Alcohol, Puberty, and Adolescent Brain Development

描述（由申请人提供）：青少年很容易发展酒精滥用。对乙醇的镇静作用不敏感可能导致这种脆弱性。对酒精类镇静剂的使用限制作用不敏感是酒精滥用发展的常见风险因素。然而，发育状态、个体差异和激素状态对乙醇不敏感性和酒精滥用的影响尚不清楚。本提案的目的是检验三个相互关联的假设：（1）对乙醇使用限制效应的不敏感性是男女青少年的特征;（2）乙醇敏感性的个体差异预测了青少年和成人的乙醇消费量，与发育状态无关;（3）青春期激素水平的变化将影响乙醇敏感性和乙醇消费量：特别地，发情周期的出现将对女性的乙醇使用限制效应和乙醇消耗引入刺激（雌二醇）和抑制（孕酮）影响，而雄激素的组织效应可能导致男性饮酒模式的不可逆变化。我们计划：（1）评价性腺类固醇对青春期乙醇敏感性和乙醇摄入量的使用限制效应的贡献，（3）评估雄性和雌性大鼠青春期乙醇敏感性和性腺类固醇个体差异对乙醇摄入量的贡献。我们将在假手术和青春期前（PN 25）或青春期后（PN 55）主动性腺切除术后出生后（PN）第30、45、60和90天以及雌激素、孕酮和睾酮替代后测量乙醇诱导的镇静、运动不协调和条件性味觉厌恶（CTA）。对于特定目标2，将对大鼠进行乙醇诱导的CTA表征，然后进入乙醇饮用方案直至青春期（开始第30、45、60天）。我们将比较性腺完整动物和青春期前或青春期后性腺切除和激素替代后动物的乙醇摄入量。乙醇敏感性、性别、年龄和激素水平对乙醇饮用三个阶段（强迫、自愿和反弹）的贡献将使用多变量统计建模。识别易使个体酗酒的行为特征可以促进有效的治疗和预防计划的发展。这些发现将为了解青春期对酒精消费发展的影响提供见解。这些信息将帮助我们为年轻的男性和女性酗酒者制定更有针对性的预防和治疗策略。 公共卫生相关性：本研究的目的是检验三个相互关联的假设：（1）对乙醇的不敏感性是青少年高乙醇摄入量的主要决定因素，（2）对乙醇不敏感性的个体差异将预测青少年和成人的乙醇消费量，（3）青春期激素水平的变化将影响乙醇敏感性和乙醇消费量。我们计划在青春期的雄性和雌性大鼠中评价乙醇诱导的镇静、运动不协调、条件性味觉厌恶和乙醇消耗。我们还将通过确定性腺切除术和激素替代对相同措施的影响来评估性腺类固醇对这些措施的作用;我们假设对使用限制效应的不敏感性，无论是来自个体差异还是内分泌状态，都将预测更高的饮酒量。

DESCRIPTION (provided by applicant): 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.