Full Text DA-98-001 NEUROBIOLOGICAL SUBSTRATES OF COGNITIVE FUNCTIONING IN DRUG ADDICTION NIH GUIDE, Volume 25, Number 38, November 8, 1996 RFA: DA-98-001 P.T. 34 Keywords: Addiction Drugs/Drug Abuse National Institute on Drug Abuse Letter of Intent Receipt Date: May 13, 1997 Application Receipt Date: June 13, 1997 PURPOSE The National Institute on Drug Abuse (NIDA) invites applications for research projects on the neural substrates of the addictive process relating to cognitive brain functions. Powerful new approaches are now available for exploring brain mechanisms underlying cognitive functions as well as the addictive process and/or its consequence. The purpose of this initiative is to encourage the use of these approaches to broaden our understanding of the relation of drug abuse and addiction with brain mechanisms underlying cognition. The results obtained from these studies should ultimately guide the development of improved drug abuse prevention and treatment strategies by identifying the brain circuits and neurobiological mechanisms specifically affected in addiction disorders. This Request for Applications (RFA) will support individual research project grants and mentored career development awards. Research proposals for projects exploring the physiological, chemical, and structural modifications in the brain associated with cognitive functioning in drug addiction will be considered. 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 RFA, Neurobiological Substrates of Cognitive Functions in Drug Abuse Disorders, is related to the priority area of alcohol and other drugs. 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 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 institutions are not eligible for FIRST Independent Research Support and Transition (FIRST) (R29) awards. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01), exploratory/developmental grant (R21), small grant (R03), and FIRST Award (R29), as well as Mentored Research Scientist Development Award (K01) and Mentored Clinical Scientist Development Award (K08) mechanisms. Most investigator-initiated research is supported by the research project grant (R01) mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 5 years. The anticipated award date is around April 1, 1998. The R29, K01, and K08 applications submitted in response to this RFA should use the Just-In-Time (JIT) submission procedures. These procedures were published in the NIH Guide, Volume 25, Number 10, March 29, 1996 with additional instructions published in Volume 25, Number 16, May 17, 1996. Copies of these two NIH Guide notices are available from the contact person listed under INQUIRIES and on the NIH (www.nih.gov) or NIDA (www.nida.nih.gov) Home Pages. The exploratory/developmental grants (R21), small grants (R03), FIRST Awards (R29), the mentored research scientist development awards (K01) and the mentored clinical scientist development awards (K08) have special requirements and criteria. Applicants intending to apply utilizing these mechanisms, are urged to contact the program person listed in INQUIRIES for further information. This RFA is an one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and will be reviewed according to the customary peer-review procedures. FUNDS AVAILABLE It is anticipated that approximately $1.5 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. However, it is anticipated that approximately six to eight new awards, ranging in size from $100,000 to $300,000 will be made under this RFA. RESEARCH OBJECTIVES Background Much progress has been made in our understanding of the neural substrates underlying cognitive functions. Still, little is known about the relationship between cognitive processes that are strong, mediating factors in the drug addiction process (such as craving, decision-making, euphoria, expectancy of output, impulsivity, learned associations, reward seeking, and risk assessment) and their precise neural substrates. For example, which neural circuits become modified and are important in the drug addiction process? How do the affected neural activities in these drug abuse- and addiction-associated systems influence normal neural functions in circuits that are thought to mediate higher brain functions such as arousal, attention, learning, memory, or even consciousness? Recent data have begun to indicate that several brain loci typically associated with memory are activated during craving; however, the relationship between drug-related neural events and those subserving different types of learning, memory, and/or emotion in these brain loci remains to be elucidated. Further, the relationship of these drug cue-associated alterations to signal processing in other brain loci mediating specific cognitive functions is also not well understood. Similarities and differences among brain activation patterns, neurochemical events, and structural modifications resulting from the use of different drugs or from drug use under different emotional states and/or vigilance levels need to be investigated. New methodological approaches in basic and clinical neurobiology now provide researchers the capability to investigate how drugs of abuse affect the brain and its function, and at the same time allow for the direct assessment of resultant alterations in cognitive functioning. This RFA provides the unique opportunity for a synergistic interaction between the areas of cognitive and addiction neuroscience in an effort to broaden significantly the understanding of the neurobiological basis of drug use and addiction. The principal goal of the research to be supported by this RFA is to integrate neurobiological research of addiction with advances in cognitive neuroscience. The following examples serve as a guide only and are not meant to constitute an exhaustive list of the types of research questions that are appropriate under this initiative. o Circuits within the brain subserving cognitive processes are likely to be involved in the development and progression of addictive disorders. Which specific brain loci and circuits are affected during each of the different stages of the addiction process? What are the similarities and/or differences in the brain activity patterns identified in association with drug use behavior compared to the activity patterns that are associated with normal cognitive processes? What neurochemical and/or structural substrates are associated with these changes in activity within brain areas involved in cognitive processing? o Drug abuse and addiction affect normal cognitive functions. Are the spatial and temporal distributions of normal brain activities affected by drugs of abuse? Do drugs of abuse alter neural circuits such as those involved in risk assessment, decision-making, or impulsivity? Are drug-related changes in cognitive brain activities more marked during certain phases of the drug addiction process? Do these changes depend on the continued presence of the drug? o Clinical studies have begun to identify activity changes in brain loci associated with shifts in vigilance levels. To understand more fully how drug use might impact on learning, memory, and related cognitive processes, it is important to establish the relationship of drug-induced altered states with the neural correlates of wakefulness, drowsiness, and sleep in human and in non-human, primate subjects. The influence of factors such as motivation, attention, emotional state, relaxation, imagery, etc. on the overall drug-related brain activity level changes is also of interest. Are the activation levels of various brain regions (the mesencephalic reticular formation and the intralaminar thalamus, for example) coordinated during drug use? What is the impact of factors such as emotional state on drug-related activation level changes? o Drugs such as PCP and LSD (and other hallucinogens) are known to produce flashbacks, or a recurrence of symptoms like those produced by the drug long after the drug use experience. What neural circuits are involved in this phenomenon? Marijuana can induce flashbacks in LSD users. What is the mechanism by which marijuana can induce flashbacks in LSD users? o What can drugs of abuse tell us about normal memory functioning? Can they provide clues about enhancing memory or reversing the memory loss associated with dementing disorders such as Alzheimer's disease or with AIDS? For example, novel marijuana receptor antagonists have recently been developed. What are the effects of these compounds on cognition? The opiate antagonist naloxone has also been shown to improve memory performance in several species under a variety of testing conditions. Are there other drugs that can be identified that could lead to therapeutic advances in treating memory loss? o Cholingeric and glutamatergic pathways in the cortex, limbic system, basal ganglia, and thalamus are involved in many aspects of learning, memory, arousal, attention, and sleep, yet little is known about the actions of drugs of abuse on these systems. Certain drugs of abuse such as marijuana and PCP have profound effects on memory and attention and both are thought to impact these two neurotransmitter systems, though a direct relationship has yet to be shown. o Several factors influence individual vulnerabilities to the addictive process in humans, including emotional states and genetic makeup. Are differences in function within brain circuits underlying cognitive processes related to individual vulnerabilities to the addictive process? o Prenatal and/or postnatal exposure to drugs of abuse may influence the development of cognitive brain processes. Are children/adolescents exposed to drugs of abuse different in their cognitive functioning from children/adolescents unexposed to drugs of abuse? Are there any special characteristics in the brain activation patterns associated with drug-seeking behaviors in age groups at high risk for drug taking, such as adolescents in their late teens? o Sex differences may influence susceptibility to addiction disorders. Are there differences between males and females in drug-induced activation patterns in cognitive neural circuits? o Disruption of cognitive functions is often an early symptom of HIV infection. Are the cognitive abnormalities associated with HIV infection in drug users different from the cognitive abnormalities associated with HIV infection in non-drug users? What are the physiological, chemical, and structural modifications in the brain associated with the cognitive disruptions of AIDS dementia in the context of drug use? All applications must address issues of project feasibility, implementation of the study, study design, sampling procedure, instrumentation and management, data collection, tracking of subjects, follow-up, and data analysis, as appropriate. Investigators are encouraged to offer HIV testing and counseling in accordance with current guidelines to subjects identified during the course of the research as being at risk for HIV acquisition or transmission. 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 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, 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 encouraged to discuss their research plans with the program staff listed under INQUIRIES. Potential applicantss are asked to submit, by May 13, 1997, 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 and title of the RFA in response to which the application is to 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 NIDA staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Director, Office of Extramural Program Review National Institute on Drug Abuse Parklawn Building, Room 10-42 5600 Fishers Lane Rockville, MD 20857 Telephone: (301) 443-2620 FAX: (301) 443-0538 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; and from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: asknih@odrockm1.od.nih.gov. The RFA label available in the PHS 398 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 2 of the face page of the application form and the YES box must be marked. FIRST (R29) award applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST (R29) award application submitted without the required number of 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 courier/overnight mail service) At the time of submission, two additional copies of the application must be sent to: Director, Office of Extramural Program Review National Institute on Drug Abuse Park law Building, Room 10-42 5600 Fishers Lane Rockville, MD 20857 Applications must be received by June 13, 1997. 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 include an introduction addressing the previous critique. Review Schedule Letter of Intent Receipt Date: May 13, 1997 Application Receipt Date: June 13, 1997 Peer Review Meeting: October/November 1997 Council Review Meeting: January 1998 REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and responsiveness by the NIDA. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, DRG staff may 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 NIDA in accordance with the review criteria stated below. REVIEW CRITERIA o relevance of proposed research to the goals and objectives of this RFA; o scientific, technical, or medical significance and impact of the proposed research; o creativity, originality, and the degree of synergy of scientific issues pertaining to the areas of cognitive and addiction neuroscience in the proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to conduct the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the appropriateness of their methodological training and their demonstrated research skill; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relationship to the proposed research; 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 Award criteria that will be used to make award decisions include: scientific and technical merit of the proposal as determined by peer review, availability of funds, program needs and balance, and adequacy of provisions for the protection of human and animal subjects. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. For inquiries on programmatic issues pertaining to human studies, contact: Chiiko Asanuma, Ph.D. Division of Clinical and Services Research National Institute on Drug Abuse Parklawn Building, Room 10A-46 Rockville, MD 20857 Telephone: (301) 443-4877 FAX: (301) 443-2317 email: cs2j@nih.gov For inquiries on programmatic issues pertaining to animal studies, contact: Thomas Aigner, Ph.D. Division of Basic Research National Institute on Drug Abuse 5600 Fishers Lane, Room 10A-19 Rockville, MD 20857 Telephone: (301) 443-6975 FAX: (301) 594-6443 Email: ta17r@nih.gov For inquiries on fiscal matters, contact: 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 Email: gf6s@nih.gov 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 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 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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