RC4 Impulsivity/Withdrawal-induced EtOH Consumption

该部分的长期目标是了解乙醇戒断严重程度与乙醇消耗和冲动性（行为抑制/去抑制）的基础水平和戒断后升级之间的遗传相互关系。来自一组8个近交系的数据表明，行为抑制指数（预期反应和在No-go提示期间的反应）受基因型的影响，并且这种遗传影响与急性和慢性的遗传贡献相关。 乙醇戒断严重程度，使用处理诱发惊厥（HIC）评估。其他数据表明慢性酒精戒断和酒精摄入之间存在负遗传关系。 拟议的研究将通过三项研究评估这些遗传相互关系。研究1通过评估选择性饲养的小鼠在长期暴露于乙醇蒸汽后的重度（近交系戒断性癫痫倾向; iWSP）与轻度（近交系戒断性癫痫抵抗; iWSR）戒断HIC严重程度中的Go/No-go任务上的基础抑制，检查了未接触乙醇的动物中的抑制水平和乙醇戒断严重程度是否受到一些相同基因的影响。研究2检查慢性乙醇暴露（72小时连续乙醇吸入）后的抑制水平，以确定何时观察到最大去抑制以及持续多长时间。与研究1一样，研究2将解决iWSP和iWSR小鼠中差异性影响戒断HIC严重程度的一些相同基因是否与这些选定品系中影响抑制和戒断诱导抑制的基因相同的问题。研究3将使用iWSP和iWSP小鼠检查非酒精依赖动物的乙醇饮用和乙醇戒断严重程度是否受到一些相同基因的影响。该研究还将评估在四个周期的慢性间歇性乙醇暴露（每个周期= 16小时乙醇：8小时空气，持续4天）后戒断对乙醇饮用影响的基因型差异。这三项研究将允许开发一个基础更广泛的描述乙醇戒断，包括冲动/抑制和乙醇饮用的变化，以及为未来的遗传图谱研究，以确定这些过程中涉及的精确基因提供关键信息。

The long term objective of this component is to understand genetic interrelationships among ethanol withdrawal severity and both basal levels and post-withdrawal escalations in ethanol consumption and impulsivity (behavioral inhibition/disinhibition). Data from a panel of eight inbred strains indicate that indices of behavioral inhibition (anticipatory responding and responding during a No-go cue) are influenced by genotype and that this genetic influence is correlated with genetic contributions to both acute and chronic ethanol withdrawal severity, assessed using the handling-induced convulsion (HIC). Other data indicate a negative genetic relationship between chronic ethanol withdrawal and alcohol intake. The proposed studies will assess these genetic interrelationships by performing in three studies. Study 1 examines whether levels of inhibition in ethanol-naive animals and ethanol withdrawal severity are influenced by some of the same genes by assessing basal inhibition on a Go/No-go task in mice selectively bred for severe (inbred Withdrawal Seizure-Prone; iWSP) versus mild (inbred Withdrawal Seizure-Resistant; iWSR) withdrawal HIC severity after chronic exposure to ethanol vapor. Study 2 examines levels of inhibition following chronic ethanol exposure (72 hrs of continuous ethanol inhalation) to establish when maximal disinhibition is seen and for how long it persists. Like Study 1, Study 2 will address the question of whether some of the same genes that affect withdrawal HIC severity differentially in iWSP and iWSR mice are the same as those affecting inhibition and withdrawal-induced inhibition in these selected lines. Study 3 will examine whether ethanol drinking in alcohol-nondependent animals and ethanol withdrawal severity are influenced by some of the same genes using the iWSP and iWSP mice. The study will also assess genotypic differences in the effects of withdrawal on ethanol drinking following four cycles of chronic intermittent ethanol exposure (each cycle = 16 hours ethanol: 8 hours air for 4 days). Taken together these three studies will permit the development of a broader-based description of ethanol withdrawal that encompasses changes in impulsivity/inhibition and ethanol drinking, as well as provide critical information for future genetic mapping studies to identify the precise genes involved in these processes.