Adolescents are vulnerable to the development of alcohol abuse. Insensitivity to the sedative effects of ethanol may contribute to this vulnerability. Insensitivity to the use-limiting effects of ethanol like sedation is a common risk factor for the development of alcohol abuse. However, the way that developmental state, individual differences and hormonal state contribute to ethanol insensitivity and the trajectory into alcohol abuse is unknown. The purpose of the present proposal is to test three interrelated hypothesis: (1) that insensitivity to use-limiting effects of ethanol are characteristic of adolescents of both sexes (2) that individual differences in ethanol sensitivity predict ethanol consumption in both adolescents and adults independently of developmental status, (3) that pubertal changes in hormone levels will influence both ethanol sensitivity and ethanol consumption: specifically the emergence of estrous cycles will introduce stimulatory (estradiol) and inhibitory (progesterone) influences on ethanol use-limiting effects and ethanol consumption in females while organizational effects of androgen may cause irreversible changes in male drinking patterns. We plan to: (1) evaluate the contribution of gonadal steroids to the use-limiting effects of ethanol sensitivity and ethanol intake during adolescence and (3) assess the contribution of individual differences in ethanol sensitivity and gonadal steroids to ethanol intake during adolescence in male and female rats. We will measure ethanol-induced sedation, motor incoordination and conditioned taste aversion (CTA) on postnatal (PN) day 30, 45 and 60 and 90 after sham and active gonadectomy prepubertally (PN 25) or post-pubertally (PN 55), and after estrogen, progesterone and testosterone replacement.
For Specific Aim 2, rats will be characterized for ethanol-induced CTA, and then entered into an ethanol drinking protocol through puberty (start days 30, 45, 60). We will compare ethanol intake in gonadally intact animals and in animals after pre- or postpubertal gonadectomy and hormone replacement. The contribution of ethanol sensitivity, sex, age and hormone levels to three phases of ethanol drinking (forced, voluntary and rebound) will be modeled using multivariate statistics. Identifying behavioral characteristics that predispose individuals to alcohol abuse can facilitate the development of effective treatment and prevention programs. These findings will provide insight into influence of puberty on the development of alcohol consumption. This information will help us develop more targeted prevention and treatment strategies for young men and women alcoholics.

Public Health Relevance

The purpose of the present proposal is to test three interrelated hypotheses: (1) that insensitivity to ethanol is a major determinant of high ethanol intake in adolescents, (2) that individual differences in insensitivity to ethanol will predict ethanol consumption in both adolescents and adults, (3) that pubertal changes in hormone levels will influence both ethanol sensitivity and ethanol consumption. We plan to evaluate ethanol-induced sedation, motor incoordination, conditioned taste aversion and ethanol consumption in male and female rats during adolescence. We will also evaluate the role of gonadal steroids on these measures by determining the effect of gonadectomy and hormone replacement on the same measures;we hypothesize that insensitivity to use-limiting effects, whether it arises from an individual difference or endocrine state, will predict higher alcohol consumption.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Grandison, Lindsey
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Duke University
Schools of Medicine
United States
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