RC4 Impulsivity/Withdrawal-induced EtOH Consumption

这一部分的长期目标是了解酒精戒断严重程度和基础水平以及戒断后酒精消费升级和冲动(行为抑制/去抑制)之间的遗传相互关系。来自8个近交系的数据表明，行为抑制指数(预期性反应和拒绝提示时的反应)受到基因的影响，这种遗传影响与急性和慢性的遗传贡献有关 酒精戒断严重程度，使用处理诱发惊厥(HIC)进行评估。其他数据表明，慢性酒精戒断和酒精摄入量之间存在负遗传关系。 拟议的研究将通过三项研究来评估这些遗传相互关系。研究1通过评估在长期暴露于乙醇蒸气后选择性培育的重度(近交系戒断发作倾向；IWSP)和轻度(近交系戒断发作抵抗；IWSR)戒断HIC严重程度的小鼠的GO/NO-GO任务的基础抑制，来检验乙醇幼稚动物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检查慢性酒精暴露(连续吸入酒精72小时)后的抑制水平，以确定何时出现最大解除抑制以及这种抑制持续多长时间。与研究1类似，研究2将解决以下问题：在IWSP和IWSR小鼠中影响戒断HIC严重程度的某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。研究3将使用IWSP和IWSP小鼠，检查非酒精依赖动物的酒精饮用量和酒精戒断严重程度是否受到一些相同基因的影响。这项研究还将评估在四个周期的慢性间歇性酒精暴露(每个周期=16小时酒精：8小时空气中4天)后，停药对饮酒的影响的基因差异。综上所述，这三项研究将使人们能够对酒精戒断进行更广泛的描述，包括冲动/抑制和饮酒方面的变化，并为未来的遗传图谱研究提供关键信息，以确定参与这些过程的准确基因。

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.