Alcohol, Puberty, and Adolescent Brain Development

描述（由申请人提供）：青少年很容易发展为酗酒。对乙醇的镇静作用不敏感可能是造成这种脆弱性的原因。对镇静等限制酒精使用的作用不敏感是导致酒精滥用的一个常见危险因素。然而，发育状态、个体差异和激素状态对乙醇不敏感和酒精滥用的影响方式尚不清楚。本提案的目的是检验三个相互关联的假设：(1)对酒精使用限制效应不敏感是男女青少年的特征；(2)酒精敏感性的个体差异独立于发育状态预测青少年和成人的酒精消费量；(3)青春期激素水平的变化将影响酒精敏感性和酒精消费量；具体来说，发情周期的出现将引入刺激性（雌二醇）和抑制性（黄体酮）对乙醇使用限制效应和女性酒精消耗的影响，而雄激素的组织效应可能会导致男性饮酒模式的不可逆转的变化。我们计划：(1)评估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作用的贡献；(3)评估雄性和雌性大鼠青春期乙醇敏感性和性腺类固醇的个体差异对乙醇摄入量的贡献。我们将在假性腺切除术和主动性腺切除术后(青春期前（PN 25）或青春期后（PN 55），以及雌激素、孕激素和睾酮替代后，于产后（PN）第30、45、60和90天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Specific Aim 2，大鼠将被表征为乙醇诱导的CTA，然后在青春期（开始的第30、45、60天）进入乙醇饮酒方案。我们将比较性腺完整的动物和青春期前或青春期后切除性腺和激素替代的动物的乙醇摄入量。乙醇敏感性、性别、年龄和激素水平对乙醇饮酒三个阶段（强迫、自愿和反弹）的影响将使用多变量统计建模。识别个人易酗酒的行为特征有助于制定有效的治疗和预防方案。这些发现将有助于深入了解青春期对酒精消费发展的影响。这一信息将有助于我们为青年男女酗酒者制定更有针对性的预防和治疗战略。

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.