NEUROPHARMACOLOGY OF ETHANOL REINFORCEMENT

乙醇在人体内具有增强作用， 酒精滥用和酒精中毒 在大鼠体内，乙醇很容易 当通过预先暴露使味觉因素最小化时， 给老鼠加糖 非依赖性和非流动性，或 非食物剥夺的大鼠在有限的访问中会选择乙醇而不是水 情况下，将杠杆按下摄取足够的数量， 产生有意义的血液乙醇水平。 在以前的资助工作 一个时期的目的是研究边缘核的作用 乙醇强化中的锥体外系环路。 结果表明 虽然中脑核中的多巴胺可以调节乙醇 强化，其他系统，如GABA和谷氨酸可能有 重要的，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中的结果扩展到其他大脑 杏仁核和其他神经递质系统。 一 进一步的目的将是检查神经药理学基础， 酒精强化依赖大鼠。 最后，可能的性行为 乙醇强化和神经药理学的差异 将探索乙醇强化的调节。 非粮食或 将训练非流体剥夺的雄性和雌性大鼠， 每天30分钟使用糖精自行服用乙醇 淡出程序。 然后将大鼠植入双侧 针对先前研究所涉及的特定大脑部位的套管 乙醇强化 建立稳定的乙醇后 自我给药，大鼠将被显微注射神经递质 拮抗剂和激动剂，然后乙醇自我给药阶段。 将使用内的拉丁方生成剂量效应函数 受试者设计多巴胺，5-羟色胺，阿片肽，GABA和 谷氨酸拮抗剂和在某些情况下的激动剂。 实验产生 将在对照实验中重复显著的结果， 接受过自我服用糖精（不含乙醇）的训练。 以下 关键部位的建立和神经药理学作用 在非依赖性大鼠中，将在依赖性大鼠中重复类似的实验。 动物和雌性大鼠。 正在测试的假设是， 乙醇可能会导致那些大脑机制的适应性变化， 对于非依赖性动物的乙醇强化， 适应可能是依赖过程中的一个关键的动机部分。 对动机方面的神经生物学基础的知识 乙醇依赖将为发展提供关键信息， 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.