Rodents with Genetic Differences in Alcohol Preference

描述（由申请人提供）：此R24酒精研究资源nt的主要目标是以成本向校外研究人员提供P/NP，HAD 1 -2/LAD 1 -2和AA/ANA选择性繁殖的大鼠，以及HAP 1 -2-3/LAP 2 -3和cHAP选择的小鼠，这些小鼠表现出遗传上的高和/或低酒精偏好。（具体目标2和3）。P/NP、HAD 1 -2/LAD 1 -2、HAP 1 -2-3/LAP 2 -3和cHAP选择的啮齿动物系是在印第安纳州大学开发的，该R24是维持HAD 1 -2/LAD 1 -2细胞核繁殖菌落（特定目标1）的唯一资金来源。来自N/Nih基础原种的HAD 1 - 2/LAD 1 -2系是为不同的酒精偏好而选择性繁殖的唯一复制大鼠系，并且它们在表型和基因型上不同于P/NP对照系。为了增加该R24的价值，AA/ANA大鼠品系的繁殖群将作为新资源从芬兰转移到印第安纳州（具体目标4）。神经化学上，AA大鼠与P大鼠显著不同，即，中脑边缘多巴胺通路在AA大鼠获得或维持高度酒精偏好中不是中心的;相反，涉及内源性阿片样物质和内源性大麻素的先天神经回路似乎是关键。为了给R24带来更多的附加值，杜克大学将获得一个合作伙伴，以创建酒精和尼古丁共同滥用的有效动物模型（具体目标5）。 这种方法是最方便的，因为Ting-Kai Li博士（创建我们的P/NP、HAD 1 -2/LAD 1 -2和HAP 1 -2/LAP 1 -2选定啮齿动物系的PI）现在是杜克大学的精神病学教授，Amir H. Rezvani和Edward D.莱文在杜克大学有一个积极的研究项目，该项目定期使用静脉注射尼古丁自我给药。这将通过首先比较具有相反酒精偏好的五对选择性繁殖的大鼠品系（即，P/NP、HAD 1/LAD 1、HAD 2/LAD 2、AA/ANA和sP/sNP），以确定其通过静脉内途径自我施用尼古丁的意愿差异，并鉴定哪种高线具有自我施用尼古丁的最高倾向。然后，将使用具有高度饮酒偏好和高尼古丁静脉自我给药的这条高线来研究非依赖性饮酒和复发样饮酒对尼古丁自我给药的影响。 相关性（参见说明）：来自不同遗传背景的多个酒精偏好大鼠品系是可用的，并且它们一起在行为上模拟了由最近的NESARC研究定义的具有高遗传负荷的酗酒者的不同亚型。该R24将为校外研究人员提供P/NP，HAD 1 -2/LAD 1 -2和AA/ANA选择性繁殖的大鼠以及HAP 1 -2-3/LAP 2 -3和cHAP选择性小鼠。此外，这种R24将创建一种新的酒精-尼古丁共滥用动物模型，这将在基础临床前研究中非常有用。

DESCRIPTION (provided by applicant): The major objective of this R24 Alcohol Research Resource nt is to supply to off-campus researchers at cost P/NP, HAD1-2/LAD1-2, and AA/ANA selectively bred rats, as well as HAP1-2-3/LAP2-3 and cHAP selected mice that show genetically high and/or low alcohol preference. (Specific Aims 2 and 3). The P/NP, HAD1-2/LAD1-2, HAP1-2-3/LAP2-3, and cHAP selected rodent lines were developed at Indiana University and this R24 is the sole funding source for maintaining the HAD1-2/LAD1-2 nucleus breeding colonies (Specific Aim 1). The HADl- 2/LAD1-2 lines from the N/Nih foundation stock are the only replicate rat lines selectively bred for divergent alcohol preference and they are phenotypically and genotypically different from the P/NP contrasting lines. In order to increase the value of this R24, a breeding colony ofAA/ANA rat lines will be transferred from Finland to Indiana as a new resource (Specific Aim 4). Neurochemically, AA rats are strikingly different from P rats, i.e., the mesolimbic dopamine pathway is not central either in the acquisition or maintenance of high alcohol preference in the AA rats; instead, innate neurocircuitries that involve endogeneous opioids and endocannabinoids appear to be the key. For the purpose of bringing further added value to this R24, Duke University will receive a subcontract to collaborate in creating a valid animal model of alcohol and nicotine co-abuse (Specific Aim 5). This approach is most expedient because Dr. Ting-Kai Li (the PI who created our P/NP, HAD1-2/LAD1-2, and HAP1-2/LAP1-2 selected rodent lines) is now a Professor of Psychiatry at Duke and Drs. Amir H. Rezvani and Edward D. Levin have active research programs at Duke that use iv nicotine self-administration routinely. This will be achieved by first comparing the five pairs of selectively bred rat lines with opposite alcohol preference (i.e., P/NP, HADl/LADl, HAD2/LAD2, AA/ANA, and sP/sNP) for their differences in willingness to self- administer nicotine by intraveneous route and to identify which high line has the highest proclivity to self- administer nicotine. This high line with both high alcohol drinking preference and high nicotine iv self- administration will then be used to investigate the effects of nondependent alcohol drinking and relapse-like alcohol drinking on nicotine self-administration. RELEVANCE (See instructions): Multiple alcohol-preferring rat lines from different genetic background are available, and together, they simulate behaviorally the distinct subtypes of alcoholics with high genetic load defined by a recent NESARC study. This R24 will supply to off-campus researchers the P/NP, HAD1-2/LAD1-2, and AA/ANA selectively bred rats as well as the HAP1-2-3/LAP2-3 and cHAP selected mice. Additionally, this R24 will create a new animal model of alcohol-nicotine co-abuse that will be extremely useful in basic preclinical research.