Behavioral Methodology Facilitating Ethanol Reward

描述（由申请人提供）： 虽然乙醇（ETOH）使用的一个有益成分是无可争议的， 这不是一个简单的任务，可以隔离和测试积极的强化效果， 实验室大鼠中的ETOH。例如，静脉内（IV）自我给药是 一种流行的行为方法，用于确定最受虐待的奖励成分， 药物，但不是ETOH。事实上，很少有关于IV ETOH的报告 自我管理和现有文件的范围有限。在这些研究中， 行为反应要求和ETOH摄入水平都非常高， 低，提出问题，是否明显的动机属性的四 ETOH是中枢介导的。然而，口服ETOH自我给药， 利用和接受作为奖励ETOH效果的指标。不幸的是， 即使利用遗传选择的大鼠品系， 在开始可靠摄入之前需要暴露于口服ETOH， 大概是为了适应令人厌恶的ETOH味道。然而，即使 避开了口味因素（例如，肠外ETOH），长期暴露于 在可以观察到EtOH条件性奖赏之前，仍然需要ETOH。后 在标准条件处理程序中，预先暴露于ETOH的大鼠证明 条件性位置偏好EtOH配对的环境，但ETOH幼稚大鼠 表现出对场所的厌恶。这些发现表明积极的强化效应 ETOH预暴露后的ETOH可能是由于EtOH诱导的神经适应性 改变而不是orosensory习惯。该提案描述了一个 在我们的实验室制定的行为模型，最终导致高 自愿IV和口服ETOH摄入。在初步研究中，预先暴露于IV的大鼠 通过自我静脉注射EtOH/可卡因组合进行ETOH，证明可靠 静脉注射依他莫司自我给药IV EtOH摄入量（0.5-2.0 g/kg/lhr）对应于血液酒精水平（BAL）约为2.5g/kg/lhr。44-221 mg/dL。这些巴尔斯清楚地表明ETOH的药理学作用， 高端）以前没有经验证明后，自愿 ETOH摄入量。此外，单独IV ETOH自我给药的动物 后来喝了一杯。0.65 g/kg ETOH，无口服ETOH蔗糖褪色 sessions.对IV ETOH自我给药的进一步分析将允许 确定ETOH奖励方面的神经生物学基质 而不受口腔感觉因素的干扰。该提案将调查 通过IV行为分析的ETOH摄入量和时间过程参数 和口服ETOH自我给药。体内微透析也将用于 比较EtOH诱导的动物间多巴胺水平升高 自我静脉注射ETOH和通过实验者接受ETOH的人- 局

DESCRIPTION (provided by applicant): Although a rewarding component of ethanol (ETOH) use cannot be disputed, it is not a trivial task to isolate and test the positive reinforcing effects of ETOH in laboratory rats. For example, intravenous (IV) self-administration is a popular behavioral method for determining reward constituents of most abused drugs, but not ETOH. Indeed, there are few reports of IV ETOH self-administration and existing papers are limited in scope. In such studies, behavioral response requirements and ETOH intake levels are both extremely low, bringing into question whether the apparent motivational properties of IV ETOH are centrally mediated. Oral ETOH self-administration, however, is widely utilized and accepted as an index of rewarding ETOH effects. Unfortunately, even with the utilization of genetically selected rat lines, sustained exposure to oral ETOH is required before reliable intake is initiated, presumably to allow for habituation to the aversive ETOH taste. Yet, even when taste factors are circumvented (e.g., parenteral ETOH), prolonged exposure to ETOH is still required before EtOH-conditioned reward can be observed. After standard conditioning procedures, rats pre-exposed to ETOH demonstrate conditioned place preferences to EtOH-paired environments, but ETOH-naive rats show place aversions. These findings suggest the positive reinforcing effects of ETOH following ETOH pre-exposure may be due to EtOH-induced neuroadaptive alterations rather than orosensory habituation. This proposal describes a behavioral model formulated in our laboratory that ultimately resulted in high voluntary IV and oral ETOH intake. In pilot studies, rats pre-exposed to IV ETOH by self-administering IV EtOH/cocaine combinations, demonstrated reliable responding to IV ETOH alone. Self-administered IV EtOH intake (0.5-2.0 g/kg/lhr) corresponded with blood alcohol levels (BAL) of approx. 44-221 mg/dL. These BALs clearly indicate pharmacological effects of ETOH and (at the high end) have not previously been empirically demonstrated after voluntary ETOH intake. In addition, animals that self- administered IV ETOH alone subsequently drank approx. 0.65 g/kg of ETOH without oral ETOH sucrose-fading sessions. Further analyses of IV ETOH self-administration will allow identification of neurobiological substrates of the rewarding aspects of ETOH without interference from orosensory factors. This proposal will investigate parameters of ETOH intake and time course through behavioral analyses of IV and oral ETOH self-administration. In vivo microdialysis will also be used to compare EtOH-induced increases in accumbens dopamine levels between animals self-administering IV ETOH and those receiving ETOH via experimenter- administration.