Alcohol intake and aversion during adolescence in 8 inbred mouse strains

描述（由申请人提供）：在青春期早期（14岁之前）开始饮酒与终生酒精依赖患病率的增加有关（Grant & Dawson, 1997）。有酗酒家族史的人将来酗酒的风险也会增加（Schuckit & Smith, 1996）。然而，为了充分了解青少年接触乙醇的影响以及与酒精中毒相关的遗传因素，有必要使用动物模型。拟议的研究将检查：在8个近亲繁殖的小鼠品系中，成年小鼠和青春期小鼠之间乙醇摄入量的差异，以及在青春期或成年期暴露于乙醇的成年小鼠之间饮酒的差异（目的1）；在青少年中诱导条件性味觉厌恶（CTA）的程度，以及在相同的8个近亲繁殖的小鼠品系中，先前的酒精暴露（无论是在青春期还是成年期）在成年期改变对酒精厌恶特性敏感性的程度（目的2），最后，在8个近亲繁殖的小鼠品系中，酒精摄入量和酒精CTA在青春期和成年期的关联程度。将C57BL/6J、DBA/2J、129S1/SvlmJ、A/J、BALB/cByJ、BTBR T+tf/tf、C3H/HeJ和FVB/NJ自交系的雄性青春期小鼠（早期：P28-32，晚期：P38-42）和成年小鼠（P70-74）连续5天，每天2小时。然后，在完成初始乙醇暴露37天后，当青少年达到成年时，对小鼠的乙醇摄入量进行重新评估（目的1）。接下来，雄性青少年和成年小鼠（相同基因型和年龄范围）将被给予10% （w/v）的糖水溶液1小时，并在糖水接触小鼠后立即腹腔注射生理盐水或乙醇（2或4 g/kg），以产生乙醇诱导的CTA。小鼠将接受这种味觉/乙醇配对3次，每次糖水/乙醇注射治疗之间有一天的恢复时间。同样，在37天的戒断期后，动物将在成年期再次暴露于CTA程序，这次使用不同的品尝剂（0.05%氯化钠）来确定先前在青春期的乙醇治疗是否会改变成年期对乙醇厌恶特性的敏感性（目的2）。最后，乙醇饮用和CTA表型将在青春期和成年小鼠的基因型中相互关联。这项工作将检查发育暴露/对乙醇的敏感性，以及由于基因型而导致的乙醇摄入量/敏感性的差异；综合研究这两种影响可能会产生重要而有趣的相互作用，从而更好地了解人类从青春期到成年期的酒精使用和滥用。

DESCRIPTION (provided by applicant): Initiation of alcohol consumption during early adolescence (before age 14) is related to an increase in lifetime prevalence of alcohol dependency (Grant & Dawson, 1997). The risk for future alcoholism also increases with a positive family history of alcohol abuse (Schuckit & Smith, 1996). However, in order to fully understand the impact of adolescent exposure to ethanol and the genetic factors associated with alcoholism, use of animal models are necessary. The proposed research will examine: differences in ethanol intake between adult and adolescent mice, as well as the differences in drinking between adult mice that were either previously exposed to ethanol during adolescence or adulthood in 8 inbred mouse strains (Aim 1); the extent to which a conditioned taste aversion (CTA) can be induced in adolescents as well as the degree to which prior ethanol exposure (either in adolescence or adulthood) alters sensitivity to the aversive properties of alcohol in adulthood in the same 8 inbred mouse strains (Aim 2) and lastly, the extent to which alcohol intake and CTA to alcohol in adolescence and adulthood will correlate across the 8 inbred mouse strains. Male adolescent (early: P28-32 and late: P38-42) and-adult (P70-74) mice ofthe C57BL/6J, DBA/2J, 129S1/SvlmJ, A/J, BALB/cByJ, BTBR T+tf/tf, C3H/HeJ, and FVB/NJ inbred strains will be given access to a 20% (v/v) ethanol solution for 2-h a day, for 5 consecutive days. Mice will then be reassessed for ethanol intake, 37 days after the completion of the initial ethanol exposure, when the adolescents reach adult-age (Aim 1). Next, male adolescent and adult mice (ofthe same genotypes and age-ranges) will be given access to a 10% (w/v) sugar-water solution for 1-h, and immediately after sugar-water access mice will be intraperitoneally (ip) injected with saline or ethanol (2 or 4 g/kg) to produce an ethanol-induced CTA to the tastant. Mice will receive this tastant/ethanol pairing 3 times, with one day of recovery between each sugar-water access/ethanol injection treatment. Again, after a 37 day abstinence period animals will be re- exposed to the CTA procedure in adulthood, this time using a different tastant (0.05% sodium-chloride) to determine whether previous ethanol treatment in adolescence will alter adult sensitivity to the aversive properties of ethanol (Aim 2). Lastly, ethanol drinking and CTA phenotypes will be correlated across genotypes for both adolescent and adult mice. This work will examine both developmental exposure/sensitivity to ethanol as well as differences in ethanol intake/sensitivity due to genotype; examining both of these influences together may yield important and interesting interactions which could result in a greater understanding of alcohol use and abuse from adolescence into adulthood in humans.