NIH GUIDE, Volume 22, Number 39, October 29, 1993

PA NUMBER:  PA-94-005

P.T. 34


  Drugs/Drug Abuse 



National Institute on Drug Abuse


The purpose of this program announcement is to encourage investigator

interest in the wide range of neuroscience research relevant to drug

addiction supported by several programmatic areas within the National

Institute on Drug Abuse (NIDA).  In light of quantum advances in

neuroscience technology, it is now possible to vastly increase our

knowledge of the relationships among neuroanatomy, neurophysiology,

neurochemistry, neuropsychopharmacology, addictive behavior, and

addictive disease.  The 12 initiatives in this program announcement

are designed to exploit this enormous potential in the service of

substantially improving our understanding of the brain mechanisms

that underlie addictive disease, an objective that is essential to

the improvement of preventive and therapeutic interventions.


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) 783-3238).


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

non-profit, public and private organizations, e.g., colleges,

universities, hospitals, laboratories, units of State or local

governments, and eligible agencies of the Federal government.

Applications from minority individuals and women are encouraged.

Foreign institutions are not eligible for First Independent Research

Support and Transition (FIRST) (R29) awards.


Support mechanisms include research project grants (R01), FIRST

Awards (R29), small grants (R03), program projects (P01), and

conference grants (R13).

Because the nature and scope of the research proposed in response to

this program announcement may vary, it is anticipated that the size

of an award will vary also.


To progress in dealing with problems of drug abuse and dependence,

expansion of research to understand the neural bases of this disease

is necessary.  The research tools available, e.g., histochemistry,

autoradiography, molecular biology, microscopy, imaging techniques

applicable to living brain (e.g., positron emission tomography

(PET)), and neurophysiology and neuropharmacology techniques (e.g.,

neural tissue transplantation, neuron cultures), especially those

monitoring neural processes during behavior (e.g., single-cell

electrophysiology, electroencephalography, microdialysis,

voltammetry) facilitate significant advances in understanding the

neurobiology mediating drug abuse, dependence, addiction, and

recovery.  These methods and the following examples of topics are not

exhaustive; applicants are invited to submit applications in a

discipline of neuroscience that will contribute to the understanding

of drug addiction.

1.  Reward Mechanisms in Drug Abuse

The brain-reward model begins to explain euphoria produced by a

variety of drug classes.  According to the model, the "high" results

from activation of a brain system that mediates the experience of

pleasure.  Identification of a neuroanatomical substrate for

drug-induced euphoria opened the door for research on the biological

basis of psychological dependence.  The various mechanisms by which

drugs affect this system is an important area of research.  The model

also provides a rationale for developing interventions to alleviate


Studies are needed to expand the model.  Mesocorticolimbic dopamine

pathways are a major component of the brain-reward system, but other

neurochemical systems should be studied for involvement in

brain-reward.  Studies of drug effects on components of the

brain-reward system and on neural events underlying tolerance,

sensitization, craving, and relapse to excessive drug intake are also

needed.  Studies that relate drugs to other reinforcers are


2.  Drug Abuse Neuropsychopharmacology

The neuroscience program seeks improved explanations of mechanisms of

drugs of abuse and of potential treatment drugs, especially

mechanisms underlying drug effects on behavior of the whole organism.

Examples include studies of (1) behavioral roles of specific

receptors and natural ligands; (2) roles of specific neurons and

neuronal systems (e.g., opioidergic); (3) preclinical models for new

treatment approaches; (4) neural mechanisms underlying drug-induced

disruption of complex behaviors, including changes in complex

behaviors during drug withdrawal and the effects on complex behavior

induced by potential treatment drugs; and (5) drug combinations,

e.g., cocaine plus ethanol, abused drug plus treatment drug.

3.  Vulnerability to Drug Addiction

The goal of this part of the program is to determine the

neurobiological bases for the predisposition to compulsively abuse

drugs, i.e., to identify and evaluate the factors that influence the

decision to continue self-administration.  An area of interest is the

genetic analyses of individual differences in response to drugs,

including differences in susceptibility to drug-seeking behavior, and

to neurotoxicity and other drug effects.  Genetic studies may include

recombinant inbred strains, determination of the genotype linked to

high or low self-administration, or the relationships of differences

in drug effects to differences in drug metabolism or receptor

subtypes.  Other studies of interest are those that determine the

influence of historical (e.g., previous drug exposure of the

organism) and environmental (e.g., social interaction) factors.

4.  Neurotoxicology of Drug Abuse

Research is encouraged to examine the neurobiological bases of the

neurotoxicology and behavioral toxicology of drugs of abuse.  Also

needed are investigations on residual effects of drug exposure that

may result in a compromised nervous system, more susceptible, later

in life, to the onset or progression of diseases not usually linked

to drug abuse, especially neurodegenerative diseases (e.g.

Parkinson's, Alzheimer's).

5.  Ontogenetic (Developmental) Neurobiology

Exposure to drugs gestationally, perinatally, or neonatally due to

drug use by the parent(s) may induce long-term cognitive, behavioral,

neurological, and neuroendocrine deficits resulting from alterations

in neuronal growth, neuronal function, or development of synapses and

neural networks.  There is need for information on the existence,

persistence, and functional significance of drug-induced changes in

the CNS due to the offspring's exposure to drugs.  Investigators are

encouraged to examine the ontogenetic consequences of exposure to

drugs of abuse by means of various neuroanatomical,

neurophysiological, neurochemical, or neurobehavioral methodologies.

6.  Long-Term Neuroplastic Changes in the CNS Due to Drug Abuse

Research is solicited on relationships of persistent neurobiological

changes due to drugs to behaviors such as tolerance, dependence, and

craving.  Evaluation of changes in reinforcement efficacy as a

function of alterations in brain-reward circuitry are of particular

interest.  Research may take advantage of the discovery that many

classes of drugs of abuse are potent inducers of immediate-early

genes (IEGs) in cells of the CNS.  Such research may explore the use

of IEG induction as a screening method to identify neuron populations

that are targets of drugs of abuse.  Such studies may also explore

the role of transcription factors in the neuroadaptive responses of

the CNS to drugs.  Investigators are encouraged to identify the

target genes that are regulated by IEGs in response to drugs.  Use of

transgenic animals to study the molecular basis of drug-seeking

behaviors should be considered to explore the effects of gene

products on specific aspects of drug-seeking behavior.

7.  Anabolic Steroid Abuse

An area of research interest to several PHS agencies is anabolic

steroid abuse.  Program announcement PA-92-80, "Research on Anabolic

Steroid Abuse," (issued May 1992) details this priority area.  As

discussed therein, research including the neurobehavioral actions of

anabolic steroids is encouraged.  Such research includes

determination of whether or not anabolic steroids can affect the

brain-reward system, assessment of dependence, elucidation of

neurobiological mechanisms and sites of action of anabolic steroid

effects on behavior, investigation of neurobiological side effects of

anabolic steroid abuse (including long-term consequences),

neuroscientific investigation of the postulated link between anabolic

steroid abuse and aggressive behavior, and interactions with other

drugs of abuse.

8.  Pain and Analgesia

This program centers on the neural bases of pain and its alleviation

and CNS mechanisms underlying opiate abuse.  Goals are to improve

understanding of (1) how transmitter systems interact with endogenous

opioid systems, and how the latter can be stimulated more effectively

to decrease pain perception; (2) mechanisms and consequences of

opioid actions in acute versus chronic pain; (3) whether the

analgesic action of opiates can be dissociated from dependence

liability; (4) other treatments for pain (e.g., efficacy and

mechanism of acupuncture, transplantation of opioid-releasing cells);

(5) the role of cognitive processes in the modulation of pain; (6)

changes in gene expression in CNS neurons in response to pain and the

relations between changes in gene expression and the behavioral

aspects of pain; (7) animal models of chronic pain; and (8)

differences between pain patients and drug-abusers in respect to

opiate use.

9.  Drug Effects on Sensory Processes

Little is known about effects of drugs on sensory systems other than

those mediating pain; i.e., the mechanisms of hallucinogen-induced

alterations in perception need study.  Studies are encouraged to

investigate effects of chronic drug exposure on sensory system

structure and function to determine changes leading to possible

neurotoxic damage and permanent sensory impairments and mental

disorders.  For example, neural damage has been described in

somatosensory cortex following certain designer drugs; the functional

consequences have not been determined.

10.  Drug Effects on Learning, Memory, and Cognition

The role of learning and memory in tolerance, dependence, and relapse

is a neglected area of neuropsychopharmacology.  Stimuli that become

associated with the drug experience elicit drug craving, yet little

information is available concerning the neural mediators of the

associative processes.  Studies of roles of, and substrates for,

learning and memory in addictive processes are encouraged.  Drugs of

abuse also impair cognitive processes and performance.  Work is

needed to characterize the chronic and residual effects of abused

drugs on learning, memory, awareness, judgment, performance, and the

variables that modify cognition, e.g., attention and motivation.

11.  Blood-Brain Barrier (BBB) and Drugs of Abuse

The goals are to determine (1) changes in BBB ultrastructure,

macromolecules, development, and function caused by drug abuse; (2)

reinforcing properties of drugs in terms of their fate at the BBB and

entry into the brain; (3) roles of the specialized BBB structures,

enzyme systems, and subcellular organelles in regard to the

neurotoxicity of abused substances; and (4) strategies for targeting

treatment drugs to the brain and for limiting the bioavailability of

drugs of abuse.

12.  Human Neuroscience

Due primarily to the rapid advances in noninvasive brain imaging

methodology, it is now feasible to scientifically study the

consequences of drug abuse on the human brain.  Since most

neuroscience research on drug abuse uses animal models, research

using human subjects is needed to test the hypotheses generated from

animal data and to fill in other gaps in our understanding of drug

abuse and addiction and their consequences.  Investigations utilizing

human subjects, including autopsy material, to study the consequences

and prerequisites of drug abuse and dependence are therefore






NIH policy is that applicants for NIH clinical research grants and

cooperative agreements will be required to include minorities and

women in study populations so that research findings can be of

benefit to all persons at risk of the disease, disorder or condition

under study; special emphasis should be placed on the need for

inclusion of minorities and women in studies of diseases, disorders

and conditions which disproportionately affect them.  This policy is

intended to apply to males and females of all ages.  If women or

minorities are excluded or inadequately represented in clinical

research, particularly in proposed population-based studies, a clear

compelling rationale should be provided.

The composition of the proposed study population must be described in

terms of gender and racial/ethnic group.  In addition, gender and

racial/ethnic issues should be addressed in developing a research

design and sample size appropriate for the scientific objectives of

the study.  This information should be included in the form PHS 398

in Sections 1-4 of the Research Plan AND summarized in Section 5,

Human Subjects.

Applicants are urged to assess carefully the feasibility of including

the broadest possible representation of minority groups.  However,

NIH recognizes that it may not be feasible or appropriate in all

research projects to include representation of the full array of

United States racial/ethnic minority populations (i.e., Native

Americans (including American Indians or Alaskan Natives),

Asian/Pacific Islanders, Blacks, Hispanics).

The rationale for studies on single minority population groups should

be provided.

For the purpose of this policy, clinical research includes human

biomedical and behavioral studies of etiology, epidemiology,

prevention (and preventive strategies), diagnosis, or treatment of

diseases, disorders or conditions, including but not limited to

clinical trials.

The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded.  However,

every effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including


If the required information is not contained within the application,

the application will be returned.

Peer reviewers will address specifically whether the research plan in

the application conforms to these policies.  If the representation of

women or minorities in a study design is inadequate to answer the

scientific question(s) addressed AND the justification for the

selected study population is inadequate, it will be considered a

scientific weakness or deficiency in the study design and will be

reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required

to address these policies.  NIH funding components will not award

grants or cooperative agreements that do not comply with these



Grant applications are to be submitted on form PHS 398 (rev. 9/91),

and will be accepted at the standard deadlines as indicated in the

application kit.  Receipt dates for applications for AIDS-related

research are found in the PHS 398 (rev. 9/91) instructions.

Application kits are available at most institutional offices of

sponsored research, and may be obtained from the Office of Grants

Information, Division of Research Grants, National Institutes of

Health, Westwood Building, Room 449, Bethesda, MD 20892 (telephone

301-435-0714).  The title and number of this announcement must be

typed in Item 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


The completed original application and five legible copies must be

sent or delivered to:

Division of Research Grant

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**


Applications will be assigned on the basis of established PHS

referral guideline.  Applications will be reviewed for scientific and

technical merit by review groups of the relevant Institute in

accordance with the standard NIH peer review procedures.  Following

scientific-technical review, the applications will receive a second

level review by the appropriate national advisory council.  Small

Grant (R03) applications do not receive a second level review.


Applications compete for available funds with all other approved

applications recommended for further consideration assigned to that

Institute.  The following will be considered in making funding

decisions:  quality of the proposed projects as determined by peer

review, program balance among research areas of the announcement, and

availability of funds.


Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or answer questions from potential applicants is


The areas of research described in this announcement reflect the

several programmatic interests with NIDA.  Direct inquiries regarding

programmatic issues to:

Roger Brown, Ph.D.

Division of Basic Research

National Institute on Drug Abuse

Parklawn Building, Room 10A-19

Rockville, MD  20857

Telephone:  (301) 443-6975

Direct inquiries regarding fiscal or grants management issues to:

Gary Fleming, J.D., M.A.

Grants Management Branch

National Institute on Drug Abuse

Parklawn Building, Room 8A-54

Rockville, MD  20857

Telephone:  (301) 443-6710


This program is described in the Catalogue of Federal Domestic

Assistance No. 93.279.  Awards are made under authorization of the

Public Health Service Act, Section 301, and administered under PHS

grants policies and Federal regulations 42 CFR 52 and 45 CFR Part 74.

This program is not subject to the intergovernmental review

requirements of Executive Order 12372 or the Health Systems Agency



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