NEUROPHARMACOLOGY OF ETHANOL REINFORCEMENT

乙醇具有增强人体功能的特性，被认为有助于 酗酒和酗酒。在大鼠体内，乙醇很容易 通过预先曝光将味觉因素降至最低时自行口服 把老鼠喂给甜味的溶液。非依赖和非流体或 非食物匮乏的大鼠将在有限的通道中选择乙醇而不是水 情况和将杠杆压力机摄取足够的量 产生有意义的血液酒精水平。在以前的资金中工作 这一时期旨在研究边缘核的作用。 乙醇强化中的伏隔-锥体外环。结果显示 虽然伏核中的多巴胺可能调节乙醇 强化，其他系统，如GABA和谷氨酸可能有 重要的角色，如果不是关键的角色。本提案的目的是 将这些早期在非依赖大鼠身上的结果推广到其他大脑 杏仁核等部位和其他神经递质系统。一个 进一步的目的将是检查神经药理学基础 乙醇对依赖大鼠的强化作用。最后，可能的性行为 乙醇强化与神经药理学的差异 还将探索乙醇增强的调制方式。非食品类或 非缺水的雄性和雌性大鼠将被训练到 每天30分钟使用糖精自我给药乙醇 淡出程序。然后，大鼠将被植入双侧 针对特定大脑部位的插管，这与以前的工作有关 乙醇加固。在建立稳定的乙醇之后 自我给药，大鼠将被显微注射神经递质 在乙醇自我给药之前使用拮抗剂和激动剂。 剂量效应函数将使用拉丁方生成 多巴胺、5-羟色胺、阿片肽、GABA和 谷氨酸拮抗剂，在某些情况下还有激动剂。实验取得成果 重要的结果将在对照实验中重复，在这些实验中，老鼠 受过自我注射糖精的训练(不含乙醇)。跟随 大鼠脑内关键部位的建立及其神经药理作用 非依赖大鼠，类似的实验将在依赖中重复 在动物和雌性大鼠身上。正在测试的假设是慢性的 酒精可能会导致那些关键的大脑机制的适应性变化 对于非依赖动物的乙醇强化，这是 适应可能是依赖过程中一个关键的动机部分。 了解精神障碍动机方面的神经生物学基础 对乙醇的依赖将为开发 酒精中毒的诊断、治疗和预防策略。

Ethanol has reinforcing properties in man that are thought to contribute to alcohol abuse and alcoholism. In rats ethanol is readily self-administered orally when taste factors are minimized by preexposing the rats to sweetened solutions. Non-dependent and non- fluid or non-food deprived rats will choose ethanol over water in limited access situations and will lever press to ingest sufficient quantities to produce meaningful blood ethanol levels. Work in the previous funding period was directed at examining the role of a limbic-nucleus accumbens-extrapyramidal circuit in ethanol reinforcement. Results show that while dopamine in the nucleus accumbens may modulate ethanol reinforcement, other systems such as GABA and glutamate may have important if not crucial roles. The purpose of the present proposal will be to extend these earlier results in non-dependent rats to other brain sites such as the amygdala and to other neurotransmitter systems. A further purpose will be to examine the neuropharmacological basis of ethanol reinforcement in dependent rats. Finally, possible sex differences in ethanol reinforcement and the neuropharmacological modulation of ethanol reinforcement will be explored. Non-food or non-fluid deprived male and female rats will be trained to self-administer ethanol in daily 30 minute sessions using a saccharin fade out procedure. The rats then will be implanted with bilateral cannulas aimed at specific brain sites implicated by previous work on ethanol reinforcement. Following establishment of stable ethanol self-administration, the rats will be microinjected with neurotransmitter antagonists and agonists prior to ethanol self-administration sessions. Dose effect functions will be generated using Latin square within subjects designs for dopamine, serotonin, opioid peptide, GABA and glutamate antagonists, and in some cases agonists. Experiments yielding significant results will be repeated in control experiments where rats are trained to self-administer saccharin (without ethanol). Following establishment of critical sites and neuropharmacological effects in non-dependent rats, similar experiments will be repeated in dependent animals and in female rats. The hypothesis under test is that chronic ethanol may result in adaptive changes in those brain mechanisms critical for ethanol reinforcement in the non-dependent animal and that this adaptation may be a crucial motivational part of the dependence process. Knowledge of the neurobiological basis of the motivational aspects of ethanol dependence will provide key information for the development of diagnosis, treatment, and prevention strategies for alcoholism.