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Abstract
Introduction
Protocol
Résultats
Discussion
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Acknowledgements
Materials
References
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Neurosciences

可卡因使用障碍大鼠模型中提示反应性测定的一种协议

Published: June 18, 2018
doi:
10.3791/55864
, , , , , ,
1Center for Addiction Research,University of Texas Medical Branch, 2Institute for Translational Sciences,University of Texas Medical Branch, 3Mitchell Center for Neurodegenerative Diseases,University of Texas Medical Branch, 4Department of Neurology,University of Texas Medical Branch, 5Department of Pathology,University of Texas Medical Branch, 6Department of Pharmacology and Toxicology,University of Texas Medical Branch

Summary

线索反应性被概念化为敏感的线索与药物服用的经验, 有助于渴望和复发的禁欲的人。提示反应性是通过测量药物相关线索的注意力取向来模拟大鼠的, 结果在自我管理和强迫禁欲后的提示反应性测试中食欲方法行为。

Abstract

可卡因使用紊乱 (反刍) 遵循重复自我管理的轨迹, 以前的中性刺激获得激励价值。提示反应性, 对先前与药物服用经验相关的线索的敏感性, 在禁欲期间对人类的渴求起着重要的作用。提示反应性可以评估为药物相关线索的注意方向, 这是可测量的食欲方法的行为, 在临床前和人类的研究。这里描述了对自我管理的可卡因训练大鼠的提示反应性的评估。可卡因自我管理与表现为条件强化的离散线索配对 (即, 房子光, 刺激光, 输液泵的声音)。在一段禁欲时期之后, 在可卡因自我管理环境中的杠杆压力和先前配对可卡因输液的离散提示被测量为提示反应性。这个模型是有用的探索神经生物学机制的基础上提示反应性过程, 并评估 pharmacotherapies 抑制提示反应性, 因此, 修改复发的弱点。该模型的优点包括其平移相关性、其表面和预测有效性。该模型的主要局限性是, 提示反应性任务只能很少执行, 只能在短时间内使用 (e., 1 小时), 否则老鼠将开始熄灭与可卡因刺激的离散线索配对。该模型可扩展到任何正向增强刺激与离散线索配对;虽然特别适用于滥用药物, 但这种模式可能会在肥胖等领域中进行未来的应用, 在这种情况下, 可口的食物奖励可以起到积极的增强刺激作用。

Introduction

可卡因使用紊乱 (反刍) 遵循重复自我管理的轨迹, 此前中性刺激获得奖励价值1。提示反应性是对先前与药物服用经验相关的暗示的敏感性, 它在人类渴求2、3、4、5中起着重要作用。人们认为, 对药物相关线索6、7敏感的个体来说, 进步到反刍的风险以及禁欲期间的复发是更高的。环境背景 (如人、建筑物、音乐流派) 和与药物相关的离散刺激 (例如, 用具) 与可卡因奖励有关;接触这些线索可以触发周围生理学的变化 (例如心率, 皮肤温度, 皮肤阻力), 大脑可塑性, 和大脑功能连接2,8,9 ,10。换言之, 再次接触可卡因相关的线索激活边缘 corticostriatal 电路唤起条件的生理和主观反应, 推动食欲方法 (药物寻求) 行为11,12 ,13,14,15。

用功能性脑成像分析测量的线索反应性是对反刍16患者复发易感性的预测。啮齿动物模型中的线索反应性测量作为复发风险的替代措施, 可用于转化研究。因此, 减少啮齿类动物的提示反应性药物治疗可以作为人类临床试验中的复发预防疗法进行。具有必要的转化优点和预测有效性的临床前模型尤其重要, 因为目前尚无 FDA 批准的 pharmacotherapies17。

啮齿动物自我管理程序是对人体药物服用18具有预测有效性的金本位、转化模型, 对了解反刍的分子和生理过程至关重要。与反应相关的可卡因暴露, 与反应无关的可卡因的传递导致不同的行为、分子和神经化学效应;e., 与反应无关的可卡因交付引起的死亡率显著高于19。此外, 从反应依赖的可卡因自我管理中禁欲的神经化学后果有别于从与反应无关的可卡因交付20的禁欲引发的影响, 21. 因此, 在评估线索反应性和相关的行动机制时, 基于反应依赖的可卡因提供的反刍模型是优越的平移模型。

在下面概述的议定书中, 可卡因是通过留置的颈内导管静脉注射的。然而, 已开发出通过口服和吸入途径自我管理药物的替代方法。重要的是, 啮齿类动物通过操作性反应控制药物的交付, 类似人类。因此, 由啮齿类动物和人类22之间的药物自我管理有很高的一致性。下面的临床前药物自我管理程序采用杠杆压制, 加强了药物传递, 以刺激反应率高于车辆控制。寻找毒品的行为是通过配对最初的 “中性” 暗示 (例如, 刺激的光或音调, 以及可卡因自我管理发生的上下文环境) 来训练可卡因注入;这些提示成为条件强化 (审查: 坎宁安 & Anastasio, 201423)。随后再次暴露于可卡因相关的线索引发啮齿类动物的寻毒行为 (即试图通过按压先前活跃的杠杆提供可卡因) 以及反刍科目24的渴求和复发,25,26,27。

通常情况下, 在可卡因自我管理之后进行的药物寻求行为的前啮齿动物研究利用在药物相关环境28、29中进行的灭绝训练和/或药物恢复,30,31,32. 在没有药物和/或提示传递的情况下, 按先前活动的杠杆, 通常构成在灭绝33、34、35之后恢复的措施。相反, 提示反应性药物寻求行为是评估后, 强迫禁欲, 没有事先灭绝训练28,36,37,38,39.

结果措施和实验变量被仔细地选择和验证, 以解剖不同的方面的神经生物学的寻求和复发的行为, 并建立了良好的 neuroadaptations 不同的模型与没有灭绝训练40,41,42,43。此外, 从平移的角度看, 由于药物相关的线索包括情绪状态、地点和人44, 啮齿类动物灭绝训练没有反映在反刍的临床环境中;这些线索的独特组合可能无法在临床环境45,46,47。因此, 这里所描述的啮齿动物模型比目前现有的许多模型更能与人类的状况相平行。

以下描述了一个验证的可卡因自我管理训练, 强迫禁欲和线索反应性测试协议的大鼠。简单地说, 老鼠被植入颈内导管, 通过 ‘ 主动 ‘ 杠杆压力训练自我管理可卡因或生理盐水, 接收可卡因或生理盐水刺激与离散的光和声音信号配对, 作为条件强化。经过14天的可卡因自我管理, 老鼠受到30天的强迫禁欲和随后60分钟的线索反应性测试, 其中杠杆压测量。提示反应性试验是可卡因复发易感性的替代措施。

Protocol

所有动物操作都按照《动物护理和使用指南》 (2011) 进行, 并得到机构动物护理和使用委员会的批准。 1. 动物 适应男性大鼠大约8-9 星期的年龄 (250-260 g) 为至少七天在殖民地房间维护在21-23 °c 和45-50% 湿气在 12 h 光黑暗的周期 (灯在 6:00-18:00 h)。 房子鼠二个或笼子并且每日处理在整个研究期间。在整个研究阶段, 在家庭笼子里提供食物和水的广告随意</em…

Representative Results

一个可卡因自我管理和禁欲实验的结果, 然后一个提示反应性测试从以前发表的研究57显示在图 1。研究时间线在图 1A中描述。 大鼠个体从 FR1 到 FR5, 因为它们符合标准。随着操作性调节在可卡因管理组中的作用, 大鼠逐渐增加输液数量直到达到高原 (<strong class="xfig"…

Discussion

暴露在药物配对的线索和生理变化响应这些线索16是与复发,11,16和可卡因线索反应性测试使用以上偶然提出可卡因配对线索在缺乏药物;因此, 以先前活动的杠杆压力机形式进行的药物寻求行为是一种复发脆弱性的度量。本文所描述的提示反应性协议是一种临床前的方法, 通过它可以测试复发修饰 pharmacotherapies, 并研究导致复发风险的遗?…

Divulgations

The authors have nothing to disclose.

Acknowledgements

所有的行为测试都是在德克萨斯大学医学科 (UTMB) 啮齿动物活体评估 (Dineley) 的核心, 由凯利博士指导, 并设在成瘾研究中心, 由凯瑟琳·坎宁安博士指导。对这项工作的支持来自于彼得 F. 美国国家环境健康科学研究所 UTMB (UL1TR001439)T32ES007254翻译科学研究所环境毒理学中心,米切尔神经退行性疾病中心和 UTMB 成瘾研究中心 (DA007287、DA070087 和试点研究基金)。

Materials

Equipment
Catheter Tubing: 0.50mm ID x 0.94mm OD x 0.2mm width Fisher Scientific, Hampton, NH, USA 11-189-15A 1/experiment
Cue Light Med-Associates Inc. St. Albans, VT, USA ENV-229M 2/operant chamber
Guide Cannulae (22 gauge, pedestal size-8mm, cut length 11 mm, 5 mm above the pedestal) Plastics One, Roanoke, VA, USA 8IC313G5UPXC 1/rat
House Light Med-Associates Inc. St. Albans, VT, USA ENV-227M 1/operant chamber
Infusion Pump Med-Associates Inc. St. Albans, VT, USA PHM-100 1/operant chamber
Levers Med-Associates Inc. St. Albans, VT, USA ENV-110M 2/operant chamber
Liquid Swivels Instech, Plymouth Meeting, PA, USA 375/22 1/operant chamber
MED-PC Package with Infusion Pump Software Med-Associates Inc. St. Albans, VT, USA SOF-735 (infusions software SOF-700RA-10 version 1.04) 1
Metal Spring Leash Plastics One, Roanoke, VA, USA C313CS/SPC 1/operant chamber
Needle (23g, 1 in) Becton Dickinson, Franklin Lakes, NJ, USA 305193 1/operant chamber
Nitex Mesh (6/6 woven mesh sheet, 12"x12", 500 microns thick, 38% Open Area) Amazon, Seattle, WA, USA CMN-0500-C, B000FMUNE6 ~1 sheet/100 rats
PCI Interface Package Med-Associates Inc. St. Albans, VT, USA DIG-700P2-R2, MED-SYST-16 1/16 operant chambers
Power Supply for Interface Modules Med-Associates Inc. St. Albans, VT, USA SG-6510D 1/16 operant chambers
Sound-attenuating Cubicle Med-Associates Inc. St. Albans, VT, USA ENV-018V 1/operant chamber
Syringes, 10 mL Luer-Lok™ tip Fisher Scientific, Hampton, NH, USA 14-827-52 1 case/experiment (1/operant chamber)
Tygon Tubing for flushes: 0.51mmID x 1.52mmOD 0.51mm thick x 152.4m Fisher Scientific, Hampton, NH, USA 14-170-15B 1/experiment
Chemicals
Acepromazine (10mg/mL) Henry Schein (Animal Health), Melville, NY, USA 003845 ~0.5mg/rat*
Acraweld Repair Resin Henry Schein (Dental), Melville, NY, USA 1013959 1/experiment
Altalube (ophthalmic ointment) Henry Schein (Dental), Melville, NY, USA 6050059 1/experiment
Cocaine NIDA North Bethesda, MD, USA N/A ~350mgs/rat for whole experiment*; requires DEA License
Heparin (10,000 USP units/10 mL) SAGENT Pharmaceuticals, Schaumburg, IL, USA NDC 25021-400-10 1/experiment (~21 units/rat*)
Jet Liquid Henry Schein (Dental), Melville, NY, USA 1256401 1/experiment
Ketamine (100mg/mL, 10mL) Henry Schein (Dental), Melville, NY, USA 1049007 ~15mg/rat*; requieres DEA license
Methohexital Sodium (Brevital®, 500 mg/50 mL) Patterson Dental, Saint Paul, MN, USA 043-5461 1/experiment; requires DEA License
Saline (0.9%, USP) Baxter, Deerfield, IL, USA 2B1307 1 case/experiment
Streptokinase from β-hemolytic Streptococcus (Lancefield Group C) ≥3,000 units/mg Sigma Aldrich, St. Louis, MO, USA S3134-250KU 1 vial/experiment (~1.5mg/rat/experiment*)
Ticarcillin Disodium Salt Fisher Scientific, Hampton, NH, USA 50-213-695 ~4 vials/exeriment or purchase the 25g vial cat.# 50-489-093 (~150mg/rat/experiment*)
Xylazine (100mg/mL) Henry Schein (Animal Health), Melville, NY, USA 033198 ~3mg/rat*
*Assumes rat age is that described in the protocol, rats self-administer for 14 days, and flushes occur for 21 days.
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Keywords: Cue ReactivityCocaine Use DisorderRelapse RiskOperant TaskDrug-seeking BehaviorPre-clinicalPharmacotherapiesGenetic FactorsEnvironmental FactorsSprague Dawley RatsJugular Vein CathetersCocaine Self-administrationFR1 ScheduleFR5 ScheduleInfusion VolumeInfusion Duration
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Dimet, A. L., Cisneros, I. E., Fox, R. G., Stutz, S. J., Anastasio, N. C., Cunningham, K. A., Dineley, K. T. A Protocol for Measuring Cue Reactivity in a Rat Model of Cocaine Use Disorder. J. Vis. Exp. (136), e55864, doi:10.3791/55864 (2018).
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