NEUROBIOLOGICAL MECHANISMS OF ADOLESCENT ALCOHOL ABUSE Release Date: November 25, 1998 RFA: AA-99-003 P.T. National Institute on Alcohol Abuse and Alcoholism Letter of Intent Receipt Date: February 23, 1999 Application Receipt Date: March 23, 1999 PURPOSE The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is seeking research grant proposals to conduct basic research, using animal models and non- invasive imaging techniques in humans, to identify the neurobiological, physiological, genetic, and environmental factors that lead to adolescent alcohol abuse and dependence. According to the 1997 Monitoring the Future Study, 54 percent of 8th graders, 72 percent of 10th graders, and 82 percent of 12th graders have used alcohol in their lifetime. (1) Of greater concern is the widespread occurrence of heavy drinking (five or more drinks in a row during the past two weeks). Among high school seniors this statistic was 31.3 percent. Furthermore, recent research has shown that individuals who start drinking at ages 14 or younger have lifetime rates of dependence of 40 percent or more compared to roughly 10 percent among those who started drinking at ages 20 and over. Despite these high rates of alcohol use and associated risks among secondary school students, relatively few studies to date define the neurobiological and physiological mechanisms of high alcohol intakes or the effects of excessive drinking in adolescents. The focus of this Request for Applications (RFA) is to stimulate research on the neurobiological mechanisms and risk factors for alcoholism during late childhood through adolescence. A second emphasis of this RFA is on the relative contribution and/or interaction of neurobiological, genetic, environmental, and social factors (e.g., family history, stress, peer influences) in the development of adolescent alcohol abuse. In addition, evaluation of the effects of alcohol ingestion during postnatal development, particularly 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. While a multidisciplinary approach is encouraged, a basic neuroscience component must be included for a proposal to be responsive to this RFA. Use of nonhuman primate models is encouraged because of their extended adolescent period. 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 activity for setting priority areas. This RFA, Neurobiological Mechanisms of Adolescent Alcohol Abuse, is related to the priority area of alcohol abuse reduction and alcoholism prevention. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 170-011-00474-0 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 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 Research support may be obtained through applications for a research project grant (R01), exploratory/developmental Grant (R21), and small grant (R03). Applicants for R01s may request support for up to 5 years. In FY 1998, the average total cost per year for new and competing renewal R01s funded by the Division of Basic Research was approximately $190,000. Currently, small grants (R03) and exploratory/developmental grants (R21) are limited to 2 years for up to $50,000 per year and $70,000 per year, respectively, for direct costs. Exploratory/developmental grants and small grants cannot be renewed, but grantees may apply for R01 support to continue research on the same topics. Applicants that anticipate submitting a small grant (R03) or exploratory/developmental grant (R21), should contact the Program Contact listed under INQUIRIES for additional information on these mechanisms. Applications requesting direct costs of $500,000 or more in any one year must obtain written agreement from the NIAAA that the application will be accepted for consideration of award, in accordance with NIH policy, which is available at https://grants.nih.gov/grants/guide/notice-files/not98-030.html. Applicants may also submit applications for Investigator-Initiated Interactive Research Project Grants (IRPG). Interactive Research Project Grants require 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. Further information on these and other grant mechanisms may be obtained from the program staff listed in the INQUIRIES section of this RFA or from the NIAAA Web site http://www.niaaa.nih.gov/. FUNDS AVAILABLE It is estimated that up to $3.0 million will be available to fund approximately 15 grants under this RFA. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. The award of grants pursuant to this RFA is contingent upon the availability of funds for this purpose. The earliest possible award date is September 30, 1999. RESEARCH OBJECTIVES Background Alcohol remains the most commonly abused substance among adolescents. Males have consistently reported more frequent and heavier use than females, but this difference has been gradually diminishing over the last decade. This is particularly important since females require less alcohol to achieve blood alcohol concentrations equivalent to males. Thus, females may be at enhanced risk for the medical consequences of alcohol abuse including liver disease, brain damage, and associated behavioral deficits. 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. To date, relatively few studies define the neurobiological mechanisms and consequences of excessive drinking in adolescents. One reason for the paucity of research in this area is the difficulty of studying the neurobiological and physiological mechanisms of alcohol abuse or dependence in human adolescents, in part, due to ethical and legal considerations, that prohibit administering alcohol to youths. Because of limitations in the types of studies that can be conducted with human adolescents, animal models need to be developed to study neural mechanisms of adolescent alcohol abuse and alcoholism. One approach, which is the most cost effective, is to use rodents. However, the adolescent period in laboratory rodents, defined as the age around the time of sexual maturation, is very brief (for males about three weeks to a month and for females about two weeks). (2) Thus, behavioral paradigms that require extensive training such as self-administration and drug discrimination may need to be modified, or new paradigms developed to accommodate the shorter developmental time period. An alternative approach, and one that is also encouraged, is the use of primate models because of their extended adolescent period (age 2-4 years) and complex social systems. 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. 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 in adolescence relative 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 and animal 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. Dopaminergic and cholinergic inputs to the PFC also 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. For example, D1 and D2 receptors show greater overproduction and decline at puberty in the striatum than in the nucleus accumbens. (5) Basal dopamine synthesis and turnover increase in the striatum and nucleus accumbens during adolescence, whereas they decrease in the PFC. (6) Finally, maturational changes occur in other brain regions and neurotransmitters systems during adolescence. 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. (7) 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 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. 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. 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. (8) More important, the neurophysiological 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 (as activated by amphetamine) 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. Ontogeny of Response and Tolerance to Alcohol. Adolescent animals consume higher absolute levels of alcohol than older animals, and that they may be able to tolerate higher levels of ethanol intakes due to their relative insensitivity to the sedating and motor impairing effects of ethanol. (10) 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 ethanol-induced 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. (11) The neurobiological mechanisms for the ontogenetic differences in alcohol sensitivity need to be explored. Behavioral and Physiological Consequences of Early Drinking. While decreased sensitivity to the sedative effects of alcohol may enable greater intakes in adolescents (see above), 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 was greater in adolescents than adults. (12) Behaviorally, adolescent rats showed greater impairment on acquisition of a spatial memory task after ethanol exposure. A 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. (2) 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. (2) Consistent with this hypothesis is the possibility that severity of alcohol and drug withdrawal symptoms may be a powerful marker of protracted neuropsychological impairments in detoxified late adolescents and young adults. Since the immature brain is more susceptible to NMDA neurotoxicity and since teenagers are more likely to engage in weekend binge drinking, it would be important to study the effects of chronic binge patterns of ethanol exposure on brain structure and function in human adolescents and on neurochemical and cognitive functioning in animal models. 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, dehydroepiandosterone). 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. (13). In adult humans and animals, the relationship among stress, drinking, and underlying neuroendocrine or neurochemical mechanisms is complex. (14) In adolescents, a few studies using non-human primates have shown that under conditions of social separation stress, subjects double their rates of alcohol consumption. In these studies, individual differences in stress-induced drinking are attributed to anxiety-like behaviors (Type I alcoholism) 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)(Type II alcoholism). (15) 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. (16) Given that adolescence is a time when hormonal systems are still developing in humans and animals and may be fluctuating wildly, 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. As mentioned above, 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 pre- or post-weaning 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. Research Areas of Interest 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 be important to identify neurobiologic and behavioral risk factors for alcoholism, and the neural consequences of heavy drinking during adolescence. For example, recent developments in noninvasive imaging, such as functional MRI, offer opportunities to study neurobiological markers for alcoholism as well as alcohol-induced brain and cognitive deficits among human adolescents. Animal models 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 studies of the relationship between environmental factors such as stress in enhancing the likelihood of early alcohol exposure and later intake. 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 Modification and/or development of animal paradigms (in conjunction with a neuroscience component) to study alcohol's hedonic effects, modes of initiation, reinforcement, drug discrimination, sensitization, tolerance and dependence during the juvenile through adolescent period. o Ontogenetic studies to compare patterns of alcohol-related behaviors (e.g., alcohol reinforcement, sensitivity) as well as their neurochemical, neuropharmacological, neurophysiological, and neuroanatomical mechanisms during each stage of postnatal development through adulthood. o 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 that could impact on problem drinking behavior. o 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. 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 Animal studies using different genetically defined strains and human studies to examine the interaction among premorbid temperament/personality, cognitive functioning, neurobiological, environmental, and genetic factors in the development of addictive behaviors in adolescents. o Use of noninvasive neuroimaging (fMRI, MRS, PET, SPECT), neurophysiological (EEG, ERP, MEG), and neuropsychological/ cognitive measures in adolescent humans/primates to study risk markers for alcoholism, ontogeny of neuroanatomical and neurochemical brain mechanisms of craving and intoxication, 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 policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). 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. NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html LETTER OF INTENT Prospective applicants are asked to submit, by February 23, 1999, 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 NIAAA 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: Office of Scientific Affairs National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 409, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-4375 FAX: (301) 443-6077 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, Email: grantsinfo@nih.gov The RFA label available in the PHS 398 (rev. 4/98) 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. The Abstract Page must clearly indicate the nature of the required neurobiological component. Page limits and limits on size of type are strictly enforced. Non-conforming applications will be returned without being reviewed. Submit a signed, typewritten original of the application, including the checklist and three signed photo copies 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 also be sent to: Office of Scientific Affairs 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) Applications must be received by March 23, 1999. If an application is received after that date, it will be returned to the applicant without review. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review (CSR) and for responsiveness by the NIAAA, including the required neurobiological component. Incomplete applications will be returned to the applicant without further consideration. 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, a process will be used by the initial review group in which applications receive a written critique and undergo a process in which only those applications deemed to a 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 National Advisory Council on Alcohol Abuse and Alcoholism. 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. Significance: Does the study address the goals of the RFA? If the aims of the study are achieved, how will scientific knowledge be advanced? Will the study advance the concepts or methods that drive this field? 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 designs? Feasibility: Can the design be implemented (including recruitment of subjects, cooperation of relevant organizations, and/or collection of necessary data)? Innovation: Does the project employ novel concepts, approaches, theories, or methods? Investigator: Are the principal investigator and key research personnel appropriately trained and well suited to carry out this work? Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Does the proposed research take advantage of the unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Budget: Is the requested budget and estimation of time to completion of the study appropriate for the proposed research? In addition, plans for the recruitment and retention of subjects will be evaluated as well as the adequacy of plans to include both genders and minorities and their subgroups and children as appropriate for the scientific goals of the research. 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 Applications recommended for approval by the National Advisory Council on Alcohol Abuse and Alcoholism will be considered for funding on the basis of the overall scientific and technical merit of the proposal as determined by peer review, NIAAA programmatic needs and balance, and the availability of funds. 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: Ellen D. Witt, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402 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 Grants Management Branch National Institute on Alcohol Abuse and Alcoholism 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 the authorization of the Public Health Service Act, Sections 301 and 464H, and administered under the 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 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. Johnston, J.D., O'Malley, P.M., Bachman, J.G. (1998) National Survey Results on Drug Use from the Monitoring the Future Study, 1975-1997,Vol I, Secondary School Students. NIH Pub. No. 98-4345. 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. Andersen, S.L., Dumont, N.L., Teicher, M.H. (1997) Developmental differences in dopamine synthesis inhibition by (+)-7-OH-DPAT. Naunyn-Schmeideberg's Archives of Pharmacology, 356, 173-181. 7. Spear, L. T., Brake, S. C. (1983) Periadolescence: age-dependent behavior and psychopharmacological responsivity in the rat. Developmental Psychobiology, 16, 83-109. 8. Hill, S.Y., 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. 9. McKinzie, D.L., McBride, W.J., Murphy, J.M., Lumeng, L., Li, T.K. ( in press) Rat lines selectively bred for alcohol preference: a potential animal model of adolescent alcohol drinking. In J.H. Hannigan, N.E. Spear, L.P. Spear, & C. Goodlett (Eds.), Alcohol and Alcoholism: Brain and Development, Mahwah, NJ: Erlbaum. 10. Silveri, M. M., Spear, L.P. (1998) Decreased sensitivity to the hypnotic effects of ethanol early in ontogeny. Alcoholism: Clinical and Experimental Research, 22: 670-676. 11. Swartzwelder, H.S., Richardson, R.C., Markwiese-Foerch, B., Wilson, W.A., Little, P.J. (1998) Developmental differences in the acquisition of tolerance to ethanol. Alcohol, 15, 1-4. 12. Swartzwelder, H.S., Wilson, W.A., Tayyeb, M.I. (1995) Age-dependent inhibition of long-term potentiation by ethanol in immature versus mature hippocampus. Alcoholism: Clinical and Experimental Research, 19, 1480-85. 13. Tschann, J.M., Adler, N.E., Irwin Jr., C.E., Millstein, S.G., Turner, R.A., Kegeles, S.M. (1994) Initiation of substance use early in adolescence: The roles of pubertal timing and emotional distress. Health Psychology, 13, 326-33. 14. Hunt, W.A., Zakhari, S. (Eds) (1995) National Institute on Alcohol Abuse and Alcoholism Research Monograph - 29: Stress, Gender, and Alcohol-Seeking Behavior. NIH Publication No. 95-3893. Rockville, MD. 15. Higley, J.D., Linnoila, M. (1997) A nonhuman primate model of excessive alcohol intake: Personality and neurobiological parallels of Type I- and Type II-like alcoholism. In M. Galanter (Ed), Recent Developments in Alcoholism, Volume 13, Alcoholism and Violence. New York: Plenum Press. 16. Grant, K.A., Azarov, A., Shively, C.A., Purdy, R.H. (1997) Discriminative stimulus effects of ethanol and 3-hydroxy-5-pregnan-20-one in relation to menstrual cycle phase in cynomolgus monkeys (Macaca fascicularis). Psychopharmacology, 130, 59-68.
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