Alcohol, Puberty, and Adolescent Brain Development

描述(由申请人提供)：青少年容易患上酗酒。对乙醇的镇静作用不敏感可能是造成这种脆弱性的原因之一。对酒精的使用限制作用不敏感，如镇静剂，是酒精滥用的常见风险因素。然而，发育状态、个体差异和荷尔蒙状态导致酒精不敏感的方式以及酒精滥用的轨迹尚不清楚。本建议的目的是检验三个相互关联的假设：(1)对乙醇的使用限制效应不敏感是男女青少年的特征(2)个体对酒精敏感性的差异独立于发育状况预测青少年和成年人的酒精消费，(3)青春期激素水平的变化将影响酒精敏感性和酒精消费：具体地说，发情周期的出现将对女性的酒精使用限制效应和酒精消费产生刺激性(雌二醇)和抑制性(孕酮)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变化。我们计划：(1)评估性腺类固醇对青春期酒精敏感性和酒精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酒精敏感性和性腺类固醇对酒精摄入量的个体差异的贡献。我们将在出生后30天、45天、60天和90天，在青春期前(PN 25)或青春期后(PN 55)，以及在雌激素、孕激素和睾酮替代后，测量乙醇诱导的镇静、运动失调和条件性味觉厌恶(CTA)。对于特定的目标2，将对大鼠进行酒精诱导的CTA的特征，然后进入青春期(开始30、45、60天)的酒精饮用方案。我们将比较性腺完整的动物和青春期前或青春期后性腺切除和激素替代后的动物的酒精摄入量。酒精敏感性、性别、年龄和激素水平对酒精饮酒三个阶段(强迫、自愿和反弹)的贡献将使用多变量统计进行建模。找出使个人容易酗酒的行为特征，有助于制定有效的治疗和预防方案。这些发现将为青春期对酒精消费发展的影响提供洞察。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.