Rodents with Genetic Differences in Alcohol Preference

描述（由申请人提供）：该 R24 酒精研究资源的主要目标是以成本向校外研究人员提供 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 选择的啮齿动物品系是在印第安纳大学开发的，该 R24 是维持 HAD1-2/LAD1-2 核心繁殖群体的唯一资金来源（具体目标 1）。来自N/Nih基础种系的HAD1-2/LAD1-2品系是针对不同的酒精偏好选择性培育的唯一复制大鼠品系，并且它们在表型和基因型上与P/NP对比品系不同。为了增加该 R24 的价值，AA/ANA 大鼠品系的繁殖群体将从芬兰转移到印第安纳州作为新资源（具体目标 4）。从神经化学角度来看，AA 大鼠与 P 大鼠显着不同，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都不是核心；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）。 这种方法是最方便的，因为李廷凯博士（创建我们的 P/NP、HAD1-2/LAD1-2 和 HAP1-2/LAP1-2 选定的啮齿动物品系的 PI）现在是杜克大学精神病学教授和博士。阿米尔·H·雷兹瓦尼 (Amir H. Rezvani) 和爱德华·D·莱文 (Edward D. Levin) 在杜克大学开展了积极的研究项目，常规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、HAD1/LAD1、HAD2/LAD2、AA/ANA和sP/sNP)在通过静脉内途径自我施用尼古丁的意愿上的差异并确定哪个高品系具有最高的自我施用尼古丁倾向来实现。然后，这条具有高饮酒偏好和高尼古丁静脉注射自我给药的高线将被用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）：可以使用来自不同遗传背景的多种嗜酒大鼠系，它们一起在行为上模拟最近 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、HAD1-2/LAD1-2 和 AA/ANA 选择性繁殖的大鼠以及 HAP1-2-3/LAP2-3 和 cHAP 选定的小鼠。此外，这种 R24 将创建一种新的酒精-尼古丁共同滥用动物模型，这对于基础临床前研究非常有用。

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.