Full Text PA-95-073 MECHANISMS OF ADOLESCENT ALCOHOL ABUSE AND ALCOHOLISM NIH GUIDE, Volume 24, Number 24, June 30, 1995 PA NUMBER: PA-95-073 P.T. 34 Keywords: Alcohol/Alcoholism Adolescents 0705048 National Institute on Alcohol Abuse and Alcoholism PURPOSE The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is seeking research grant proposals to conduct basic research, using animal models and state-of-the-art imaging techniques in humans, to identify the neurobiological, physiological, and genetic factors that lead to adolescent alcohol abuse and dependence. Despite the fact that alcohol use is high among secondary school students, relatively few studies to date define the neurobiologic and physiologic mechanisms of high alcohol intake or the effects of excessive drinking in adolescents. Studies of neurobiologic mechanisms and risk factors for alcoholism during late childhood through adolescence would increase our ability to predict which individuals will be most likely to develop alcoholism early in life. In addition, evaluation of the effects of alcohol ingestion during postnatal development, particularly during adolescence, would further our understanding of alcohol's immediate consequences and the contribution of early alcohol exposure to excessive drinking and abnormal cognitive and social functioning during subsequent developmental stages. Finally, results obtained will help develop strategies for treatment and prevention of adolescent alcohol abuse and alcoholism. 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 program announcement, Mechanisms of Adolescent Alcohol Abuse and Alcoholism, is related to the priority area of alcohol abuse and alcoholism. 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 Applications may be submitted by foreign and domestic, 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) Awards (R29). MECHANISM OF SUPPORT Research support may be requested through applications for a regular research project grant (R01), FIRST Award (R29), exploratory/developmental grant (R21), and small grant (R03). Applicants for R01s may request support for up to five years. In FY 1994, the average total cost per year for new and competing renewal R01s funded by the Division of Basic Research was approximately $170,000. FIRST Award applications must be for five years. Total direct costs for the five-year period may not exceed $350,000 or $100,000 in any one budget period. Small grants (R03) and exploratory/ developmental grants (R21) are limited to two years for up to $50,000 per year and $70,000 per year, respectively, for direct costs. FIRST Awards, exploratory/developmental grants, and small grants cannot be renewed, but grantees may apply for R01 support to continue research on the same topics. Potential applicants for the FIRST Award (R29), exploratory/developmental grant (R21), and small grant (R03) should obtain copies of the specific announcements for these programs from the National Clearinghouse for Alcohol and Drug Information, P.O. Box 2345, Rockville, MD 20847-2345, telephone 301-468-2600 or 1-800-729-6686. Investigators submitting applications that exceed $500,000 for direct costs in any one year should contact program staff before submitting an application. Applicants may also submit applications for Investigator-Initiated Interactive Research Project Grants (IRPG) (PA-94-086, NIH Guide, Vol. 23, No. 28, July 29, 1994). Interactive Research Project Grants require the coordinated submission of related research project grant (R01) and, to a limited extent, FIRST Award (R29) applications 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 and R29 applications. Applicants may be from one or several institutions. Further information on these and other grant mechanisms may be obtained from the program staff listed under INQUIRIES. RESEARCH OBJECTIVES Alcohol remains the most commonly abused substance among adolescents. According to the National Adolescent Student Health Survey, 75.9 percent of 8th graders and 87.3 percent of 10th graders have used alcohol in their lifetime (Windle, 1990). Of greater significance is the widespread occurrence of heavy drinking (defined as consuming five or more drinks in a row during the past two weeks). Among high school seniors this statistic is 28 percent. Males have consistently reported more frequent and heavier use than females, but this difference has been gradually diminishing over the last decade (Johnston, et al., 1994). This is particularly important since females require less alcohol to achieve blood alcohol concentrations equivalent to males (Frezza, et al, 1990). Thus, if females begin drinking heavily during adolescence and continue throughout life, they may be at enhanced risk for the medical consequences of alcohol abuse including liver disease (Norton, et al, 1987), brain damage (Harper, et al., 1990), and associated behavioral deficits (Glenn & Parsons, 1992). Given the early onset of drinking and its frequency, the consequences of alcohol's acute and chronic effects on physiological growth and maturation, as well as its potential deleterious effects on the development of social and interpersonal competencies, are of major concern. 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 (Watkins and Williams, 1992). In addition, hormonal levels change dramatically during adolescence as a result of the onset of puberty. Corresponding to the shifts in brain and hormonal status are significant transitions in cognitive, psychological, and social development (Susman and Petersen, 1992). 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 (Ingersoll, 1992). Thus, environmental influences during adolescence, including alcohol consumption, 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 genetic, neurobiologic, psychosocial and environmental factors could lead to earlier and more effective prevention and treatment strategies. To date, relatively few studies define the neurobiological and physiological effects of alcohol in adolescents, in part due to ethical considerations that prohibit administering alcohol to youths. Neurobehavioral research in human adolescents has been largely limited to studies of 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 (Begleiter, et al, 1984; Hill, et al, 1990; Porjesz and Begleiter, 1993; Whipple, et al, 1991). More importantly, the neurophysiological abnormalities are most pronounced during the prepubertal and late adolescent years, are highly dependent on the differential rates of nervous system development in boys and girls, and may reflect maturational lag in children who are at high risk for developing alcoholism (Hill and Steinhauer, 1993; Steinhauer and Hill, 1993). This latter finding underscores the importance of considering developmental stages, particularly adolescence, when trying to identify early risk markers for alcoholism. Evidence from animal studies indicates that unique neurochemical and behavioral changes are occurring during postnatal development, including adolescence, that could mediate the response to alcohol (see Witt, 1994, for review). While the various neurotransmitter systems develop at different rates, the ontogeny of several neurotransmitter systems extends into the adolescent period. For example, in the rat, neurochemical markers of dopamine activity in the striatum, such as levels of postsynaptic receptors and presynaptic dopamine content, show a gradual increase until adult levels are reached around puberty (Coyle and Harris, 1987; Noison and Thomas, 1988). Similarly, in animals and humans, presynaptic cholinergic markers in the cortex do not reach adult levels until the adolescent period (Coyle and Yamamura, 1976; Virgili, et al., 1990; Court et al., 1993). 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 (Spear and Brake, 1983). Periadolescent animals are more "hyperactive" as measured by tests of exploratory behavior and social play, and have difficulty with complex discrimination learning tasks. Pharmacologically, periadolescent animals are less responsive (hyposensitive) to drugs affecting the catecholaminergic system (Spear, et al., 1980; Shalaby and Spear, 1980), which may be due to functional immaturity of self-inhibitory presynaptic dopamine autoreceptors in mesolimbic brain regions during the periadolescent period (Spear et al., 1981). 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. Dopamine is one of many neurotransmitter systems that have been implicated in the alcohol addiction process. An understanding of the ontogeny of psychopharmacological responsiveness in neurotransmitter systems related to mechanisms of alcohol reinforcement, alcohol preference, or alcohol's subjective effects could be extremely important in understanding the development of alcohol addiction during adolescence. Finally, animal studies of the ontogeny of alcohol's acute effects on learning and memory have shown early age-dependent changes in alcohol's effect on selective learning tasks (e.g., sensory preconditioning) (Chen, et al., 1992). However, more studies are needed to look at ethanol's influence on age-related changes on other cognitive measures and the neurochemical mechanisms underlying these changes. Similarly, few studies have investigated the effects of chronic ethanol use on cognition and brain function. A recent study of alcohol-abusing teenagers found that both male and female adolescent alcohol abusers were inferior in language skills, but only females were impaired on tests of abstract reasoning and cognitive flexibility (Moss, et al., 1994). Furthermore, chronic ethanol treatment may lead to increased N-methyl-D-aspartate (NMDA)-mediated neurotoxicity (Crews & Chandler, 1993), which could be exacerbated by repeated withdrawals such as during binge drinking (Hunt, 1993). Since the immature brain is more susceptible to NMDA neurotoxicity (Garthwaite & Garthwaite, 1986) and since teenagers are more likely to engage in weekend binge drinking, it would be important to study the effects of such patterns of ethanol exposure on neurochemical parameters and cognitive functioning using adolescent animals models. More basic research is needed in humans and animals to elucidate the neurobiological mechanisms of alcoholism and the effects of alcohol ingestion throughout the period of postnatal maturation. Human studies would also be important to identify neurobiologic and behavioral risk factors for alcoholism during postnatal development, particularly adolescence. For example, with the advent of noninvasive imaging techniques such as PET and SPECT as well as the development of radioactive ligands to label dopamine and benzodiazepine receptors, it may be possible to study the functioning of various neurotransmitter systems in children at risk for developing alcoholism and, more importantly to identify those who are likely to become alcoholic during adolescence. Animal studies will be important for investigating the neurochemical, neuropharmacological, and behavioral mechanisms underlying the variable response to alcohol during ontogeny, examining the consequences of acute and chronic alcohol ingestion on the immature central nervous system, and for controlled studies of gene- environment interactions as they relate to patterns of adolescent drinking. Areas needing further research include, but are not limited to: Development of animal paradigms to study modes of initiation of alcohol-seeking behavior and alcohol's effects on reinforcement, drug discrimination, sensitization, tolerance, and dependence during the juvenile through adolescent period. Ontogenetic studies to compare patterns of alcohol-related behavior (e.g., alcohol reinforcement, sensitivity) as well as their neurochemical, neuropharmacological, neurophysiological, and neuroanatomical mechanisms during each stage of postnatal development through adulthood. Animal studies of the acute and chronic effects of alcohol on brain and behavioral functioning during adolescence, and the effects of early exposure on adult functioning. Studies of recovery of neural and behavioral function following alcohol consumption to determine if the adolescent brain is more or less vulnerable than the adult brain to alcohol's acute and chronic effects. 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 of alcohol-induced hormonal/ neurotransmitter disturbances during adolescence on the development of gender differences in behavior (including mood, stress, peer relationships, sexual behavior, aggression, cognitive functioning). Human studies and animal studies using different genetically defined strains to examine the interaction among premorbid temperament/personality, cognitive functioning, neurobiological, environmental, and genetic factors in the development of addictive behaviors in adolescents. Use of noninvasive neuroimaging (MRI, MRS, PET, SPECT), neurophysiological (EEG, ERP, MEG), and neuropsychological/cognitive measures in adolescent humans/animals to study brain mechanisms of craving, intoxication, and withdrawal, and to assess progression of damage and recovery of function following abstinence. 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 affect 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 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. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted at the standard application deadlines as indicated in the application kit. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, Division of Research Grants, National Institutes of Health, 6701 Rockledge Drive, Suite 3032, MSC 7762, Bethesda, MD 20892-7762, telephone 301-710-0267. The title and number of the program announcement must be typed in section 2a on the face page of the application. Applications for the FIRST award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The completed original application and five legible copies must be sent or delivered to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817-7710 (for express/courier service) REVIEW CONSIDERATIONS Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council. Review Criteria Criteria for scientific/technical merit review of applications for regular research grants (R01) are as follows: 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; 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. The review criteria for Small Grants (R03), Exploratory/Developmental Grants (R21), and FIRST Awards (R29) are contained in their program announcements. AWARD CRITERIA Applications will compete for available funds with all other approved applications assigned to the Institute. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquires regarding programmatic issues to: Ellen Witt, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism Willco Building, Suite 402 6000 Executive Boulevard 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: Linda Hilley Office of Planning and Resource Management National Institute on Alcohol Abuse and Alcoholism Willco Building, Suite 504 6000 Executive Boulevard MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-0915 FAX: (301) 443-3891 Email: 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 the Public Health Service Act, Sections 301 and 464H, and administered under PHS policies and Federal Regulations at Title 42 CFR Part 52, and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract 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 routing 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 Begleiter, H., Porjesz, B., Bihari, B., & Kissin, B. (1984). Event- related brain potentials in boys at risk for alcoholism. Science, 255, 1493-1496. Chen, W., Spear, L. P., & Spear, N. E. (1992). Enhancement of sensory preconditioning by a moderate dose of ethanol in infant and juvenile rats. 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Event- related potential characteristics in children of alcoholics from high density families. Alcoholism: Clinical and Experimental Research, 14, 6-16. Hill, S. Y. and Steinhauer, S. R. (1993). Assessment of prepubertal and postpubertal boys and girls at risk for developing alcoholism with P300 from a visual discrimination task. Journal of Studies on Alcohol, 54, 350-358. Hunt, W. A. (1993). Are binge drinkers more at risk for developing brain damage? Alcohol, 10, 559-561. Ingersoll, G. (1992). Psychological and social development. In E. R. McAnarney, R. E. Kreipe, D. P. Orr, & G D. Comerci (Eds.), Textbook of adolescent medicine (pp. 91-98). Philadelphia: W. B. Saunders Company. Johnston, L. D., O'Malley, P. M., & Bachman, J. G. (1994). National survey results on drug use from monitoring the future study, 1975-1993, Volume 1, secondary students. National Institute on Drug Abuse. NIH Pub. No.94-3809. Washington, D.C.: Supt. of Docs., U. S. Govt. Print. Off. Moss, H. 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Mechanisms of alcohol abuse and alcoholism in adolescents: A case for developing animal models. Behavioral and Neural Biology, 62, 168-177. .
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