Full Text DA-95-003 HUMAN BASIC AND CLINICAL NEUROSCIENCE OF DRUG ADDICTION NIH GUIDE, Volume 24, Number 4, February 3, 1995 RFA: DA-95-003 P.T. 34 Keywords: Neuroscience Drugs/Drug Abuse Addiction National Institute on Drug Abuse Letter of Intent Receipt Date: April 3, 1995 Application Receipt Date: May 9, 1995 PURPOSE A generation of neuroscientific research utilizing animal models has provided the identification of receptors for every major abused drug and many of their endogenous ligands. A variety of models have been developed to explain the fundamental behavioral and biological mechanisms of addiction, e.g., brain reward, tolerance, and dependence. These discoveries and models, coupled with the rapid advances in noninvasive brain imaging methodology, now make it feasible to study drug addiction and the human brain to determine the etiology and the biomedical and biobehavioral consequences of drug abuse, as well as the effects of treatment of this disorder. The National Institute on Drug Abuse (NIDA) proposes to initiate a major program using noninvasive technologies or autopsy materials to study the human brain and the etiology and consequences of drug abuse and to translate this information into novel prevention, diagnostic, and treatment strategies. Research applications proposing to use current or to develop new noninvasive techniques to assess neuroanatomical, neurochemical, or other functional differences or changes in human brain that contribute to vulnerability to drug abuse, are a consequence of drug use, or result from pharmacological or non- pharmacological treatment are therefore invited. Investigators interested in research of this type with respect to AIDS etiology, consequences, and treatment in connection with drug abuse and addiction are particularly encouraged to apply. 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), Human Basic and Clinical Neuroscience of 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). ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, for-profit and nonprofit organizations, public and private such as colleges, universities, hospitals, laboratories, units of State and local government, and eligible agencies of the Federal government. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Racial/ethnic minority individuals, women and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the NIH research project grant (R01), exploratory/developmental research award (R21), FIRST (R29) award, and small grant (R03). Investigators may also respond to this RFA under the Interactive Research Project Grant Program (IRPG), which utilizes the R01 and R29 mechanisms. If an IPRG is proposed, it must consist of a minimum of two independent applications (see PA-94-086, NIH Guide for Grants and Contracts, Vol. 23, No. 28, July 29, 1994). However, if the IRPG mechanism is used under this RFA, the receipt date of this RFA takes precedence over the IRPG special receipt date. Research grants are awarded to institutions on behalf of Principal Investigators who have designed and will direct a specific project or set of projects. FUNDS AVAILABLE It is anticipated that approximately $3 million will be available to support projects submitted under this RFA. Because the nature and scope of the research proposed in response to this RFA may vary, the size of an award will vary also. It is anticipated that approximately 8 to 10 new awards will be made under this RFA. RESEARCH OBJECTIVES This program is intended to support research on basic and clinical human neuroscience of addiction. Research using animals is not excluded, but their use in projects submitted under this RFA must be specifically justified. Effort is to be made to use state-of-the-science approaches. Individual research project grants funded under this RFA may conduct research that uses various imaging or other innovative technologies, living neural tissue, or postmortem tissue to: 1. elucidate in humans the basic mechanisms of action of drugs of abuse, including interaction with other drugs and with mental or physical conditions, such as psychiatric disorders or AIDS; 2. examine the neurobiological factors, including those related to AIDS, that contribute to vulnerability to drug abuse; 3. examine the central nervous system (CNS) status of patients during diagnosis and treatment for drug dependency disorders; HIV infected persons or persons with AIDS may be special populations for such studies. 1. Basic Human Neuroscience Investigators are invited to study the effects of substance abuse on the structure and function of the human brain using various imaging and other technologies (e.g., ligand PET scanning, functional magnetic resonance imaging, magnetic source imaging, electroencephalography, magnetic resonance spectroscopy), autopsy material, or other methods (e.g., neural tissue transplantation, neuron cultures, analytical neurochemistry). The main goals of the basic research supported through this initiative are to: (1) identify in humans the neuronal systems involved in mediating the pleasurable or reinforcing experiences associated with substance abuse (the human brain reward system), and (2) characterize in humans the neurochemical, neuroanatomical, and neurophysiological changes that underlie states of drug tolerance and dependence, as well as to characterize the reversible and irreversible brain changes that result from drug abuse. Investigators are further encouraged to verify in man observations made in animal studies that drug abuse produces long-lasting changes in neurochemical markers and morphological features of specific sets of neurons. The effects of different types of drugs of abuse on neurochemical markers could be assayed in postmortem human brain tissue samples. Such studies should measure fundamental neuronal and glial structure and function including morphology, activity of enzymes involved in neurotransmitter synthesis and degradation, receptor densities and distribution, second messenger systems, and measurements of gene expression. Changes in these due to drug- related HIV infection are also subjects of interest. Of particular interest are studies that will take advantage of the opportunity to correlate directly the changes in the patterns of biologic activity in the human brain with the subjective experiences of the individual exposed to drugs of abuse. This research should help elucidate the precise neural mechanisms affected by drugs of abuse as well as reveal how drug-induced alterations might lead to and maintain drug-seeking behavior and addiction. Also important are studies assessing brain function during various stages of withdrawal and abstinence, which should provide important information about the neural substrates involved in drug craving. Studies are also encouraged that would refine current imaging techniques or develop new ones, elucidating the basic mechanisms and correlations that relate images to neuronal activity, for example, establishing the mathematical relationships between blood flow, metabolism, and cellular activity, or providing greater levels of refinement for viewing anatomical structures; e.g., applications of magnetic resonance microscopy which attempt to provide resolution at the cellular level. Again, alterations due to drug-related HIV infection are suitable topics for this request for applications. Research in the chemistry necessary to human brain imaging is also encouraged, for example, the synthesis of novel imaging reagents for use in humans. Another area of interest is the application of imaging technologies to pharmacokinetics. 2. Vulnerability and Etiological Investigations In humans, neurobiological factors that relate to high vulnerability to abuse drugs or to high vulnerability to suffer the adverse health consequences of drug abuse are not currently defined. NIDA is also interested in research on neurobiological aspects of drug abuse that might be unique to special groups, such as women and youth. In this connection, NIDA also encourages applications that focus specifically on HIV positive populations or individuals at risk for acquiring AIDS. Applications for support under this RFA will use original approaches to apply the latest in imaging and other innovative techniques to the examination of neurobiological factors underlying the etiology of and vulnerability to drug abuse in humans. Such projects might use noninvasive techniques to: a. Examine factors contributing to the biomedical etiology of drug abuse; for example, studies evaluating genetic, developmental, and environmental factors in drug addiction, including nutritional and environmental toxic elements; or examining the neurobiological relationship between early use of tobacco and alcohol and later development of cocaine and heroin addictions. b. Identify the type and distribution of the biomedical consequences of abusing drugs because of as-yet-unidentified neurobiological predispositions. c. Assess the prevalence, distribution, and epidemiology of biobehavioral risk factors underlying the vulnerability to abuse drugs. This might include investigations of the role of various stressors in vulnerability to drug addiction (e.g., links between post traumatic stress disorders and drug seeking behaviors or between HIV infection and drug addiction). d. Modify and further develop existing technologies and methodologies for studying the neurobiological risk factors of drug abuse. Projects should develop new information about how individual differences in genetics, neurobiological profiles, or psychological behaviors predict drug abuse or, alternatively, protect from drug abuse. 3. Clinical and Treatment Neuroscience Clinical and treatment-oriented neurobiological researchers are encouraged to submit applications that utilize state-of-the-art brain imaging, analytical neurochemistry, electrophysiology, neuropsychological assessment, genetic analysis, and other technology to elucidate the CNS status of patients during various stages of diagnosis and treatment of drug dependency disorders. For example, studies might examine neurotransmitter metabolites appearing in blood and cerebrospinal fluid as neurochemical markers for diagnosis, as correlates of mood and behavior, and as predictors of clinical outcome. This example also encompasses metabolic changes in response to various treatment interventions, pharmacological, behavioral, and psychosocial. It is important to describe the changes that occur in the endogenous opioid system, neuroendocrine system, and other neuronal systems in patients throughout all stages of the addictive process, including protracted abstinence, response to treatment, recovery, and long-term cognitive, perceptual, motor, or other deficits resulting from drug abuse. HIV-positive subjects or AIDS patients might be special populations in such applications. Studies evaluating the relationship between drug seeking behavior and preexisting neurological deficits, particularly hypofrontality and attention deficit hyperactivity disorders, or the comorbidity of drug use and of other mental disorders, especially depression, schizophrenia, anti-social personality, or AIDS-related dementia, are also encouraged. Research investigating the relationship between drug abuse and development of various neurological disorders such as Parkinson's disease, Alzheimer's disease, etc., is also of interest. Since many drug addicts are polydrug abusers, studies to investigate the neurological, neurochemical, pharmacological, pathological, and psychological consequences of interactions among abused drugs, such as cocaine, heroin, alcohol, nicotine, marijuana, anabolic steroids, and inhalants, are also encouraged. SPECIAL REQUIREMENTS The exploratory/developmental grant (R21) and small grant (R03) applications are limited to two years, are non-renewable, and are limited in direct cost amount per year (R03, $50,000; R21, $90,000). The R03 mechanism is intended for new, inexperienced investigators and both are intended for established investigators exploring new areas or departing from their usual research topics. There are special requirements for these mechanisms. An applicant intending to apply for them under this RFA should contact the program person listed under INQUIRIES for further information. 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 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. LETTER OF INTENT Prospective applicants are asked to submit, by April 3, 1995, a letter of intent that includes a descriptive title of the proposed research, the proposed mechanism of support, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institution, and the number and title of this RFA. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains allows NIDA staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: Director Office of Extramural Program Review, NIDA 5600 Fishers Lane, Room 10-42 Rockville, MD 20857 Telephone: (301) 443-2755 FAX: (301) 443-0538 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms 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 240, Bethesda, MD 20892, telephone 301-710-0267. FIRST award (R29) applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST award applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The RFA label in the PHS 398 must be affixed to the bottom of the original face page. Failure to use the RFA 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 in Item 2a on the face page of the application form and the YES box must be marked. 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 Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must also be sent to: Director Office of Extramural Program Review National Institute on Drug Abuse 5600 Fishers Lane, Room 10-42 Rockville, MD 20857 Applications must be received by May 9, 1995. If an application is received after that date will be held for the next regular receipt date and reviewed under standard circumstances. However, it will not be considered as a response to this RFA. The Division of Research Grants (DRG) will not accept any application in response to the 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 include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the Division of Research Grants (DRG) and responsiveness by NIDA. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, the applicant may be contacted 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/technical merit by an appropriate peer review group convened by NIDA in accordance with the review criteria stated below. As part of the initial merit review, a triage will 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 this RFA. 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. Review Criteria o scientific, technical or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; and o 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. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA The anticipated date of award is September 30, 1995. Applications recommended for further consideration by the NIDA Advisory Council will be considered for funding on the basis of overall scientific and technical merit of the application as determined by peer review, appropriateness of budget estimates, program needs and balance, policy considerations, adequacy of provisions for the protection of human subjects, and availability of funds. Special award criteria apply to R03 and R21 mechanisms. Applicants should contact the program person listed under INQUIRIES. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Harold W. Gordon, Ph.D. or Arthur Horton, Ph.D. Division of Clinical and Services Research National Institute on Drug Abuse 5600 Fishers Lane, Room 10A-38 Rockville, MD 20857 Telephone: (301) 443-4877 Email: hgordon@aoada.ssw.dhhs.gov Direct inquiries regarding fiscal or grants management issues to: Chief, Grants Management Branch National Institute on Drug Abuse 5600 Fishers Lane, Room 8A-54 Rockville, MD 20857 Telephone: (301) 443-6710 Email: gfleming@aoada.ssw.dhhs.gov The National Institute of Mental Health is not participating in this RFA, but continues to fund research in the area of basic human neuroscience through the unsolicited grant application process. For more information contact: Dr. Israel Lederhendler Systems Neuroscience Program National Institute of Mental Health 5600 Fishers Lane, Room 11-102 Rockville, MD 20857 Telephone: (301) 443-1576 FAX: (301) 443-4822 AUTHORITY AND REGULATIONS 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 at Title 42 CFR 52 "Grants for Research Projects," Title 45 CFR Part 74 & 92, "Administration of Grants," and 45 CFR Part 46, "Protection of Human Subjects." Title 42 CFR Part 2, "Confidentiality of Alcohol and Drug Abuse Patient Records" may also be applicable to these awards. 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. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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