Method Article

A Protocol for Measuring Cue Reactivity in a Rat Model of Cocaine Use Disorder

DOI:

10.3791/55864

⸱

June 18th, 2018

 ,  ,  ,  ,  ,  , 
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

* These authors contributed equally

In This Article

Summary

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Cue reactivity is conceptualized as sensitivity to cues linked with drug-taking experiences that contribute to craving and relapse in abstinent humans. Cue reactivity is modeled in rats by measuring attentional orientation toward drug-associated cues that results in appetitive approach behavior in a cue reactivity test following self-administration and forced abstinence.

Abstract

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Cocaine use disorder (CUD) follows a trajectory of repetitive self-administration during which previously neutral stimuli gain incentive value. Cue reactivity, the sensitivity to cues previously linked with the drug-taking experience, plays a prominent role in human craving during abstinence. Cue reactivity can be assessed as the attentional orientation toward drug-associated cues that is measurable as appetitive approach behavior in both preclinical and human studies. Herein describes an assessment of cue reactivity in rats trained to self-administer cocaine. Cocaine self-administration is paired with the presentation of discrete cues that act as conditioned reinforcers (i.e., house light, stimulus light, infusion pump sounds). Following a period of abstinence, lever presses in the cocaine self-administration context accompanied by the discrete cues previously paired with cocaine infusion are measured as cue reactivity. This model is useful to explore neurobiological mechanisms underlying cue reactivity processes as well as to assess pharmacotherapies to suppress cue reactivity and therefore, modify relapse vulnerability. Advantages of the model include its translational relevance, and its face and predictive validities. The primary limitation of the model is that the cue reactivity task can only be performed infrequently and must only be used in short duration (e.g., 1 hour), otherwise rats will begin to extinguish the pairing of the discrete cues with the cocaine stimulus. The model is extendable to any positively reinforcing stimulus paired with discrete cues; though particularly applicable to drugs of abuse, this model may hold future applications in fields such as obesity, where palatable food rewards can act as positively reinforcing stimuli.

Introduction

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Cocaine use disorder (CUD) follows a trajectory of repetitive self-administration during which previously neutral stimuli gain incentive value1. Cue reactivity is the sensitivity to cues previously linked with the drug-taking experience, and it plays a prominent role in human craving2,3,4,5. The risk of progression to CUD, as well as relapse during abstinence, is thought to be higher for individuals who express high sensitivity to drug-associated cues6,7. Both environmental contexts (e.g., people, buildings, music genres) and discrete drug-associated stimuli (e.g., paraphernalia) become associated with the cocaine reward; exposure to these cues can trigger changes in peripheral physiology (e.g., heart rate, skin temperature, and skin resistance), brain plasticity, and brain functional connectivity2,8,9,10. In other words, re-exposure to cocaine-associated cues activates limbic corticostriatal circuits to evoke conditioned physiological and subjective responses that drive appetitive approach (drug-seeking) behavior11,12,13,14,15.

Cue reactivity measured with functional brain imaging analyses is predictive of relapse vulnerability in subjects with CUD16. Cue reactivity measurements in rodent models serve as a surrogate measure for relapse risk and can be exploited for translational studies. Thus, a pharmacotherapy that decreases cue reactivity in rodents may be carried forward as a relapse-prevention treatment in human clinical trials. Preclinical models with the necessary translational merit and predictive validity are especially important since there are currently no FDA-approved pharmacotherapies for CUD17.

The rodent self-administration procedure is the gold standard, translational model with predictive validity for human drug-taking18 and critically important to understanding the molecular and physiological processes underlying CUD. Response-independent delivery of cocaine results in distinct behavioral, molecular, and neurochemical effects relative to response-dependent cocaine exposure; e.g., response-independent cocaine delivery evokes significantly higher mortality19. Furthermore, the neurochemical consequences of abstinence from response-dependent cocaine self-administration are distinct from those triggered by abstinence from response-independent cocaine delivery20,21. Thus, CUD models based upon response-dependent delivery of cocaine are superior translational models when assessing cue reactivity and associated mechanisms of action.

In the protocol outlined below, cocaine is delivered intravenously through an indwelling intra-jugular catheter. However, alternative methods to self-administer drug via oral and inhalation routes have been developed. Importantly, rodents control delivery of the drug, analogous humans, through operant responses. Therefore, there is high concordance between drugs self-administered by rodents and humans22. The preclinical drug self-administration procedure below employs lever pressing, reinforced by drug delivery, to motivate response rates higher than vehicle control. Drug-seeking behavior is trained by pairing originally "neutral" cues (e.g., a stimulus light or tone and the contextual environment in which cocaine self-administration occurs) with cocaine infusion; these cues become conditioned reinforcers (for review: Cunningham & Anastasio, 201423). Subsequent re-exposure to cocaine-associated cues triggers drug-seeking behavior in rodents (i.e., attempts to deliver cocaine through pressing on the previously-active lever) as well as craving and relapse in CUD subjects24,25,26,27.

Typically, preclinical rodent studies of drug-seeking behavior following cocaine self-administration utilize extinction training and/or drug reinstatement conducted within the drug-associated environment28,29,30,31,32. Presses on the previously-active lever, in the absence of drug and/or cue delivery, typically constitute the measure of reinstatement following extinction33,34,35. On the contrary, cue reactivity drug-seeking behavior is assessed following forced abstinence without prior extinction training28,36,37,38,39.

Outcome measures and experimental variables have been carefully chosen and validated to dissect different aspects of the neurobiology of drug-seeking and relapse-like behavior, and it is well-established that neuroadaptations differ between models with and without extinction training 40,41,42,43. Furthermore, from a translational perspective, rodent extinction training is not mirrored in clinical settings for CUD since drug-related cues include mood states, places, and people44; the unique combination of these cues are likely not available in a clinical environment45,46,47. Thus, the rodent model described herein acts as a better parallel to the human condition than many of the models currently available.

The following describes a validated cocaine self-administration training, forced abstinence and cue reactivity test protocol for rats. Briefly, rats are implanted with intra-jugular catheters, trained to self-administer cocaine or saline via 'active' lever press, and receipt of the cocaine or saline stimulus is paired with discrete light and sound cues which serve as conditioned reinforcers. Following 14 days of cocaine self-administration, rats are subjected to 30 days of forced abstinence and a subsequent 60-min cue reactivity test in which lever pressing is measured. The cue reactivity test is a surrogate measure for cocaine relapse vulnerability in humans.

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Protocol

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All animal manipulations are carried out in accordance with the Guide for the Care and Use of Laboratory Animals (2011) and with approval from the Institutional Animal Care and Use Committee.

1. Animals

  1. Acclimate male Sprague Dawley rats approximately 8-9 weeks of age (250-260 g) for a minimum of seven days in a colony room maintained at 21-23 °C and 45-50% humidity on a 12 h light-dark cycle (lights on 6:00-18:00 h).
  2. House rats two/cage and handle daily throughout the study. Provide food and water ad libitum in the home cage throughout all phases of the study.
    NOTE: Food restriction increases the saliency of the cocaine reward48, potentiates cocaine-induced locomotor activity49, and acts as a stressor for reinstatement50 and thus may also impact cue reactivity.
  3. Randomly assign rats to saline or cocaine treatment groups.

2. Surgery

  1. Place rat under anesthesia using a cocktail containing 8.6 mg/kg of xylazine, 1.5 mg/kg of acepromazine, and 43 mg/kg of ketamine suspended in bacteriostatic saline. Confirm that the rat is sufficiently anesthetized by pinching its toe and monitoring motor reflexes and respiration. Apply ophthalmic ointment directly to eyes to prevent eye dryness.
    NOTE: If the rat is not sufficiently anesthetized it will exhibit a motor response to the toe pinch, and the rat's breathing rate may rapidly increase.
    1. Using aseptic technique while the rat is under anesthesia, implant an intravenous catheter into the jugular vein connected to a back mount with a cannula. After surgical implantation, allow rats to recover for 5-7 days 28,36,37,51.
      NOTE: The intravenous route of cocaine self-administration in humans results in rapid increases in brain cocaine levels52,53. Thus, in one of its most common preclinical variants, rats are trained to self-administer cocaine via an intra-jugular catheter.
  2. Maintain catheter patency with daily flushes using a solution of 0.1 mL of bacteriostatic saline containing heparin sodium (10 U/mL), streptokinase (0.67 mg/mL), and ticarcillin disodium (66.67 mg/mL). Begin catheter flushing the day after surgery and continue each day following self-administration sessions.
    1. Fill a syringe with the solution and connect the back mount to the syringe via polyethylene tubing to flush.
    2. Verify proper catheter function periodically throughout the experiment by intravenous administration of 10 mg/kg of methohexital sodium.
      NOTE: This is a dose sufficient to briefly anesthetize the animal only when administered intravenously.

3. Self-Administration

  1. Use software programming to generate 4 separate programs as described below.
    1. Code two programs for self-administration on a fixed ratio (FR) 1 schedule, i.e., where one active lever press results in one infusion. For program #1, code the left lever as the active lever; for program #2, code the right lever as the active lever. Construct both programs to be 180-min in length, and deliver the cocaine stimulus and discrete cue complex in the following manner:
      1. Have one active lever press cause simultaneous illumination of both the house light and the stimulus light above the active lever.
      2. After a 1-s delay, have the infusion pump deliver 0.1 mL of solution over 6-s.
      3. Have the stimulus light shut off after 7-s (inactivating at the same time as the infusion pump).
      4. Have the house light shut off after 27-s, with the last 20-s indicating a time-out period during which active lever presses have no scheduled consequences, yet these are still recorded.
      5. For data output, collect infusions, active lever presses, inactive lever presses, and latency to first active lever press.
    2. Code two more programs for self-administration on a FR5 schedule, i.e., where five lever presses result in one infusion. Again, make one program with the active lever as left, and one program with the active lever as right. Make both programs 180-min in length, and deliver the reinforcer and discrete cue complex in the following manner:
      1. Have five active lever presses cause simultaneous illumination of both the house light and the stimulus light above the active lever.
      2. Repeat Steps 3.1.1.2 through 3.1.1.5.
  2. Self-Administration Training
    1. Prepare the cocaine solution daily in sterile 0.9% NaCl to a dose of 0.75 mg/kg/0.1 mL.
      NOTE: Over the duration of each 180 min self-administration session, rats administer approximately 4-5 mL of cocaine solution, thus to prepare in excess, anticipate approximately 8 mL/rat daily.
    2. Fill the catheter syringe (10 mL) with at least 8 mL of cocaine or saline solution. After ensuring that the cocaine/saline solution is flowing, insert the syringes into the infusion pump and connect to the polyethylene tubing encased by a metal spring leash at the start of each self-administration session. Carefully adjust the syringe in each infusion pump such that the solution is evenly and completed distributed in the polyethylene tubing prior to attaching to each catheter.
    3. Place rats into respective standard operant conditioning chambers housed in ventilated, sound-attenuating cubicles with fans. Consistently place each rat in the same operant chamber, and keep the active lever on the same side throughout all experiments. Counterbalance assignment of rats between left and right active levers.
      NOTE: Each chamber is equipped with a pellet receptacle flanked by two retractable response levers, a stimulus light above each response lever, and a house light opposite the levers. Cocaine/saline syringes are connected to a 23g needle (filed to avoid poking tubing) attached to polyethylene tubing encased inside a metal spring leash which connects to each rat's catheter and is operated on a liquid swivel. Syringes are placed into infusion pumps located adjacent to the cubicle.
    4. Train rats to lever press for cocaine infusions (0.75 mg/kg/0.1 mL infusion) or saline infusions (0.1 mL) during daily 180-min sessions using established methods28,36,37,51.
      NOTE: This training is performed simply by placing the rat into the operant chamber and allowing it to lever press; pressing the active lever will result in receipt of the discrete cue complex and cocaine infusion, while pressing the inactive lever bears no scheduled consequences.
      1. Schedule completions on the active lever result in delivery of a cocaine or saline infusion over a 6-s period paired simultaneously with illumination of the house light and stimulus light above the active lever and activation of the infusion pump (this is the discrete cue complex paired with cocaine delivery); inactive lever presses produce no scheduled consequences. Following reinforcer (cocaine) delivery, the stimulus light as well as the infusion pump are inactivated; the house light remains on for an additional 20-s to indicate a timeout period during which lever presses have no scheduled consequences.
        NOTE: A description of how to set this up is found in Steps 3.1.1.1-3.1.1.4
    5. Upon completion of the 180-min session, remove each rat from its operant conditioning chamber and flush its catheter (Step 2.2). Carefully clean the chambers between sessions, wiping each surface with a 70% ethanol solution.
      NOTE: Rats that receive cocaine during the self-administration session may be difficult to remove from the chamber and are more likely to be aggressive. Use slow, careful motions to disconnect each rat from its tether.
    6. Train rats on a FR1 schedule of reinforcement and progress to a FR5 schedule after achieving a criterion of seven infusions/h with less than 10% variability in the total number of infusions per session for three consecutive days. Continue self-administration sessions until rats have reached a total of 14 days of self-administration training.
      NOTE: This is one variant of operant learning; some protocols prefer to have rats remain at FR1 throughout the entirety of the experiment. Changes in fixed ratio schedule from FR1 to FR5 do not impact the number of infusions an animal self-administers54,55. However, increasing the fixed ratio size helps to ensure stability of responding in the rat, and may increase the saliency of the reward56. Additionally, if a treatment during forced abstinence is desired, rats should be pseudo-randomly assigned to treatment groups upon achieving stability (less than 10% variability in the total number of infusions per session for a minimum of 3 consecutive days) at the FR5 schedule. Additionally, saline rats will not progress from FR1 to FR5, as the saliency of saline is not sufficient to achieve the stability required to progress from FR1 to FR5.

4. Forced Abstinence

  1. Place rats into forced abstinence for 30 days; that is, do not provide rats with the opportunity to self-administer cocaine or saline for a duration of 30 days. Importantly, during this period do not return rats to the operant chambers (the previous context of self-administration). However, remove rats from home cages for daily handling and weighing, as a measure of general health.
    NOTE: The duration of forced abstinence can be altered, but it is important to choose a duration that is sufficient to avoid ceiling and floor effects. Factors to be cognizant of when choosing the duration of the forced abstinence period include rodent strain, age, self-administration session length and duration, drug, drug dose and infusion duration, and the sex of the animal.

5. Cocaine Cue Reactivity

  1. Code two software programs for the cue reactivity task at a FR1 schedule; one program with the left lever as the active lever, and one with the right lever as the active lever. Construct each program to collect lever pressing data for 60-min and deliver the discrete cue complex as described below.
    1. Repeat Steps 3.1.1.1-3.1.1.4
    2. For data output, collect cue presentations (previously known as infusions), previously-active lever presses, inactive lever presses, and latency to first lever press.
  2. Cocaine Cue Reactivity Test Session
    1. Assess cue reactivity on day 30 of forced abstinence in a 60-min operant test session. Stagger start times of rats to facilitate rapid decapitation and brain harvest. Importantly, for the cue reactivity test, do not place the syringe in the infusion pump so that the sound of the infusion pump serves as an auditory cue but no cocaine reinforcement is delivered.
      NOTE: Cue reactivity can be assessed on days other than day 30 of forced abstinence, however the fact that responsiveness to cocaine-paired cues varies over time34 should be kept in mind when choosing the date for the cue reactivity test.
    2. Place each rat in the self-administration chamber in which it was trained and tether to its cannula as during the daily self-administration sessions. Presses on the lever that previously delivered cocaine or saline are now only reinforced by delivery of the discrete cue complex (i.e., the stimulus light and house are illuminated, and the infusion pump is activated) on a FR1 schedule (i.e., one discrete cue complex is presented per active lever press); count the cue presentations and previously-active lever presses during one 60-min session, and also record the number of inactive lever presses. However, as with self-administration, inactive lever presses produce no scheduled consequences.
      NOTE: An additional control option is to record previously-active and inactive lever presses in the absence of scheduled consequences (i.e., no discrete cue complex reinforcer).
    3. Upon completion of the cue reactivity test session, immediately euthanize rats to capture the biochemical effects of re-exposure to the operant conditioning chamber and discrete cue complex.

6. Data Collection, Organization, and Analysis

  1. Break down data into three conventional categories: general health, self-administration, and cue reactivity.
    1. Monitor general health (e.g., animal weight, fur condition) throughout the experiment, and provide animals with veterinary care, if necessary, or remove from the study if lever pressing appears affected by health.
    2. Collect self-administration data during the 14 days of self-administration. Use an unpaired, two-tailed t-test to determine statistical differences between cocaine and saline self-administration groups for total number of infusions, active lever presses, inactive lever presses, and latency to first active lever press.
      NOTE: Self-administration data needs to be analyzed prior to forced abstinence if one desires to study the effect of a treatment during forced abstinence on cue reactivity (so that groups can have an equal average number of infusions, as well as active and inactive lever presses). If a two-by-two design is chosen (cocaine ± treatment, saline ± treatment), a two-way ANOVA with appropriate post hoc analysis should be used to analyze this data.
    3. For cue reactivity data to collect and analyze for the total number of cue presentations, previously-active lever presses, inactive lever presses, and latency to first lever press. Also analyze this data with an unpaired, two-tailed t-test to determine differences between animals self-administering cocaine and those self-administering saline.
      NOTE: Again, if a two-by-two design is chosen (cocaine ± treatment, saline ± treatment), a two-way ANOVA with appropriate post hoc analysis should be used to analyze this data.

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Results

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Results of a cocaine self-administration and abstinence experiment followed by a cue reactivity test from a previously published study57 are shown in Figure 1. The study timeline is depicted in Figure 1A.

Rats individually transition from FR1 to FR5 as they meet criteria. As operant conditioning proceeds in the cocaine-administering group, rats g...

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Discussion

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Exposure to drug-paired cues and physiological changes in response to these cues16 are associated with relapse,11,16 and the cocaine cue reactivity test employed above contingently presents cocaine-paired cues in the absence of drug; thus, drug-seeking behavior in the form of previously-active lever presses serves as a measure of relapse vulnerability. The cue reactivity protocol described herein is a preclinical means by which relaps...

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Disclosures

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The authors have no conflicts of interest to disclose.

Acknowledgements

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All behavioral testing was performed in the University of Texas Medical Branch (UTMB) Rodent In Vivo Assessment (RIVA) Core, directed by Dr. Kelly Dineley and housed within the Center for Addiction Research, directed by Dr. Kathryn Cunningham. Support for this work came from the Peter F. McManus Charitable Trust, National Institute of Environmental Health Sciences Center for Environmental Toxicology at UTMB (T32ES007254), Institute for Translational Sciences at UTMB (UL1TR001439), Mitchell Center for Neurodegenerative Diseases, and Center for Addiction Research at UTMB (DA007287, DA070087, and pilot study funds).

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Materials

List of materials used in this article
NameCompanyCatalog NumberComments
Equipment
Catheter Tubing: 0.50mm ID x 0.94mm OD x 0.2mm widthFisher Scientific, Hampton, NH, USA11-189-15A1/experiment
Cue LightMed Associates Inc., St. Albans, VT, USAENV-229M2/operant chamber
Guide Cannulae (22 gauge, pedestal size-8mm, cut length 11 mm, 5 mm above the pedestal)Plastics One, Roanoke, VA, USA8IC313G5UPXC1/rat
House LightMed Associates Inc., St. Albans, VT, USAENV-227M1/operant chamber
Infusion PumpMed Associates Inc., St. Albans, VT, USAPHM-1001/operant chamber
LeversMed Associates Inc., St. Albans, VT, USAENV-110M2/operant chamber
Liquid SwivelsInstech, Plymouth Meeting, PA, USA375/221/operant chamber
MED-PC Package with Infusion Pump SoftwareMed Associates Inc., St. Albans, VT, USASOF-735 (infusions software SOF-700RA-10 version 1.04)1
Metal Spring LeashPlastics One, Roanoke, VA, USAC313CS/SPC1/operant chamber
Needle (23g, 1 in)Becton Dickinson, Franklin Lakes, NJ, USA3051931/operant chamber
Nitex Mesh (6/6 woven mesh sheet, 12"x12", 500 microns thick, 38% Open Area)Amazon, Seattle, WA, USACMN-0500-C, B000FMUNE6~1 sheet/100 rats
PCI Interface PackageMed Associates Inc., St. Albans, VT, USADIG-700P2-R2, MED-SYST-161/16 operant chambers
Power Supply for Interface ModulesMed Associates Inc., St. Albans, VT, USASG-6510D1/16 operant chambers
Sound-attenuating CubicleMed Associates Inc., St. Albans, VT, USAENV-018V1/operant chamber
Syringes, 10 mL Luer-Lok™ tipFisher Scientific, Hampton, NH, USA14-827-521 case/experiment (1/operant chamber)
Tygon Tubing for flushes: 0.51mmID x 1.52mm OD 0.51mm width x 152.4m lengthFisher Scientific, Hampton, NH, USA14-170-15B1/experiment
Chemicals
Acepromazine (10mg/mL)Henry Schein (Animal Health), Melville, NY, USA003845~0.5mg/rat*
Acraweld Repair ResinHenry Schein (Dental), Melville, NY, USA10139591/experiment
Altalube (ophthalmic ointment)Henry Schein (Dental), Melville, NY, USA60500591/experiment
CocaineNIDA North Bethesda, MD, USAN/A~350mgs/rat for whole experiment*; requires DEA License
Heparin (10,000 USP units/10 mL)Sagent Pharmaceuticals, Schaumburg, IL, USANDC 25021-400-101/experiment (~21 units/rat*)
Jet LiquidHenry Schein (Dental), Melville, NY, USA12564011/experiment
Ketamine (100mg/mL, 10mL)Henry Schein (Dental), Melville, NY, USA1049007~15mg/rat*; requieres DEA license
Methohexital Sodium (Brevital®, 500 mg/50 mL)Patterson Dental, Saint Paul, MN, USA043-54611/experiment; requires DEA License
Saline (0.9%, USP)Baxter, Deerfield, IL, USA2B13071 case/experiment
Streptokinase from β-hemolytic Streptococcus (Lancefield Group C) ≥3,000 units/mgSigma Aldrich, St. Louis, MO, USAS3134-250KU1 vial/experiment (~1.5mg/rat/experiment*)
Ticarcillin Disodium SaltFisher Scientific, Hampton, NH, USA50-213-695~4 vials/exeriment or purchase the 25g vial cat.# 50-489-093 (~150mg/rat/experiment*)
Xylazine (100mg/mL)Henry Schein (Animal Health), Melville, NY, USA033198~3mg/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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