研究压力诱导的海洛因复发的程序寻求惩罚强加的禁欲
Summary
描述了一种手术，该手术表明在惩罚实施禁欲后，强烈急性食物剥夺诱导海洛因复发。使用海洛因自我管理的寻找和获取链时间表成功实施了惩罚实施的禁欲模型。然后在食物剥夺应激24小时后进行海洛因寻求测试。
Abstract
惩罚施加的禁欲程序模拟了人类由于与吸毒相关的不良后果而发起的自我禁欲。该模型已在使用不同类型的滥用物质（如甲基苯丙胺，可卡因和酒精）的实验中实施。然而，在受过海洛因训练的动物中，惩罚诱导的禁欲尚未得到证实。此外，急性应激是人类和动物模型复发的关键触发因素。先前已经证明，严重的食物匮乏有力地诱发了灭绝的可卡因和海洛因的恢复寻找。这里描述的程序可用于评估急性应激暴露对在惩罚实施禁欲后寻求海洛因的影响。共8只大鼠被植入慢性静脉注射（i.v.）导管，并接受自我给药训练（0.1mg / kg /输注）18天。完成寻道链接可以访问与海洛因输注配对的取样杆。寻道杆采用可变间隔60加固时间表（VI60）进行编程，而取向杠杆则以固定比率1加固时间表（FR1）进行编程。经过自我管理培训后，对已完成的寻道链接的30%而不是取向杆的延伸，进行了轻度足部冲击。脚击强度每天增加0.1 mA，从0.2 mA增加到1.0 mA。海洛因寻求测试是在食物剥夺（FD）或饱腹条件下24小时后进行的。处于急性食物匮乏状况下的老鼠在惩罚性禁欲后强烈增加海洛因。
Introduction
复发是药物治疗中最具挑战性的问题1，2.然而，只有少数药物治疗被批准用于帮助避免人类复发3。北美目前面临的阿片类药物流行病就是一个突出的例子，它要求考虑对阿片类药物复发的动物模型采取不同的方法。
急性应激已被证明是人类复发的关键触发因素4.通常与药物成瘾相关的一个环境压力源是食物剥夺。吸毒者往往选择分配资源来获取药物而不是食物。热量缺乏已被证明与香烟5 和酒精6 的复发率较高有关。由于伦理和实际问题，在过去的几十年里，动物模型已经发展起来，以促进该领域的研究。在动物模型中，急性食物匮乏已被证明可以有力地恢复灭绝的海洛因寻求7。目前，大多数动物复发模型基于禁欲程序，这些程序要么不能代表人类禁欲（例如，基于灭绝的模型），要么仅包含由于监禁或住院治疗而被迫禁欲的一小部分吸毒者（例如，强制禁欲模型）。吸毒者选择戒毒的主要原因是与寻求毒品和服用8相关的负面后果。惩罚施加的禁欲是一种动物模型，它模仿了与寻求毒品相关的负面后果，对人类自我强加的禁欲。该模型引入了一种厌恶刺激，例如，轻度脚震，寻求或服用药物，导致动物自愿停止服用药物。另一个包含对药物寻求的负面影响的程序是药物戒毒和复发的电屏障冲突模型9。大鼠必须穿过电屏障才能执行与药物自我给药相关的操作行为。该模型被成功地用于证明自愿戒断和复发精神兴奋剂和阿片类药物10，11。然而，在电屏障程序下，寻求药物的努力总是与令人厌恶的事件有关，这与人类状况不同。此外，吸毒本身可能与电击重叠，因为动物再次穿过屏障在输液后返回安全区域。
惩罚规定的禁欲已与其他滥用药物一起使用，如可卡因12，酒精13，甲基苯丙胺14，瑞芬太尼15，但它从未应用于海洛因训练的动物。该模型已被用于研究由启动14 和药物相关线索16诱导的复发，但它没有整合到应激诱导的复发程序中。这里描述的程序用于证明急性食物匮乏诱导的海洛因复发，在雄性大鼠中强制戒酒后寻求惩罚。
Protocol
Representative Results
Discussion
本文有两个重要的演示。首先，使用寻找和获取带有海洛因的链条来验证惩罚强加的禁欲。其次，证明在惩罚实施的禁欲程序中可以观察到压力诱导的复发。这些都是重要的证明，因为（i）惩罚诱导的禁欲程序更接近于人类状况，因为它导致自愿禁欲，即不是由于寻求药物的灭绝或被迫从吸毒环境中移除18，（ii）使用生态相关的压力源证明了可靠的复发：急性食物剥夺压力。</…
Disclosures
The authors have nothing to disclose.
Acknowledgements
这项工作得到了自然科学与工程委员会发现计划（美国：RGPIN-2016-06694）的支持。
Materials
| Anafen Injection 100 mg/mL Vial/50 mL | MERIAL Canada, Inc. | 1938126 | anti-inflammatory drug |
| Balance arm | Coulbourn Instruments | H29-01 | |
| Cannulae (22 G, 5-up) | Plastics One | C313G-5up | |
| Environment connection board & Linc cable | Coulbourn Instruments | H03-04 | |
| Fixed speed infusion pump (3.3 RPM) | Coulbourn Instruments | A73-01-3.3 | |
| GE Marine Silicon | GE | SE-1134 | |
| Graphic State Notation 3 | Coulbourn Instruments | GS3 | Software |
| Habitest universal Linc | Coulbourn Instruments | H02-08 | |
| Heroin HCl | National Institute for Drug Abuse, Research Triangle Park, NC, USA | ||
| House light-Rat | Coulbourn Instruments | H11-01R | |
| Isofluorane USP 99.9% Vial/250 mL | Fresenius Kabi Canada Ltd | 2237518 | |
| Liquid Swivels, Plastic, 22 G | Lomir Biomedical, Inc. | RSP1 | |
| Rat test cage | Coulbourn Instruments | H10-11R-TC | Operant conditioning chambers |
| Retractable lever-Rat | Coulbourn Instruments | H23-17RA | |
| Silastic tubing (ID 0.02, OD 0.037) | Fisher Scientific (Canada) | 1118915A | |
| Single high-bright cue-Rat | Coulbourn Instruments | H11-03R | |
| Sound attenuation boxes | Concordia University | Home made | |
| Stainless steal grid floor | Coulbourn Instruments | H10-11R-TC-SF | |
| System controller 2 | Coulbourn Instruments | SYS CTRL 2 | |
| System power base | Coulbourn Instruments | H01-01 | |
| Tone module 2.9 KHz | Coulbourn Instruments | H12-02R-2.9 | |
| Tygon tubing (ID 0.02, OD 0.060) | VWR | 63018-044 |
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