiction

The drug self-administration paradigm has been a mainstay in research on the
behavioral neurobiology of drug abuse and addiction.  From that has evolved the
brain reward hypothesis of addiction.  A need exists to expand that model to
include the functional role of brain structures beyond the nucleus accumbens. For
example, some progress is being made in studies concerned with the neural
mechanisms underlying the development of salient associations to the drug
experience.  It is important to focus in on this avenue, because a possible cause
of relapse is believed to be exposure to environmental cues that are associated
with drug taking or seeking.  In addition, other aspects of addictive behaviors
need to be modeled and the associated underlying brain mechanisms determined. 
These areas of study include:  (1) drug craving; (2) switch in state; i.e., from
voluntary to uncontrolled intake in spite of increasing negative consequences;
(3) loss of control/narrowing of behavioral repertoire; and (4) the role of
stress in reinstatement of drug taking behavior. Studies employing standard and
developing innovative neuroimaging techniques to study the neurobiology of
addiction are highly encouraged.

2.  Vulnerability to Drug Addiction

Current research suggests that there may be certain predisposing factors that
account for individual differences in drug preference, tolerance, sensitization,
abstinence signs, reinforcing efficacy, rate of acquisition of drug taking,
maintenance, resistance to extinction, and reinstatement of drug taking. 
Research is solicited to determine the neurobiological antecedents of compulsive
drug taking behavior; i.e., to identify and evaluate the neurobiological factors
that influence the continuation, escalation, and/or relapse of drug-seeking and
drug self-administration.

One of the vulnerability factors of interest to NIDA is the genetic influence,
which might be involved in the reinforcing efficacy of drugs and the sensitivity
to toxic consequences of drug taking; such as, seizures, cognitive decline, or
frank neurotoxicity.  Genetic studies may use, for example, inducible knock-out
and other transgenic mice, mutagenesis screens, recombinant inbred strains,
determination of genotypes linked to differences in drug self-administration, or
the relationship between differences in drug effects and differences in drug
metabolism or receptor subtypes.  It is expected that these studies would be
driven by specific hypotheses concerning genetic vulnerability.  In addition to
investigations in rodents, investigators are encouraged to employ model genetics
systems such as zebrafish, drosophila, and C. elegans for the genetic analysis
of addiction.

Other predisposing factors that may influence a person's decision to use drugs
include critical periods of development (particularly adolescence), gender,
immunological status, stress, environmental stimulation, expectation, previous
drug use (possibly involving cross sensitization within and between classes of
drugs), and psychological disorders.  In addition, certain social or hierarchical
situations (e.g., aggression or the self-administration of anabolic steroids) can
alter drug use. Further study in animal models is required to identify the
neurobiological substrates that underlie these phenomena and how drugs of abuse
modify these substrates.

3.  Neuroadaptation and Neurotoxicity

Scientific evidence indicates that repeated drug intake can lead to transient and
persistent neural adaptations in adult animals. Research is solicited on the
relationships between drug-induced long-lasting neural adaptations and behaviors,
such as tolerance, sensitization, and the somatic and motivational aspects of
dependence.  Evaluation of changes in the ability of drugs of abuse to alter
behavior as a function of alterations in brain-reward circuitry and its
extensions are of particular interest.  Study of the adaptations unmasked by drug
withdrawal following continuous or intermittent drug intake, especially those
neuroadaptations that can lead to reinstatement of drug seeking and self-
administration (i.e., relapse), is encouraged.

The neurotoxicology of drugs of abuse, especially the relationship of
neurotoxicity to behavioral toxicity (e.g., animal models of drug-induced
psychoses, cognitive impairment, or negative motivational state), is also an
under-studied area of investigation.  Also needed are investigations of residual
effects of drug exposure that may contribute to the onset or progression of
diseases not usually linked to drug abuse, especially neurodegenerative disorders
(e.g., Parkinson's and Alzheimer's diseases).  Investigations of the mechanisms
of structural and functional recovery from neuronal insults and of interventions
that might improve recovery are encouraged.

Research on the mechanisms of drug-induced neuroadaptation and neurotoxicity is
encouraged.  The studies may include cellular and molecular examinations of
transcription factors, neurotrophic factors, neuropeptides, neurosteroids, and
intracellular signaling pathways; mechanisms of cell death; and alterations in
the binding, density, and trafficking of receptors.  Such research may also
include studies of the regulatory elements of neurotransmission, including
neuronal membrane channels, enzymes, synaptic connectivity in well-defined neural
circuits, and other factors that may mediate long-term neural and behavioral
plasticity.  Also of interest is the effect of drugs of abuse on cellular
processes of endothelial cells that form the blood-brain barrier.  Structure-
function analysis of receptors, analysis of ligand-receptor interactions,
crystallization of receptors and signaling molecules, and X-ray crystallographic
studies are encouraged.  Studies on persistent adaptations within and beyond the
mesolimbic dopamine system are especially encouraged.

4.  Developmental (Ontogenetic) Neurobiology

Gestational, perinatal, or neonatal exposure to drugs may induce long-term
attentional, cognitive, behavioral, neurological, and neuroendocrine deficits
resulting from alterations in neuronal growth, neuronal function, expression of
receptors, and/or development of synapses and neural networks.  Information is
needed to determine the existence, persistence, and functional significance of
drug-induced neuronal changes due to an offspring's exposure to drugs.  The
actions of abused drugs during other critical periods of development, especially
adolescence, are similarly of interest.  Investigators are encouraged to examine
the ontogenetic consequences of exposure to drugs of abuse using neuroanatomical,
neurophysiological, neurochemical, or neurobehavioral methodologies.  The use of
laboratory animal models to determine the neuronal bases for drug-induced
developmental behavioral effects is encouraged.

Studies may focus on the direct effects of a given drug on the developing brain
or on the role of indirect CNS effects, such as drug-influenced maternal
malnutrition, maternal behavior, blood flow to the fetal brain, and other factors
involved in rearing.  Studies are needed on the developmental effects not only
of drugs of abuse, but also of treatment drugs (e.g., methadone) and potential
treatment drugs.  Studies examining possible differential drug-induced effects
in male and female offspring would also be of interest.

Investigators interested in NIDA programs that support studies on the molecular
and cellular mechanisms of development of brain structures that mediate addiction
should consult PA-98-032, "ROLE OF LIMBIC SYSTEM AND BRAIN ONTOGENY IN DRUG
ABUSE" (http://www.nih.gov/grants/guide/pa-files/PA-98-032.html).

5.  Drugs and Learning, Memory, and Cognition

The role of learning and memory in drug tolerance, sensitization, dependence, and
relapse is an emerging area of study.  Stimuli that become associated with the
drug experience are thought to elicit drug craving, yet little information is
available concerning the neural mediators of the associative processes involved. 
Studies on the roles of, and substrates for, learning and memory in addictive
processes are encouraged.

Drugs of abuse can also impair cognitive processes and performance.  Research is
needed to characterize the chronic and residual neural effects of abused drugs
on learning, memory, awareness, judgment, and performance, as well as the
variables that modify cognition, such as attentional processes.

Studies are encouraged that define mechanisms of learning, memory, and cognition,
and how they are affected by drugs of abuse.  Studies may employ models using
laboratory animals, in vitro brain slices, or cell cultures to study phenomena
such as long-term potentiation (LTP), long-term depression (LTD), silent
synapses, and non-classical neuronal communication, such as volume transmission. 
Studies are also encouraged that examine the influence of commonly prescribed
psychoactive drugs that are subject to abuse (e.g., methylphenidate and
benzodiazepines) on learning and memory mechanisms.

6.  Pain and Analgesia

Many drugs producing analgesia have abuse liability, and the potential
development of drug dependence is a significant consideration when various
analgesics are used for the long-term treatment of chronic pain.  A variety of
research related to pain and analgesia is encouraged, including the following:

o  Studies of the neural adaptations that occur during the long-term pain state,
studies of how the resulting data might be applied to treatment of chronic pain,
and studies of how these adaptations compare to the general adaptation syndrome.

o  Studies developing more effective analgesics with little or no abuse or
dependence liability.

o  Studies evaluating analgesic efficacy and abuse potential of new compounds.

o  Studies on basic pain mechanisms employing multidisciplinary system
approaches.

o  Studies on analgesics elucidating differences in mechanisms associated with
addiction compared to dependence.

o  Studies on the neurobiological substrates of non-pharmaceutic pain treatments.

7.  Drug Effects on Sensory and Perceptual Systems

Little is known about effects of drugs of abuse on sensory systems (with the
exception of those mediating pain).  For example, the mechanisms of hallucinogen-
induced alterations in perception are in need of study.  Also, pruritus (itch)
is induced by several drugs of abuse (e.g., heroin) and is a symptom of numerous
diseases, yet has received little research attention.  Studies are encouraged to
investigate the effects of acute and chronic drug exposure on sensory system
structure and function.  These studies could focus on either transient drug-
induced sensory changes or more permanent sensory impairments and mental
disorders that may be the result of neural damage.  For example, neural damage
has been described in the somatosensory cortex following exposure to certain
drugs (e.g., methamphetamine).  The functional consequence of this type of damage
could be examined.  In addition, the role of these sensory and perceptual changes
in drug-taking behavior and relapse needs study.  This research could help
determine to what degree drug-induced alterations in sensation and perception can
affect drug-taking behavior.

Studies are encouraged on a variety of neuroanatomical structures, ranging from
the primary afferents to sensory cortex, with an emphasis on correlating
molecular, cellular and circuit changes with behavioral changes during and
following drug use.

8.  Drugs of Abuse, Sleep and Circadian Rhythms

There are gaps in knowledge about the role of sleep and changes in circadian
rhythms in drug abuse, addiction, and in pharmacological and other treatments for
drug abuse and co-morbid conditions.  Studies are encouraged that explore
questions regarding the relationship of drugs of abuse to sleep disturbances
including the neurochemical mechanisms responsible, how these relate to chronic
sleep disturbances that have been shown to promote depressive symptoms, and
whether sleep disturbances may be a contributing factor to relapse.  Studies are
needed to determine (1) the patterns of sleep associated with vulnerability or
resilience to drug abuse and its effects, and (2) the kinds and patterns of sleep
that are associated with drug abuse treatment.

9.  Neuropsychopharmacology of Drugs of Abuse

Neuropharmacological studies of the mechanisms underlying the behavioral effects
of specific abused drugs or drug classes and of potential treatment drugs are
encouraged.  Areas of interest include, but are not limited to, the following: 
(1) behavioral roles of specific receptors for drugs of abuse or their natural
ligands (e.g., roles of cannabinoid receptors and their endogenous ligands in
states of health and disease, roles of cholinergic receptors in nicotine
addiction), (2) functional relationships between peptides and classical
transmitters, (3) the cellular or systems level locus of drug interactions (e.g.,
interactions between cocaine and ethanol, abused drug and treatment drug), and
(4) roles of the blood-brain barrier (BBB) in drug abuse phenomena (e.g., changes
in BBB structure, development, or function caused by drug abuse; role of BBB in
regard to the neurotoxicity of abused substances; strategies for targeting
treatment drugs to the brain and for limiting the bioavailability of drugs of
abuse).

Also appropriate are studies of neural mechanisms underlying disruptions of
complex behaviors induced by drugs of abuse, drug withdrawal, or potential
treatment drugs.  Examples include studies of:  (1) preclinical models of drug-
induced aggressive and fighting behavior (e.g., studies of the neural mechanisms
underlying aggression following phencyclidine or anabolic steroid administration,
or during drug withdrawal), (2) neuronal substrates through which drugs can alter
social behavior in animals (e.g., parental and other affiliative behaviors, or
responses to social stimuli), and (3) neuropharmacological mechanisms underlying
drug-induced psychoses, hallucinations and flashbacks. 

10.  CNS Interaction with Other Systems

Through its direct effects on the CNS, drug abuse can influence other systems of
the body.  Likewise, the CNS may be affected by drug actions on peripheral
systems.  Therefore, research is solicited involving (1) interactions between
drugs of abuse and classical neurotransmitters and neuropeptides (e.g.,
corticotropin-releasing factor, cholecystokinin, neurotensin, neuropeptide Y),
cytokines (e.g., the interleukins), and chemokines; (2) neuromodulation of the
endocrine, reproductive, immune, cardiovascular, respiratory, and
gastrointestinal systems; and (3) feedback from peripheral organs impacting on
CNS functions.  Studies on the allostatic regulation of these systems, especially
with regard to aspects of stress and drug-taking, are particularly encouraged.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application deadlines as indicated in
the application kit. Application kits are available at most institutional offices
of sponsored research and may be obtained from the Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email:
[email protected].  The title and number of the program announcement must be
typed on line 2 of the face page of the application form and the YES box must be
marked.

Applicants planning to submit an investigator-initiated new (type 1), competing
continuation (type 2), competing supplement, or any amended/revised version of
the preceding grant application types requesting $500,000 or more in direct costs
for any year are advised that he or she must contact the Institute or Center (IC)
program staff before submitting the application, i.e, as plans for the study are
being developed. Furthermore, the application must obtain agreement from the IC
staff that the IC will accept the application for consideration for award.
Finally, the applicant must identify, in a cover letter sent with the
application, the staff member and Institute or Center who agreed to accept
assignment of the application.

This policy requires an applicant to obtain agreement for acceptance of both any
such application and any such subsequent amendment. Refer to the NIH Guide for
Grants and Contracts, March 20, 1998 at
http://www.nih.gov/grants/guide/notice-files/not98-030.html

The completed original application and five legible copies must be sent or
delivered 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)

REVIEW CONSIDERATIONS

Applications that are complete will be evaluated for scientific and technical
merit by an appropriate peer review group convened in accordance with the
standard peer review procedures.  As part of the initial merit review, all
applications will receive a written critique and undergo a process in which only
those applications deemed to have the highest scientific merit, generally the top
half of applications under review, will be discussed, assigned a priority score,
and receive a second level review by the appropriate national advisory council
or board.

REVIEW CRITERIA

The goals of NIH-supported research are to advance the 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)?

(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 protection for animals or the environment, to the
extent they may be adversely affected by the project proposed in the application.

AWARD CRITERIA

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

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Roger M. Brown, Ph.D.
Division of Basic Research
National Institute on Drug Abuse
6001 Executive Boulevard, Room 4284, MSC 9555
Bethesda, MD  20892-9555
Telephone:  (301) 443-6975
FAX:  (301) 594-6043
Email:  [email protected]

Applicants who are interested in pursuing aspects of topics covered in this
program announcement within a context of basic behavioral sciences should contact
Dr. Minda Lynch, telephone (301) 443-1263, Email: [email protected].

Direct inquiries regarding fiscal matters to:

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
6001 Executive Boulevard, MSC 9541
Bethesda, MD  20892-9541
Telephone:  (301) 443-6710
FAX:  (301) 594-6847
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.279.  Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241
and 285) and are administered under PHS grants policies and Federal Regulations
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 Public Health Service (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.

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