RFA-AA-02-006: NONHUMAN PRIMATE MODELS OF NEUROBIOLOGICAL MECHANISMS OF ADOLESCENT ALCOHOL ABUSE AND ALCOHOLISM

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NONHUMAN PRIMATE MODELS OF NEUROBIOLOGICAL MECHANISMS OF ADOLESCENT ALCOHOL ABUSE AND ALCOHOLISM Release Date: October 4, 2001 RFA: RFA-AA-02-006 National Institute on Alcohol Abuse and Alcoholism (http://www.niaaa.nih.gov/) Letter of Intent Receipt Date: January 21, 2002 Application Receipt Date: February 19, 2002 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE The National Institute on Alcohol Abuse and Alcoholism (NIAAA) invites applications using nonhuman primate models to focus on the following areas: 1) neurobiological mechanisms and risk factors for alcoholism during late childhood through adolescence, 2) the relative contribution and/or interaction of genetic, environmental, and social factors (e.g., stress, peer influences) with neurobiological mechanisms in the development of adolescent alcohol abuse, 3) evaluation of the immediate and long-term consequences of heavy drinking during adolescence on cognitive/brain functioning, and 4) the contribution of early alcohol exposure (juvenile and adolescent periods) to excessive drinking and abnormal cognitive and social functioning during subsequent developmental stages. It is the intent of this Request for Applications (RFA) to foster interdisciplinary research (e.g., behavior, neuroanatomy, neurophysiology, neuropharmacology, neuroimaging). Therefore, good integration among components with diverse scientific disciplines is essential. NIAAA strongly encourages investigators with expertise in primate developmental biology and behavior to seek collaborations with established alcohol researchers in order to elucidate the neurobiological mechanisms of adolescent alcohol abuse and alcoholism. A high priority will be given to applications that include integrated research. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS- led national activity for setting priority areas. This Request for Applications (RFA), Title of RFA, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. 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. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) and the NIAAA exploratory/developmental (R21) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for a research project grant (R01) application submitted in response to this RFA may not exceed 5 years. Exploratory/developmental grants (R21) are limited to 3 years for up to $100,000/year for direct costs. (See Program Announcement PA- 99-131, NIAAA Exploratory/Developmental Grant Program, http://grants.nih.gov/grants/guide/pa-files/PA-99-131.html, for a complete description of the R21 mechanism.) Applicants are also encouraged to submit applications for Investigator- Initiated Interactive Research Project Grants (IRPG) which is available at http://grants.nih.gov/grants/guide/pa-files/PA-96-001.html. The IRPG mechanism requires the coordinated submission of related research project grants (R01) 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 applications. Applicants may be from one or several institutions. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 29, 2002. FUNDS AVAILABLE The NIAAA intends to commit approximately $2.5 million in FY 2002 to fund approximately 6 to 8 new and/or competitive continuation grants in response to this RFA. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NIAAA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES Background Although NIAAA recently launched a basic research initiative on adolescence, relatively few studies to date define the neurobiological mechanisms and consequences of heavy drinking in adolescents. One reason for the paucity of research in this area is the difficulty of studying the neurobiological and physiological (e.g., endocrine, heart rate, neurophysiology) mechanisms of alcohol abuse or dependence in human adolescents, in part, due to ethical and legal considerations, that prohibit administering alcohol to youths. Most of the controlled laboratory studies on the neurobiological and behavioral mechanisms of adolescent drinking have been conducted in rodents. However, there are several reasons that nonhuman primate models may be more advantageous for evaluating the etiology and consequences of adolescent alcoholism and for investigating cross-generational phenomena. First, nonhuman primates are genetically more similar to humans than rodents, with some species sharing between 90 to 99% of their DNA with humans. Because of the significant genetic overlap, many of the physiologic systems in nonhuman primates are highly similar to humans in terms of patterns of development and vulnerability to environmental influences including alcohol exposure (1). Second, the adolescent period in laboratory rodents is very brief (for males, about three weeks to a month and for females, about two weeks). Behavioral paradigms and social/environmental manipulations used in adult rodent studies may require weeks or even months of training, periods that extend well beyond the rodent adolescent window. Nonhuman primate models are a better approach because of their extended adolescent period (2-4 years or longer in some species) and complex behavioral repertoires and social systems. Furthermore, because of their protracted lifespan, it is possible to perform more extensive and elaborate studies on alcohol exposure during the adolescent period and determine the long-term consequences of this early exposure. For these reasons, NIAAA proposes an initiative to focus on neurobiological mechanisms of adolescent alcohol abuse and dependence, neurobiological and physiological risk factors for development of alcoholism, and consequences of excessive drinking in adolescents using nonhuman primate models. 1. Characteristics of Normal Adolescent Development During the period of late childhood and adolescence, development of neurobiologic systems is incomplete. Although final brain size and available neurons are largely fixed early in infancy, plasticity of the brain continues during adolescence through the processes of overproduction and elimination of synapses, progressive myelination, variation in the evolution of neurotransmitter systems, and changes in the rate of brain electrical and metabolic activity (2). In addition, hormonal levels change dramatically during adolescence as a result of the onset of puberty. The first change indicative of puberty is the secretion of adrenal androgens and neuroactive steroids. After a prolonged period of suppression during the childhood/ juvenile period, there is reactivation of the hormonal regulatory systems that control reproduction (3). This reinstatement stimulates the release of gonadal hormones (e.g., testosterone in males and estrogen in females). Pulsatile release of growth hormones also increases during the growth spurt of adolescence. Corresponding to the shifts in brain and hormonal status are significant transitions in cognitive, psychological, and social development. Adolescence is marked by the emergence of new thinking skills, reassessment of body image, focus on peer relationships, and a desire to establish self-identity and distance from parents. Sensation seeking and risk taking behaviors also increase relative in adolescence to other ages, which is consistent with the need to establish new social relationships, explore novel domains, and achieve parental independence. Thus, environmental influences during adolescence, including alcohol consumption per se, may interact with unique neurobiological and physiological strengths and weaknesses to predispose or protect an individual from alcohol abuse and/or dependence. A better understanding of alcohol"s effects during adolescence on the complicated interaction among neurobiologic, genetic, psychosocial and environmental factors could lead to earlier and more effective prevention and treatment strategies. 2. Neural and Behavioral Changes Unique to Adolescence Evidence from human, nonhuman primate, and rodent studies indicates that unique neuroanatomical, neurochemical and behavioral changes are occurring during postnatal development, including adolescence. The prefrontal cortex (PFC), an area thought to mediate higher cognitive abilities, undergoes major changes during adolescence in humans and other animals (4). Absolute volume of the PFC declines during adolescence, and connectivity of the PFC and other cortical regions are substantially refined through preferential synapse elimination. At the same time that loss of excitatory input to the PFC is occurring through synpatic pruning, dopaminergic and cholinergic inputs to the PFC increase during adolescence relative to other developmental stages. In addition, several neurochemical markers in the cortico-mesolimbic dopamine system experience reorganization during adolescence, suggesting possible shifts in the relative balance of dopamine activity between the PFC and subcortical structures in the mesolimbic system. For example, D1 and D2 receptors show overproduction and decline at puberty in the striatum and nucleus accumbens.(5) Basal dopamine synthesis and turnover in the striatum and nucleus accumbens are lower in early adolescence than in late adolescence, whereas the converse is true in PFC. Finally, maturational changes occur in other limbic regions (hippocampus and amygdala) and neurotransmitters systems during adolescence (6). During the 7- to 10-day period just prior to the onset of puberty, referred to as "periadolescence," both male and female rats are behaviorally and pharmacologically distinct from younger and older animals. Periadolescent animals are more "hyperactive" as measured by tests of exploratory behavior and social play, and have difficulty with complex discrimination learning tasks (7). Pharmacologically, periadolescent animals are less responsive (hyposensitive) to the stimulatory effects of catecholaminergic agonists, but more sensitive to the dopamine antagonist haloperidol, a pattern suggestive of functional immaturity of dopamine autoreceptors, or postsynaptic dopamine receptors, in mesolimbic brain regions. Dopamine is one of many neurotransmitters in the cortico-mesolimbic reward system that have been implicated in the alcohol addiction process. However, whether periadolescent animals drink more alcohol than early postpubertal or adult rats because of an immature dopaminergic system, are more susceptible to alcohol dependence, or fail to attain mature dopamine function following high early intakes are important research questions that need to be explored. Nonhuman primates also undergo major social and behavioral changes during adolescence that distinguish this stage of development. While females remain in their natal troop at the onset of puberty, males typically leave their troop and join all-male gangs before entering a new troop. This adolescent emigration period is especially risky for males, since they engage in substantial amounts of aggressive behavior with peers and competitive adults. They are also subjected to predation and possible malnourishment as they explore new environments and emigrate to new territory (1,6). Data exists regarding behavioral changes and synaptic pruning of various neurotransmitter receptors in primate cortex during adolescence. However, less normative data is available on other neurochemical and pharmacological aspects of nonhuman primate neurodevelopment and their interaction with cognitive and social development. Given the relatively prolonged adolescent period in nonhuman primates, an understanding of the ontogeny of psychopharmacological responsiveness in neurotransmitter systems related to mechanisms of alcohol reinforcement, or alcohol"s subjective effects using primate models could be extremely important in understanding the development of alcoholism during adolescence. 3. Current Research on Neurobiological and Behavioral Mechanisms of Adolescent Drinking Predisposition to Alcoholism: Neurobehavioral research in human adolescents has largely been limited to studies of vulnerability in children who are at high risk because of a positive family history of alcoholism. These investigations suggest that there are neurocognitive and neurophysiological abnormalities in children of recovering alcoholics that could be early indicators of risk for alcoholism. Recently, it was found that high risk children of alcoholics show reduced right amygdala volumes, an area responsible for emotional processing (8). More important, the neurophysiological and neuroanatomical abnormalities may be most pronounced during the prepubertal and late adolescent years. This latter finding underscores the importance of considering developmental stages, particularly adolescence, when trying to identify early risk markers for alcoholism. Animal studies have found functional differences in the dopamine system between the selectively bred alcohol-preferring and nonpreferring lines of rats as early as 28 days of age (9). Given that the divergent drinking characteristics of these lines are also evident at this age, it is possible that hyposensitivity of the dopamine system may be a potential biological marker for susceptibility to alcohol abuse. Rhesus monkeys with low serotonin metabolite (5-HIAA) levels in cerebrospinal fluid and greater availability of serotonin transporters are more aggressive and exhibit less intoxication on initial exposure to alcohol (10). This pattern of behavioral and biochemical markers is similar to those predisposing to early onset alcoholism in humans, and may be related to early developmental stress (see below). It would be important to determine the relationship among environmental factors, genetic backgrounds, and neurobiological and behavioral markers in predisposing to alcoholism using primate models. Ontogeny of Response and Tolerance to Alcohol: Adolescent rats consume higher absolute levels of alcohol than older animals, possibly due to their relative insensitivity to the sedating and motor impairing effects of ethanol (6). The relative insensitivity of young rats to ethanol is seen not only with ethanol-induced sleep time and motor performance, but also with ethanol- induced hypothermia. This invulnerability, which occurs despite slower rates of ethanol metabolism in younger animals, is due to a lower initial brain sensitivity to ethanol, and to accentuated development of acute and chronic tolerance early in life. Although research in nonhuman primates suggests that low sensitivity to alcohol may be present in this species as well, more research is needed on neurobiological mechanisms for the ontogenetic differences in alcohol sensitivity. Behavioral and Physiological Consequences of Early Drinking: While decreased sensitivity to the sedative effects of alcohol may enable greater intakes in adolescents, this increased exposure to alcohol could have harmful effects. Investigators have found that inhibition by ethanol of hippocampal NMDA- mediated synaptic potentials and long-term potentiation is greater in adolescents than adults (11). Behaviorally, adolescent rats show greater impairment on acquisition of a spatial memory task after ethanol exposure, and binge alcohol exposure in rats during adolescence produces long-lasting changes in memory function (12). Furthermore, chronic ethanol treatment may lead to increased N-methyl-D-aspartate (NMDA)-mediated neurotoxicity, which could be exacerbated by repeated withdrawals such as during binge drinking. Consistent with this hypothesis is the finding that severity of alcohol and drug withdrawal symptoms may be a powerful marker of neuropsychological impairments in detoxified late adolescents and young adults (13). Furthermore, a recent study found reduced hippocampal volumes in adolescents with a history of alcohol abuse/dependence disorder (14). Juvenile animals exposed to heavy binge-like episodes of ethanol develop damage in the frontal olfactory cortex and limbic system structures, including the hippocampus (15). The immature brain is more susceptible to NMDA neurotoxicity and since teenagers are more likely to engage in weekend binge drinking, it is important to study the effects of chronic binge patterns of ethanol exposure on brain structure, neurochemistry, and cognitive functioning. Primate models may be a better choice for studying the long-term consequences of alcohol exposure because of the prolonged adolescent period, which allows extensive manipulation of different types and length of exposure. This coupled with the new neuroanatomical and neuroimaging techniques offers a unique opportunity to study the brain changes associated with adolescent drinking. Stress, Hormones, Adolescence, and Alcohol Abuse: Late childhood and adolescence are periods of extreme flux in terms of both sexual and psychosocial development. The stress response system (hypothalamic- pituitary-adrenal axis) develops between 5 and 9 years of age, resulting in increased secretion of many adrenal steroids (cortisol, androstenedione, dehydroepiando-sterone). This is followed by increased activity of gonadotropins and then sex steroids (estradiol in females and testosterone in males). Increased life stressors associated with sexual and social maturation together with hormonally-induced mood and behavior changes could contribute to increased consumption of alcohol during the adolescent period (16). In adult humans and animals, the relationship among stress, drinking, and underlying neuroendocrine or neurochemical mechanisms is complex. In adolescents, a few studies using nonhuman primates have shown that under conditions of social separation stress, subjects double their rates of alcohol consumption (17,18). In these studies, individual differences in stress-induced drinking are attributed to anxiety-like behaviors mediated by ontogenetic changes in cortisol and corticotropin levels or to poor impulse control and impaired social competence associated with reduced serotonin functioning (a trait-like marker present in infancy). With respect to sex steroid hormones, recent evidence from adult nonhuman primates indicates that sensitivity to the subjective effects of ethanol changes during different phases of the menstrual cycle due to alterations in endogenous levels of ovarian-derived hormones (19). Given that adolescence is a time when hormonal systems are still developing in humans and animals, and may be fluctuating, research on the interaction among life stressors, affective states, and hormonal changes may be critical to understanding the onset and continuation of adolescent drinking. Early Exposure as a Predictor of Later Alcohol Abuse. Early exposure to alcohol at or before 14 years has been shown to be a powerful predictor of later alcohol abuse and dependence. There are two possible explanations for this effect. First, early alcohol use may simply be a marker, not a causative factor, of later alcohol abuse. Second, it is possible that alcohol exposure during adolescence may actually alter neurodevelopmental processes in such a way that the likelihood of later abuse is increased. However, there have been relatively few reports using animal models to study the effects of early exposure to alcohol (including adolescence) on later alcohol consumption, and the results have been conflicting. More studies are needed to explore whether there is a causal relationship between early chronic exposure to alcohol and later alcohol problems, as well as the underlying mechanisms for this effect. Primates, because of their extended adolescent period, offer a good opportunity to study this early exposure effect. Research Areas of Interest More basic research is needed using nonhuman primate models to elucidate the neurobiological mechanisms of alcoholism and the effects of alcohol ingestion throughout the juvenile/adolescent period. Nonhuman primate models would be important to identify neurobiologic and behavioral risk factors for alcoholism, the neural consequences of heavy drinking during adolescence, as well as to determine the role of environmental factors such as stress in enhancing the likelihood of early alcohol exposure and later intake. Primate models will be important for investigating the neurochemical, neuropharmacological, and behavioral mechanisms underlying the variable response to alcohol during ontogeny with respect to alcohol sensitivity, reinforcement, and discrimination. The complex social groups of advanced nonhuman primates containing well-established relationships and multigenerational lineage are conducive to interdisciplinary studies incorporating genetic, neurobiological, and environmental factors. The advent of PET and SPECT neuroimaging technologies and radioactive ligands that label dopamine, opiate, and benzodiazepine receptors could allow investigations of the functional ontogeny of various neurotransmitter systems in adolescent primates, as well as the effects of early alcohol exposure on development of these systems, and the relationship of these changes to future drinking and social functioning. Additional areas needing further research include, but are not limited to: o Use of PET and SPECT neuroimaging in combination with behavioral measures to identify risk markers for alcoholism, the ontogeny of neuroanatomical and neurochemical circuits of intoxication and reinforcement, and to assess progression of alcohol damage and recovery of function during abstinence. o Ontogenetic studies to compare patterns of alcohol-related behaviors (e.g., alcohol reinforcement, sensitivity) and their neurochemical, neuropharmacological, neurophysiological, and neuroanatomical mechanisms during each stage of postnatal development through adulthood. o Studies of the role of prefrontal cortex in alcohol-seeking behavior and alcohol consumption during the adolescent period. Use of prefrontal anatomy/circuitry, physiology, and pharmacology to study alcohol-induced changes rewiring of synaptic connections and in cognitive functioning at multiple levels of analysis from cellular responses to behavioral functioning. o Studies of gender differences in alcohol"s effect on normal hormonal activation during puberty, mechanisms of alcohol"s effect on neuroendocrine- neurotransmitter interactions, and the relationship among hormonal changes, affective state, and stress on drinking during adolescence. o Studies to examine the interaction among premorbid temperament/ personality, cognitive functioning, neurobiological, environmental, and genetic factors in the development of addictive behaviors in adolescents. SPECIAL REQUIREMENTS This RFA is intended to publicize NIAAA’s interest in the use of primate models of development in the study of neurobiological mechanisms of adolescent drinking. Investigators wishing to obtain support for such research who lack expertise in alcohol research should seek collaboration with investigators experienced in alcohol research, insofar as such experience will prove essential for proper study design and data analysis. Investigators desiring to establish such collaborations are encouraged to contact the individual mentioned under INQUIRIES, below. Awardees will be expected to attend one joint meeting every two years in or near Washington, DC, in order to review progress, and should include sufficient funds in their budgets to support such attendance. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. LETTER OF INTENT Prospective applicants are asked to submit 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 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 IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to: RFA-AA-02-006 Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 409, MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-4375 FAX: (301) 443-6077 by the letter of intent receipt date listed. APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable PDF format. Beginning January 10, 2002, however, the NIH will return applications that are not submitted on the 5/2001 version. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions provided in Section C of the application instructions. The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package 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) At the time of submission, two additional copies of the application must be sent to: Chief, Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism Willco Bldg, Suite 409 6000 Executive Blvd, MSC 7003 Bethesda, MD 20892-7003 Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) 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 CSR 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 CSR and responsiveness by the NIAAA. If the application is not responsive to the RFA, CSR 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 the NIAAA in accordance with the review criteria stated below. 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 the applications under review, will be discussed, assigned a priority score, and receive a second level review by the NIAAA National Advisory Council or Board. Review Criteria The goals of NIH-supported research are to advance our 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)? Will the team of investigators and collaborators receive sufficient participation or guidance from individuals with expertise in nonhuman primate/developmental neurobiology/alcohol research. (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 plan to share data, if appropriate.) Schedule Letter of Intent Receipt Date: January 21, 2002 Application Receipt Date: February 19, 2002 Peer Review Date: April-May 2002 Council Review: August 2002 Earliest Anticipated Start Date: September 29, 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Ellen D. Witt, Ph.D. Neuroscience and Behavioral Research Branch National Institute on Alcohol Abuse and Alcoholism Willco Bldg., Suite 402 6000 Executive Blvd., MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-6545 FAX: (301) 594-0673 Email: ewitt@willco.niaaa.nih.gov Direct inquiries regarding fiscal matters to: Ms. Judy Simons Grants Management Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Blvd, Suite 504, MCS 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-2434 FAX (301) 443-3891 Email: jsimons@willco.niaaa.nih.gov lhilley@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 authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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. 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. REFERENCES 1. Suomi, S.J., Rasmussen, K.L., Higley, J.D. (1992) Primate models of behavioral and physiologic change in adolescence. In E. R. McAnarney, R. E. Kreipe, D. P. Orr, & G. D. Comerci (Eds.), Textbook of adolescent medicine (pp. 135-139). Philadelphia: W. B. Saunders Company. 2. Witt, E.D. (1994) Mechanisms of adolescent alcohol abuse and alcoholism: A case for developing animal models. Behavioral and Neural Biology, 62, 168- 177. 3. Reiter, E.O., Kulin, H.E. (1992) Neuroendocrine regulation of puberty. In E. R. McAnarney, R. E. Kreipe, D. P. Orr, & G. D. Comerci (Eds.), Textbook of adolescent medicine (pp. 99-106). Philadelphia: W. B. Saunders Company. 4. Lewis, D.A. (1997) Development of the prefrontal cortex during adolescence: insights into vulnerable neural circuits in schizophrenia. Neuropsychopharmacology, 16, 385-98. 5. Teicher, M.H., Andersen, S.L., Hostetter Jr., J.C. (1995) Evidence for dopamine receptor pruning between adolescence and adulthood in striatum but not nucleus accumbens. Developmental Brain Research, 89, 167-72. 6. Spear, L.P. (2000) The adolescent brain and age-related behavioral manifestations. Neuroscience and Biobehavioral Reviews, 24, 417-463. 7. Spear, L. T., Brake, S. C. 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