这项工作是由瑞典研究理事会的支持。

所有程序都符合美国国立卫生研究院指南实验动物的护理和使用进行。 1.动物护理和房屋<ol><li>当在菌落到来，房子的雄性Wistar大鼠，体重200 - 在一个温度（21℃）和湿度控制的环境有一个扭转12小时明暗周期到达成对225克。 注:根据实验的基本原理，老鼠可以是单住。 </li><li>允许大鼠适应环境的动物饲养和光周期为至少一个星期开始实验之前和每天处理它们。称量动物每周一次。 </li><li>给大鼠自由获取食物和自来水为实验期间（禁水是没有必要发起响应12）。在光暗周期在一个黑暗的检测室的黑暗阶段进行的所有行为测试。 注意:尽管我们经常使用年轻成年雄性Wistar大鼠（出生后62天 - 65），这名Protocol理论上可以是适用于研究大鼠的其它菌株，以及性别和/或年龄的差异。 </li></ol> 2.操作性培训<ol><li>开展以相同的操作室的所有行为训练和测试测量30.5×29.2×24.1厘米和含床上用品内衬格子地板和废盘（改变了动物之间，以减少气味线索），安置在装有排风扇通风声音衰减柜。 注意:大鼠被操作性调节从训练1天受训（上一杠杆的应答是必要的，以获得一个加强件）+ 1 H和暗循环的+ 8小时之间。没有预先接触酒精，也不是食品或液体酒精整形赛前训练。 </li><li>装备有刺激灯，注射泵和横向移动到液体容器杯收放2杠杆每个操作性室。接口室和控制使用适当的软件的计算机。 注意:大多数供应商将提供包含所有必要的组件需要控制腔自我管理包以及软件和接口。 </li><li>写发起根据制造商的说明在20％乙醇加固的固定比率（FR）调度（一个操作性日程表，其中，响应只响应一个指定的数量后强化）的操作性调节程序。例如，在一个固定比率1，大鼠必须产生一个响应，以获得加强件（见用于FR1程序的一个例子的补充编码文件部分）。执行以下命令。 <ol><li>扩展两个杠杆，以纪念在会议开始和信号酒精可用性。 注意:用乙醇（活动）相关联的杆的一个杠杆按由100微升20％乙醇的体积的水在相邻饮用井水输送奖励并启动由信号伴随5 - S的超时周期的照明线索光杆之上。该线索光介绍了关于训练的第一天。 </li><li>在超时期间，记录响应虽然它没有排定的后果。另一杆（未激活）记录的反应，虽然他们从来没有行为后果。注意:非活性杠杆作为控制，以评估非特定行为。 </li><li>记录在主动杆（反应率）和挣得20％乙醇的奖励的数量的响应次数。 </li><li> 30分钟已经过去之后，收回两个杠杆信号会话的结束和对信号的醇可用性结束。 </li><li>保存和归档的所有数据。 </li></ol></li><li>在开始训练之前，先检查每个操作性室所有设备的正常功能（可伸缩的杠杆，流体分配器）。 </li><li>制备190证明（95％）乙醇在自来水中稀释的20％V / V乙醇溶液。 注意:乙醇溶液可保持在室温。根据上的制造商，库存乙醇溶液可高达99.98％。还要注意的是，虽然在大多数发表的手稿，乙醇浓度通常作为体积/体积，一些可呈现它们作为重量/体积。 </li><li>填用20％乙醇溶液的注射器，并确保有在输液线没有泄漏或气泡。手动推乙醇小体积过输注线路，以确保乙醇将被正确地输送到容器从第一增强响应。干后用纸巾插座中，并确保它是启​​动会话之前空。 </li><li>加载控制20％乙醇加固的FR日程表软件</li><li>在30分钟的会议下FR1时间表，列车operant-和药物天真大鼠的自我管理20％乙醇无禁水。 <ol><li>从动物饲养到使用传输笼考场运输的影响。 </li><li>每只大鼠分配到一个房间。就拿从运输笼每个老鼠，并把它在分配的自我管理室。 </li><li>尽量保持实验，每天保持一致的条件。因此，总是每天测试的大鼠以相同的自我管理室在大致相同的时间。 </li><li>开始发起20％的乙醇加固FR1时间表软件。 </li><li>在会议结束时，从自我管理室取出老鼠，并将其退回到动物饲养。 </li><li>为了手动确认的酒精溶液被消耗的动物，用纸巾和检查插座干燥。或者，使用1或2毫升的注射器，并收集残留在容器来估计未消耗的体积的流体。 注意:对于一个更精确的测量（但也更贵），所以可以装备每个室连接到所述液体杯容器中的舔食测试器系统，使舔的精确的计数■通过自我管理会话期间大鼠产生的。 </li><li>清洁用表面消毒剂各室的壁和格栅地板。 </li><li>使用后，通过用70％的乙醇溶液清洗他们保持输液线。在不使用时，插入所述盖，以避免模具和灰尘。 </li></ol></li><li>每次会议之后，收集和分析产生的数据。更具体地说，计算主动杆压力机的平均数，得到的醇的奖励的平均数以及非活性杠杆压力机的平均数。 注意:在大部分纸，酒精消耗也呈现为克/公斤（体重）乙醇的摄入量。乙醇摄入可以使用下列公式计算: <img alt="公式1" src="/files/ftp_upload/53305/53305equation1.jpg" /> 用消耗的体积（毫升） - 0.789克/毫升 - 在室温下获得±酉体积/奖励和乙醇密度奖励数量。 例如，如果一个老鼠称重400克获得20雷瓦的20％V / V乙醇溶液RDS: <img alt="方程2" src="/files/ftp_upload/53305/53305equation2.jpg" /></li><li>进行会话5/6天每周直到性能（定义为至少15的会话，并没有变化，在过去3次会话赢得奖励的总数大于15％）稳定。 注意:一旦大鼠已经在FR1达到稳定的基线，所述操作条件反射程序可根据制造商的说明，以增加的必要，以获得醇奖励响应的数量进行修改。固定比例可以例如，以最小化意外加固增加到FR2或FR3制作的。 </li><li>测量血液中乙醇浓度: <ol><li>以确认以自管理会话得到的奖励是由大鼠消耗时，测量以下自我施用血液乙醇浓度。一旦老鼠已经达到了一个稳定的基线，收集来自横向尾静脉取血后立即会话。插入23政针插入血管，并收集用毛细管50微升血样。 </li><li>转移50微升血样至10ml顶空小瓶中，并添加50微升的1:1000的异丙醇作为内标。从乙醇标准准备的标准曲线10〜300毫克/分升。过程的样品与根据制造商设置的层析柱13的顶空取样。 </li></ol></li><li>渐进比<ol><li>使用累进比率（PR）的时间表来评估动物的动力消耗的奖励14。公关是一个操作性的时间表中的反应获得强化物的数量逐渐增加（在其他方面，老鼠要更努力为每个连续的奖励）。 注:相反，FR会议，公关会话不定时的，只会被终止后30分钟没有完成比例已过。 <ol><li>将大鼠分配给他们的操作性箱，并允许他们为下加强件的PR时间表20％乙醇响应:保持相同的那些对FR调度所使用的所有的实验条件（见步骤2.3），除了增加内会话的响应要求或成本（ 即 ，杠杆按压的次数1，2，3，4，6，8，10，12，16，20，24，28，32 ...注意:的一个例子，根据下面的公式来接收单个乙醇奖励）上需要主动杆PR程序在补充编码文件部分提供。 </li><li>终止PR会议一次30分钟后没有奖励过去了。 注意:断点被定义为PR会议期间最后完成的响应的要求。 </li></ol></li></ol></li></ol> 3.测试酒精自我管理的操作性模型的预测效度注意:一旦大鼠已经获得了稳定的自给药基线（见步骤2）中，有可能通过以评估该模型的预测效测试纳曲酮的功效，一个目前FDA批准用于减少20％乙醇自身给药酒精依赖的药物。我们建议在做培训（FR2）期间所取得的最高FR这个测试，如果反应是可靠的高。一旦预测效度的建立，该模型可以用来评估新的候选药物。 <ol><li>测试前一天，给大鼠皮下注射盐水注射之前自我管理会话最少两个连续的自我管理的会话期间将它们habituate到注射或直到响应的乙醇不会受盐水注射（定义为没有变化30分钟在过去的2会议期间获得的奖励）的总人数超过15％。 </li><li>溶解纳曲酮在盐水中并调节pH达到中性，以便于注射至动物。注射药物以1.0毫升/体积公斤30分钟的会话之前，使用给药的皮下途径。注:升ATURE提供了良好的证据0.1范围之间的剂量的选择 - 为1mg / kg的，所以0.1,0.3和1mg / kg的在这个协议中被使用。 注:研究表明使用的管理的纳曲酮皮下和腹腔内的路线，虽然其效力可皮下注射是不同的30倍更有效的腹腔注射15。出于这个原因，建议使用皮下途径的使用为纳曲酮的注入此路线的已被验证，并在一范围0.1和1mg之间浓度的各种实验室复制/ kg的12,15,16。 </li><li>在测试当天，注入大鼠以平衡/随机顺序在受试者间设计横过自管理会话前30分钟的四个纳曲酮给药周期（0，0.1，0.3和1毫克/千克）中的一个。 </li><li>每个给药周期之间，只允许以最小的两个连续的自我管理会话或直到响应的洗出的药物乙醇是回到基线。注意:作为一个结果，在试验结束时，所有的大鼠被注射每四个剂量。 </li><li>这个阶段后，选择最有效的剂量（1毫克/千克）和测试对动物的动机纳曲酮的使用效果渐进比时间表消耗酒精（见步骤2.12）。 </li></ol>

<ol>
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F., Weiss, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pharmacology+of+drug+self-administration.">Pharmacology of drug self-administration.</a> Alcohol. 7, 193-197 (1990).</li><li>Schank, J. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+Role+of+the+Neurokinin-1+Receptor+in+Stress-Induced+Reinstatement+of+Alcohol+and+Cocaine+Seeking.">The Role of the Neurokinin-1 Receptor in Stress-Induced Reinstatement of Alcohol and Cocaine Seeking.</a> Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. , (2013).</li><li>Avena, N. M., Bocarsly, M. E., Rada, P., Kim, A., Hoebel, B. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=After+daily+bingeing+on+a+sucrose+solution,+food+deprivation+induces+anxiety+and+accumbens+dopamine/acetylcholine+imbalance.">After daily bingeing on a sucrose solution, food deprivation induces anxiety and accumbens dopamine/acetylcholine imbalance.</a> Physiology. 94, 309-315 (2008).</li><li>Avena, N. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+study+of+food+addiction+using+animal+models+of+binge+eating.">The study of food addiction using animal models of binge eating.</a> Appetite. 55, 734-737 (2010).</li><li>Morgan, D., Sizemore, G. 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作者什么都没有透露。

有了这个协议，我们提出一种新的方法来获得并维持20％乙醇的稳定口服自我管理的，相反，乙醇自我管理的经典机型，不需要使用禁水，扩展访问训练大鼠，或糖精/蔗糖衰落12。此外，纳曲酮，当前FDA批准用于酒精依赖药物治疗，成功地降低酒精的自我管理和消费这一协议训练有素的Wistar大鼠酒精的动机。这个结果提供了协议的一个重要的药理学验证，因为它是与表示纳曲酮是有效减少非依赖大鼠16-18饮酒先前的报告一致。纳曲酮是一种阿片受体拮抗剂，在酒精摄入和临床试验的动物模型已经显示出有希望的结果。在动物模型中，纳曲酮是在减少饮酒和自一个有效dministration在非依赖动物16,17,19，在不影响非特定行为（不活动杠杆压力机）12。它也证明在减少食物摄取效率。例如，它成功地降低糖精两者甜无热量的溶液，以及一个高适口性和热量的巧克力饮料20的老鼠的液体摄入。纳曲酮也减少在两瓶的选择设置22蔗糖自我施用16，禁水21后水的摄入量，以及糖精选择。总之，这些结果表明，纳曲酮可能不会影响醇通过调制液体增强剂的热值作出响应，但通过降低醇的直接奖励值的可能性较大。 有对这种模型的几个重要的优点。首先，将采集周期是比以前的范式更快。大鼠达到有关文件积极杠杆率压在一个星期内的乙醇23 VELS。糖衰落基于范式必要六到八周的测试，以产生可靠摄入乙醇1,3，从而浪费了宝贵的时间和资源。其次，这种模式消除了乙醇消费量显着减少常见的去除甜味剂以下，因此可能会降低消耗乙醇自我管理率24研究。八种不同的大鼠总金额为239 operant-和药物天真Wistar大鼠组都使用此协议只有9满足标准未能在过去3中获得自我管理（定义为至少10主动杠杆压力机运行稳定的固定比率1次）。因此，这种新颖的培训协议产生的96％，令人印象深刻的成功采集率。与此协议，大鼠达到健壮响应率不到两周，产生0.86克/千克的平均摄入乙醇。这种消费水平相当于通过与蔗糖/糖精的衰落，通常0.5和0.8g之间实现了平均消费程序训练大鼠达到了那些/公斤1,2,23,25。 此外，该模型简化通过删除的困惑乙醇自我管理研究的解释是由于老鼠糖精和蔗糖的固有属性奖励。食物奖励和更具体的可口的食品，如糖的电位成瘾特性已在近几年的兴趣的受试者，并最终强调乙醇自身给药的更具体的模型的需要。例如，有证据支持这一想法，蔗糖本身可以是大鼠上瘾，如大鼠响应于过多蔗糖摄取26-28显示行为，如暴食，寻求和撤出。此外，蔗糖和糖精比滥用药物如可卡因和鸦片制剂6-8,29和这些甜味剂多个加强改变的Fos激活的大脑区域包括类似于乙醇和滥用9的其他药物的方式，伏隔核。最后，这种模式适用于研究复吸的动物模型。我们以前曾表明，使用这种方法训练的动物能够有力地扑灭他们的反应对酒精12，类似于什么通常是用乙醇自我管理25经典款获得。这些动物可以再利用应激12或重新引进的提示灯30复职。 乙醇是一种矛盾的药物，发挥奖励和厌恶的属性。它被广泛认为乙醇的主要厌恶味道是一个主要的障碍在大多数鼠类实现稳定的自管理，尤其是在高浓度的1。然而，研究调查了广泛的乙醇浓度的大鼠的味道反应性（从5％至40％体积/体积）surprisingly发现的享乐，但不是厌恶的数量，口面的反应趋于增加具有更高的乙醇浓度31。而且，随着反复暴露于醇，当大鼠暴露于高的乙醇浓度的厌恶口面响应的数量下降（20至40％体积/体积），而它仍然具有较低的浓度保持不变（5％至10％体积/体积）。类似地，有两个乙醇溶液23并发操作性访问大鼠反应比较对于较高浓度（20或40％体积/体积）比下部（10％体积/体积，即主要在蔗糖中使用的浓度/糖精衰落程序），自我管理口服乙醇20％的乙醇浓度11显示具有最高摄入乙醇自我管理中一个倒U形的剂量反应曲线。这些数据表明，乙醇较高浓度可能更有益的和更少厌恶给大鼠，解释为什么大鼠获得20％的乙醇的自我施用在邻乌拉圭回合协议而无需乙醇暴露前或蔗糖/糖精衰落过程。 不过，需要注意的是这个模型不生产乙醇的自我管理和高酒精浓度的血液进一步升级的水平是很重要的。因此，这种模式不诱导大鼠身体依赖性和如果实验的目的是诱导过量饮酒在啮齿类动物应该与其他模型相结合。 与许多行为任务，第一关键参数是保持实验尽可能每天为一致的情况。更确切地说，大鼠应始终在相同的自我管理室进行试验。会话应该发生在同一时间（±30分钟）在整个实验。腔室（参见步骤2.2）的结构应保持不变。在自我管理训练，第一会话可以是至关重要的。应特别注意给予THÈ药物输送管道，液体杯容器，杆和注射器泵。至关重要的是，乙醇被正确递送到来自第一增强反应容器中，如任何故障可延缓或损害采集乙醇自身给药的。 综上所述，训练老鼠在此协议极大地描述口腔酒精操作性自我管理的新模式提高了通过减少培训时间，提高了采集速率的效率，简化了整个过程以及结果的解释，并进行验证由纳曲酮的实验乙醇饮酒的良好典范。这个协议是适用于大鼠调查醇的奖励和激励性，并且可以与经典操作性自我施用方法如reinstatements模型来评估的乙醇寻求行为的神经基础组合。

动物模型来研究药物的增强效果的发展已经证明研究人类药物成瘾的重要工具。更具体地，操作性自我施用是一种广泛使用的行为模型，这是最有效的手段，以评估口服消耗乙醇溶液的阳性增强效果之一。与开发这样一个模型的早期问题是高浓度的乙醇对大多数鼠类主厌恶味道，即，可以在与醇1很少或没有经验的人类共享的现象。一个标准的协议来克服这一障碍需要禁水和/或糖精或蔗糖衰落收购和自我管理的维护。然而，这两种方法都不是有利的。他们需要的培训长时间简单地启动响应为乙醇和收购取得的相对成功率。使用甜味剂还引入了一个潜在的偏见自我管理数据的解释。这些限制并不适用于以下协议。 简单地说，参孙和同事2表明，溶解在20％蔗糖的甜美乙醇溶液中，然后在4周的训练淡出了甜头需要发起水响应的10％的乙醇。此外，可靠乙醇摄入6至8周1-3通常实现。这种方法是很成问题。首先，它要求的训练长时间之前研究者可以开始测量乙醇自身给药。相比之下，可卡因或海洛因静脉自身给药需要0 -在限食动物食品提供杠杆药物前培训1天，稳定的响应药物通常是在10实现- 1天4,5。该方法的另一限制是，糖精和蔗糖是高度有益的大鼠和引发脑激活图形Similar滥用药物，从而带来了潜在的的困惑在乙醇的自我管理研究6-9。最后，由于不成功的采集和/或应答率不足大鼠取得使用在获得和反应率1,10-此方法显示变性的乙醇溶液，与实验一致排除大鼠相当比例的自我给药。 相比之下，有此协议，我们提出收购，并在水中的解决方案，并不需要禁水，蔗糖/糖精的衰落和扩展访问培训20％乙醇的口腔自我管理维护一个简单而有效的方法。最近的调查发现，在20％的乙醇浓度的自我管理期间，自我给药用于口服乙醇显示具有最高乙醇摄取一个倒U形的剂量反应曲线，从而为在我们的experim选择20％的乙醇溶液中提供理ental设计11。

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a method for evaluating the reinforcing properties of ethanol in rats without water deprivation, saccharin fading or extended access training

操作性口服自我施用方法通常用于研究的动物的乙醇补强性。然而，标准方法需要糖精/蔗糖衰落，禁水和/或延长培训发起操作性大鼠响应。本文介绍一种新颖且有效的方法来快速启动操作性响应的乙醇也方便实验者和不需要水剥夺或糖精/蔗糖衰落，从而消除在乙醇操作性自我施用研究使用甜味剂的电位变乱。用这种方法，将Wistar大鼠通常获得并维持20％的乙醇溶液的自我施用在不到两周的训练。此外，血液中乙醇浓度和奖励一个30分钟的自我管理会话是正相关的。此外，纳曲酮，已被证明酒精依赖FDA批准的药物来抑制乙醇的自我管理在啮齿动物，剂量依赖性减少酒精摄入和动力消耗对大鼠自我施用20％乙醇的醇，从而验证使用这种新方法的研究在大鼠醇的补强性能。

图1显示了operant-和药物天真大鼠代表自我管理行为（八个不同的队列数额总计为239只）训练了FR1时间表进行自我管理20％乙醇停水剥夺或糖精/蔗糖衰落在30分钟的会议。有了这个协议，只启动杆挤压很快得到乙醇的奖励，已经获得第一届（ 图1A）在10多个奖励。它们通过自我管理的会议10到达上主动杆稳定响应率，从而获得的在FR1（ 图1B）23.7±0.7奖励的平均，对应于0.86克/千克的平均摄入乙醇。 图2示出了对酒精自我施用不同剂量的纳曲酮的影响。为了评估一个企业的预测效度乙醇求的动物模型，纳曲酮的功效，一个目前FDA批准用于酒精依赖用药，应在一组下一个扩展的固定比率-3（FR3）加固时间表受过训练的动物的验证。纳曲酮的处理预计将产生在酒精自我给药的剂量依赖性降低（ 图2A和2B），以及减少的动机，以获得醇使用渐进比时间表（ 图2C）进行评估。 <img alt="图1" src="/files/ftp_upload/53305/53305fig1.jpg" /> 图1:Wistar大鼠获得并保持20％乙醇的自我管理。 答:平均回报（±SEM）在20％乙醇（N = 239只）的30分钟的自我管理会话（FR1，采集阶段）获得。在30分钟的自我管理会话（FR1，FR2，获得稳定的回报均值:乙20％（N = 239只）相）。 C:平均活跃和不活跃杆压力机（±SEM）中的20％（N = 239只）30分钟自我管理会话（FR1，FR2，稳定期）完成。 ð:一个30分钟的自我管理会话与BEC（毫克/分升）时获得的奖励数（n = 36只，R 2 = 0.67，P &lt;0.001）。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53305/53305fig1large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图2" src="/files/ftp_upload/53305/53305fig2.jpg" /> 图2:纳曲酮降低了自我管理和动力消耗酒精。 答:按照Wistar大鼠盐水或纳曲酮治疗（0.1，0.3或1毫克/公斤）（N = 16）20％乙醇30分钟的自我管理会话（FR3）期间完成的平均活跃杆压力机（±SEM） （** = p &lt;0.01，*** = P &lt;0.001）。 A:按照Wistar大鼠盐水或纳曲酮治疗（0.1，0.3或1毫克/公斤）（N = 16）20％乙醇30分钟的自我管理会话（FR3）期间平均回报（±SEM）获得（ ** = p &lt;0.01，*** = p &lt;0.001）。 C:平均断点（±SEM）以下的20％乙醇的公关会议期间达成盐水或Wistar大鼠纳曲酮治疗（1毫克/公斤）（16）（* = P &lt;0.05）。 D:按照Wistar大鼠盐水或纳曲酮治疗（1毫克/公斤）（N = 16）20％乙醇的公关会议期间奖励数（±SEM）获得（* = P &lt;0.05）。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53305/53305fig2large.jpg" target="_blank">请点击此处查看该图的放大版本。</a>

Watch this Scientific Journal Video about A Method for Evaluating the Reinforcing Properties of Ethanol in Rats without Water Deprivation, Saccharin Fading or Extended Access Training at JoVE.com

A Method for Evaluating the Reinforcing Properties of Ethanol in Rats without Water Deprivation, Saccharin Fading or Extended Access Training

本协议描述为一种新型快捷的方法来快速启动操作性的，相反，标准方法，不需要水剥夺或糖精/蔗糖衰落的开始响应响应大鼠乙醇。

一种用于评价大鼠乙醇的补强性能没有禁水，糖精衰落或扩展访问训练方法

Operant oral self-administration methods are commonly used to study the reinforcing properties of ethanol in animals. However, the standard methods ...

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Nanyang Technological University

Research

JoVE Journal

Behavior

9.5K 次观看.  Linköping University. 本协议描述为一种新型快捷的方法来快速启动操作性的，相反，标准方法，不需要水剥夺或糖精/蔗糖衰落的开始响应响应大鼠乙醇。 

视频: A Method for Evaluating the Reinforcing Properties of Ethanol in Rats without Water Deprivation, Saccharin Fading or Extended Access Training

A Procedure to Study the Effect of Prolonged Food Restriction on Heroin Seeking in Abstinent Rats

In human drug addicts, exposure to drug-associated cues or environments that were previously associated with drug taking can trigger relapse during abstinence. Moreover, various environmental challenges can exacerbate this effect, as well as increase ongoing drug intake.
The procedure we describe here highlights the impact of a common environmental challenge, food restriction, on drug craving that is expressed as an augmentation of drug seeking in abstinent rats.
Rats are implanted with chronic intravenous i.v. catheters, and then trained to press a lever for i.v. heroin over a period of 10-12 days. Following the heroin self-administration phase the rats are removed from the operant conditioning chambers and housed in the animal care facility for a period of at least 14 days. While one group is maintained under unrestricted access to food (sated group), a second group (FDR group) is exposed to a mild food restriction regimen that results in their body weights maintained at 90% of their nonrestricted body weight. On day 14 of food restriction the rats are transferred back to the drug-training environment, and a drug-seeking test is run under extinction conditions (i.e.&#160;lever presses do not result in heroin delivery).
The procedure presented here results in a highly robust augmentation of heroin seeking on test day in the food restricted rats. In addition, compared to the acute food deprivation manipulations we have used before, the current procedure is a more clinically relevant model for the impact of caloric restriction on drug seeking. Moreover, it might be closer to the human condition as the rats are not required to go through an extinction-training phase before the drug-seeking test, which is an integral component of the popular reinstatement procedure.

A procedure that allows a demonstration of robust augmentation of drug seeking in food-restricted rats is described. Following heroin self-administration training, rats go through an abstinence period, in a drug-free environment, during which they are mildly food restricted. Drug seeking is then tested in the drug-associated environment.

一个过程来研究延长食品的限制对海洛因寻求戒断大鼠的影响

In human drug addicts, exposure to drug-associated cues or environments that were previously associated with drug taking can trigger relapse during ...

科研

行为学

A Novel Procedure for Evaluating the Reinforcing Properties of Tastants in Laboratory Rats: Operant Intraoral Self-administration

This paper describes a novel method for studying the bio-behavioral basis of addiction to food. This method combines the surgical component of taste reactivity with the behavioral aspects of operant self-administration of drugs. Under very brief general anaesthesia, rats are implanted with an intraoral (IO) cannula that allows delivery of test solutions directly in the oral cavity. Animals are then tested in operant self-administration chambers whereby they can press a lever to receive IO infusions of test solutions. IO self-administration has several advantages over experimental procedures that involve drinking a solution from a spout&#160;or operant responding for solid pellets or solutions delivered in a receptacle. Here, we show that IO self-administration can be employed to study self-administration of high fructose corn syrup (HFCS). Rats were first tested for self-administration on a progressive ratio (PR) schedule, which assesses the maximum amount of operant behavior that will be emitted for different concentrations of HFCS (i.e.&#160;8%, 25%, and 50%). Following this test, rats self-administered these concentrations on a continuous schedule of reinforcement (i.e.&#160;one infusion for each lever press) for 10 consecutive days (1 session/day; each lasting 3 hr), and then they were retested on the PR schedule. On the continuous reinforcement schedule, rats took fewer infusions of higher concentrations, although the lowest concentration of HFCS (8%) maintained more variable self-administration. Furthermore, the PR tests revealed that 8% had lower reinforcing value than 25% and 50%. These results indicate that IO self-administration can be employed to study acquisition and maintenance of responding for sweet solutions. The sensitivity of the operant response to differences in concentration and schedule of reinforcement makes IO self-administration an ideal procedure to investigate the neurobiology of voluntary intake of sweets.

The current study evaluates a novel procedure for assessing the reinforcing effects of palatable solutions in laboratory rats: intraoral self-administration. To this end, operant responding (i.e.&#160;lever pressing) for intraoral infusions of sweet solutions at different concentrations was measured on continuous and progressive ratios schedules of reinforcement.

一种新的方法为评估味质的实验室大鼠的补强性能:操作性口腔自我管理

This paper describes a novel method for studying the bio-behavioral basis of addiction to food. This method combines the surgical component of taste ...

A Procedure to Observe Context-induced Renewal of Pavlovian-conditioned Alcohol-seeking Behavior in Rats

Environmental contexts in which drugs of abuse are consumed can trigger craving, a subjective Pavlovian-conditioned response that can facilitate drug-seeking behavior and prompt relapse in abstinent drug users. We have developed a procedure to study the behavioral and neural processes that mediate the impact of context on alcohol-seeking behavior in rats. Following acclimation to the taste and pharmacological effects of 15% ethanol in the home cage, male Long-Evans rats receive Pavlovian discrimination training (PDT) in conditioning chambers. In each daily (Mon-Fri) PDT session, 16 trials each of two different 10 sec auditory conditioned stimuli occur. During one stimulus, the CS+, 0.2 ml of 15% ethanol is delivered into a fluid port for oral consumption. The second stimulus, the CS-, is not paired with ethanol. Across sessions, entries into the fluid port during the CS+ increase, whereas entries during the CS- stabilize at a lower level, indicating that a predictive association between the CS+ and ethanol is acquired. During PDT each chamber is equipped with a specific configuration of visual, olfactory and tactile contextual stimuli. Following PDT, extinction training is conducted in the same chamber that is now equipped with a different configuration of contextual stimuli. The CS+ and CS- are presented as before, but ethanol is withheld, which causes a gradual decline in port entries during the CS+. At test, rats are placed back into the PDT context and presented with the CS+ and CS- as before, but without ethanol. This manipulation triggers a robust and selective increase in the number of port entries made during the alcohol predictive CS+, with no change in responding during the CS-. This effect, referred to as context-induced renewal, illustrates the powerful capacity of contexts associated with alcohol consumption to stimulate alcohol-seeking behavior in response to Pavlovian alcohol cues.

A procedure to study the capacity of an alcohol associated environmental context to trigger the renewal of alcohol-seeking behavior in rats is described.

一个过程来观察大鼠巴甫洛夫空调酒精寻求行为的背景下引发的重建

Environmental contexts in which drugs of abuse are consumed can trigger craving, a subjective Pavlovian-conditioned response that can facilitate ...

Training Rats to Voluntarily Dive Underwater: Investigations of the Mammalian Diving Response

Underwater submergence produces autonomic changes that are observed in virtually all diving animals. This reflexly-induced response consists of apnea, a parasympathetically-induced bradycardia and a sympathetically-induced alteration of vascular resistance that maintains blood flow to the heart, brain and exercising muscles. While many of the metabolic and cardiorespiratory aspects of the diving response have been studied in marine animals, investigations of the central integrative aspects of this brainstem reflex have been relatively lacking. Because the physiology and neuroanatomy of the rat are well characterized, the rat can be used to help ascertain the central pathways of the mammalian diving response. Detailed instructions are provided on how to train rats to swim and voluntarily dive underwater through a 5 m long Plexiglas maze. Considerations regarding tank design and procedure room requirements are also given. The behavioral training is conducted in such a way as to reduce the stressfulness that could otherwise be associated with forced underwater submergence, thus minimizing activation of central stress pathways. The training procedures are not technically difficult, but they can be time-consuming. Since behavioral training of animals can only provide a model to be used with other experimental techniques, examples of how voluntarily diving rats have been used in conjunction with other physiological and neuroanatomical research techniques, and how the basic training procedures may need to be modified to accommodate these techniques, are also provided. These experiments show that voluntarily diving rats exhibit the same cardiorespiratory changes typically seen in other diving animals. The ease with which rats can be trained to voluntarily dive underwater, and the already available data from rats collected in other neurophysiological studies, makes voluntarily diving rats a good behavioral model to be used in studies investigating the central aspects of the mammalian diving response.

Detailed instructions are provided on how to train rats to voluntarily dive underwater through a 5 m long Plexiglas maze. Because the brains of rats have been very well characterized, voluntarily diving rats may help elucidate the central pathways of the mammalian diving response.

训练大鼠自愿潜水水下:哺乳动物潜水响应调查

Underwater submergence produces autonomic changes that are observed in virtually all diving animals. This reflexly-induced response consists of apnea, a ...

The Modified Hole Board - Measuring Behavior, Cognition and Social Interaction in Mice and Rats

This protocol describes the modified hole board (mHB), which combines features from a traditional hole board and open field and is designed to measure multiple dimensions of unconditioned behavior in small laboratory mammals (e.g., mice, rats, tree shrews and small primates). This paradigm is a valuable alternative for the use of a behavioral test battery, since a broad behavioral spectrum of an animal&#8217;s behavioral profile can be investigated in one single test.
The apparatus consists of a box, representing the &#8216;protected&#8217; area, separated from a group compartment. A board, on which small cylinders are staggered in three lines, is placed in the center of the box, representing the &#8216;unprotected&#8217; area of the set-up. The cognitive abilities of the animals can be measured by baiting some cylinders on the board and measuring the working and reference memory. Other unconditioned behavior, such as activity-related-, anxiety-related- and social behavior, can be observed using this paradigm. Behavioral flexibility and the ability to habituate to a novel environment can additionally be observed by subjecting the animals to multiple trials in the mHB, revealing insight into the animals&#8217; adaptive capacities.
Due to testing order effects in a behavioral test battery, na&#239;ve animals should be used for each individual experiment. By testing multiple behavioral dimensions in a single paradigm and thereby circumventing this issue, the number of experimental animals used is reduced. Furthermore, by avoiding social isolation during testing and without the need to food deprive the animals, the mHB represents a behavioral test system, inducing if any, very low amount of stress.

This protocol describes the modified hole board, which is a behavioral test set-up that comprises the characteristics of an open field and a traditional hole board. This set-up enables the differential analysis of unconditioned behavior of small laboratory mammals as well as the analysis of cognitive abilities.

修改后的孔板 - 测量行为，认知和社会互动小鼠和大鼠

This protocol describes the modified hole board (mHB), which combines features from a traditional hole board and open field and is designed to measure ...

A Treatment Package without Escape Extinction to Address Food Selectivity

Feeding difficulties and feeding disorders are a commonly occurring problem for young children, particularly children with developmental delays including autism. Behavior analytic interventions for the treatment of feeding difficulties oftentimes include escape extinction as a primary component of treatment. The use of escape extinction, while effective, may be problematic as it is also associated with the emergence of challenging behavior (e.g., extinction burst). Such challenging behavior may be an acceptable side effect in treatment cases where feeding problems are severe and chronic (e.g., failure to thrive). However, in more acute cases (e.g., selective eating), the negative side effect may be unwarranted and undesired. More recent research on the behavioral treatment of food selectivity has begun to evaluate treatments for feeding difficulties that do not include escape extinction (e.g., demand fading, behavioral momentum), with some success. However, research to date reveals individual differences in responsiveness to such treatments and no clear preferable treatment has emerged. This manuscript describes a multi-component treatment package that includes shaping, sequential presentation and simultaneous presentation, for the treatment of food selectivity in four young children with developmental delays. This treatment package extends the literature on the behavioral treatment for food selectivity and offers a multi-component treatment protocol that may be clinically applicable across a range of treatment scenarios and settings.

Feeding difficulties are a common problem for children with developmental disorders, including autism, and behavioral interventions often include escape extinction. Recent research has begun to evaluate treatments that do not include escape extinction. This manuscript describes a multicomponent treatment package that does not use escape extinction to treat feeding difficulties.

一个疗程装没有逃脱灭绝解决粮食选择性

Feeding difficulties and feeding disorders are a commonly occurring problem for young children, particularly children with developmental delays including ...

Pavlovian Conditioned Approach Training in Rats

Cues that are contingently paired with unconditioned, rewarding stimuli can acquire rewarding properties themselves through a process known as the attribution of incentive salience, or the transformation of neutral stimuli into attractive, &#34;wanted&#39; stimuli capable of motivating behavior. Pavlovian conditioned approach (PCA) develops after the response-independent presentation of a conditioned stimulus (CS; e.g., a lever) that predicts the delivery of an unconditioned stimulus (US; e.g., a food pellet) and can be used to measure incentive salience. During training, three patterns of conditioned responses (CRs) can develop: sign-tracking behavior (CS-directed CR), goal-tracking behavior (US-directed CR), and an intermediate response (both CRs). Sign-trackers attribute incentive salience to reward-related cues and are more vulnerable to cue-induced reinstatement of drug-seeking as well as other addiction-related behaviors, making PCA a potentially valuable procedure for studying addiction vulnerability. Here, we describe materials and methods used to elicit PCA behavior from rats as well as analyze and interpret PCA behavior in individual experiments.

Here, we present a protocol to elicit Pavlovian conditioned approach behavior in rats. This procedure can be used to measure individual differences in the tendency to approach and attribute incentive salience to reward-related cues and investigate addiction vulnerability.

大鼠条件性巴甫洛夫训练方法

Cues that are contingently paired with unconditioned, rewarding stimuli can acquire rewarding properties themselves through a process known as the ...

The Rodent Psychomotor Vigilance Test (rPVT): A Method for Assessing Neurobehavioral Performance in Rats and Mice

The human Psychomotor Vigilance Test (PVT) is a widely used procedure for measuring changes in fatigue and sustained attention. The present article describes a rodent version of the PVT&#8212;termed the &#34;rPVT&#34;&#8212;that measures similar aspects of attention (i.e., performance accuracy, motor speed, premature responding, and lapses in attention). Data are presented that demonstrate both the short- and long-term usefulness of the rPVT when employed with laboratory rats. Rats easily learn the rPVT, and learning to perform the basic procedure takes less than two weeks of training. Once acquired, rat performances in the rPVT show a high degree of similarity to these same performance measures in the human PVT, including similarities in, lapses in attention, reaction times, vigilance decrements across session time (i.e., the human &#34;time-on-task&#34; effects), and the response-stimulus interval (RSI) effect described for humans. Thus the rPVT can be an extremely valuable tool for assessing the effects of a wide range of variables on sustained attention quite similar to human PVT performances, and thus can be useful for developing novel treatments for neurobehavioral dysfunctions.

The Rodent Psychomotor Vigilance Test rPVT: A Method for Assessing Neurobehavioral Performance in Rats and Mice

A rat version of the human Psychomotor Vigilance Test (PVT) is described that measures aspects of attention similar to those measured with the human PVT, including aspects of human vigilance such as performance accuracy, motor speed, premature responding, and lapses in attention.

鼠类精神运动警觉测试（rPVT）:一个在大鼠和小鼠的神经行为评估性能的方法

The human Psychomotor Vigilance Test (PVT) is a widely used procedure for measuring changes in fatigue and sustained attention. The present article ...

The Knob Supination Task: A Semi-automated Method for Assessing Forelimb Function in Rats

Tasks that accurately measure dexterity in animal models are critical to understand hand function. Current rat behavioral tasks that measure dexterity largely use video analysis of reaching or food manipulation. While these tasks are easy to implement and are robust across disease models, they are subjective and laborious for the experimenter. Automating traditional tasks or creating new automated tasks can make the tasks more efficient, objective, and quantitative. Since rats are less dexterous than primates, central nervous system (CNS) injury produces more subtle deficits in dexterity, however, supination is highly affected in rodents and crucial to hand function in primates. Therefore, we designed a semi-automated task that measures forelimb supination in rats. Rats are trained to reach and grasp a knob-shaped manipulandum and turn the manipulandum in supination to receive a reward. Rats can acquire the skill within 20 &plusmn; 5 days. While the early part of training is highly supervised, much of the training is done without direct supervision. The task reliably and reproducibly captures subtle deficits after injury and shows functional recovery that accurately reflects clinical recovery curves. Analysis of data is performed by specialized software through a graphical user interface that is designed to be intuitive. We also give solutions to common problems encountered during training, and show that minor corrections to behavior early in training produce reliable acquisition of supination. Thus, the knob supination task provides efficient and quantitative evaluation of a critical movement for dexterity in rats.

This manuscript describes a semi-automated task that quantifies supination in rats. Rats reach, grasp, and supinate a spherical manipulandum. The rat is rewarded with a pellet if the turn angle exceeds a criterion set by the user. This task increases throughput, sensitivity to injury, and objectivity compared to traditional tasks.

旋钮旋任务: 一种半自动评估大鼠前肢功能的方法

Tasks that accurately measure dexterity in animal models are critical to understand hand function. Current rat behavioral tasks that measure dexterity ...

A New Method for Inducing a Depression-Like Behavior in Rats

Contagious depression is a phenomenon that is yet to be fully recognized and this stems from insufficient material on the subject. At the moment, there is no existing format for studying the mechanism of action, prevention, containment, and treatment of contagious depression. The purpose of this study, therefore, was to establish the first animal model of contagious depression.
Healthy rats can contract depressive behaviors if exposed to depressed rats. Depression is induced in rats by subjecting them to several manipulations of chronic unpredictable stress (CUS) over 5 weeks, as described in the protocol. A successful sucrose preference test confirmed the development of depression in the rats. The CUS-exposed rats were then caged with na&#239;ve rats from the contagion group (1 na&#239;ve rat/2 depressed rats in a cage) for an additional 5 weeks. 30 social groups were created from the combination of CUS-exposed rats and na&#239;ve rats.
This proposed depression-contagion protocol in animals consists mainly of cohabiting CUS-exposed and healthy rats for 5 weeks. To ensure that this method works, a series of tests are carried out - first, the sucrose preference test upon inducing depression to rats, then, the sucrose preference test, alongside the open field and forced-swim tests at the end of the cohabitation period. Throughout the experiment, rats are given tags and are always returned to their cages after each test.
A few limitations to this method are the weak differences recorded between the experimental and control groups in the sucrose preference test and the irreversible traumatic outcome of the forced swim test. These may be worth considering for suitability before any future application of the protocol. Nonetheless, following the experiment, na&#239;ve rats developed contagion depression after 5 weeks of sharing the same cage with the CUS-exposed rats.

This protocol describes a new model by which healthy rats could contract depression over a given time periodthrough contagion by exposure to chronic unpredictable stressed (CUS) rats.

一种诱导大鼠抑郁症状行为的新方法

Contagious depression is a phenomenon that is yet to be fully recognized and this stems from insufficient material on the subject. At the moment, there is ...