Rodents with Genetic Differences in Alcohol Preference

描述（由申请人提供）：本R24酒精研究资源项目的主要目标是向校外研究人员提供成本P/NP、HAD1-2/LAD1-2和AA/ANA选择性繁殖的大鼠，以及HAP1-2-3/LAP2-3和cHAP选择的小鼠，这些小鼠在遗传上表现出高和/或低酒精偏好。（具体目标2和3）。P/NP, HAD1-2/LAD1-2， HAP1-2-3/LAP2-3和cHAP选择的啮齿动物系是在印第安纳大学开发的，该R24是维持HAD1-2/LAD1-2核心繁殖菌落的唯一资金来源（具体目标1）。来自N/Nih基金会的HADl- 2/LAD1-2系是唯一选择性繁殖的具有不同酒精偏好的重复大鼠系，它们在表型和基因表型上都不同于P/NP对照系。为了提高R24的价值，一个aa /ANA大鼠系的繁殖群体将作为一种新的资源从芬兰转移到印第安纳州（具体目标4）。在神经化学上，AA大鼠与P大鼠有着显著的不同，即，中边缘多巴胺通路在AA大鼠获得或维持高度酒精偏好中都不是中心通路；相反，涉及内源性阿片类药物和内源性大麻素的先天神经回路似乎是关键。为了给R24带来进一步的附加价值，杜克大学将获得一份分包合同，合作创建酒精和尼古丁共同滥用的有效动物模型（具体目标5）。这种方法是最有利的，因为李廷恺博士（创建了我们的P/NP， HAD1-2/LAD1-2和HAP1-2/LAP1-2选定的啮齿动物系的PI）现在是杜克大学精神病学教授。阿米尔·h·雷兹瓦尼和爱德华·d·莱文在杜克大学有一个活跃的研究项目，常规使用静脉尼古丁自我给药。这将通过首先比较具有相反酒精偏好的五对选择性繁殖大鼠系（即P/NP， HADl/LADl, HAD2/LAD2， AA/ANA和sP/sNP）通过静脉途径自我给药尼古丁的意愿差异来实现，并确定哪一个高品系具有最高的自我给药尼古丁倾向。这条高酒精偏好和高尼古丁自我给药的高线将用于研究非依赖性饮酒和复发性饮酒对尼古丁自我给药的影响。相关性（见说明）：来自不同遗传背景的多种偏好酒精的大鼠系是可用的，它们一起模拟了最近NESARC研究中定义的具有高遗传负荷的不同亚型的酗酒者的行为。该R24将为校外研究人员提供P/NP、HAD1-2/LAD1-2和AA/ANA选择性饲养的大鼠以及HAP1-2-3/LAP2-3和cHAP选择性饲养的小鼠。此外，R24将创造一种新的酒精-尼古丁共同滥用的动物模型，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.