Prime‐, Stress‐, and Cue‐Induced Reinstatement of Extinguished Drug‐Reinforced Responding in Rats: Cocaine as the Prototypical Drug of Abuse

Patrick M. Beardsley1, Keith L. Shelton1

1 Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 9.39
DOI:  10.1002/0471142301.ns0939s61
Online Posting Date:  October, 2012
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Abstract

This unit describes the testing of rats in prime‐, footshock‐, and cue‐induced reinstatement procedures. Evaluating rats in these procedures enables the assessment of treatments on behavior thought to model drug relapse precipitated by re‐contact with an abused drug (prime‐induced), induced by stress (footshock‐induced), or by stimuli previously associated with drug administration (cue‐induced). For instance, levels of reinstatement under the effects of test compound administration could be compared to levels under vehicle administration to help identify potential treatments for drug relapse, or reinstatement levels of different rat strains could be compared to identify potential genetic determinants of perseverative drug‐seeking behavior. Cocaine is used as a prototypical drug of abuse, and relapse to its use serves as the model in this unit, but other self‐administered drugs could readily be substituted with little modification to the procedures. Curr. Protoc. Neurosci. 61:9.39.1‐9.39.40. © 2012 by John Wiley & Sons, Inc.

Keywords: drug relapse; drug abuse; cocaine

     
 
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Table of Contents

  • Introduction
  • Strategic Planning
  • Basic Protocol 1: Train and Test Rats in Cocaine‐Induced Reinstatement Procedures
  • Support Protocol 1: Preparation of Catheter Lock/Antibiotic Solution
  • Support Protocol 2: Construction of a Catheter Introducer
  • Support Protocol 3: Construction of a Flush Syringe Assembly and Catheter Cap
  • Support Protocol 4: Construction of a Tapered Polyurethane Chronic Intravenous Catheter for Rats
  • Support Protocol 5: Self‐Administration Catheter Implantation in the Rat
  • Basic Protocol 2: Train and Test Rats in Cocaine‐Cue Induced Reinstatement Procedures
  • Basic Protocol 3: Train and Test Rats in Footshock‐Induced (Stress) Reinstatement Procedures
  • Commentary
  • Literature Cited
  • Figures
  • Tables
     
 
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Materials

Basic Protocol 1: Train and Test Rats in Cocaine‐Induced Reinstatement Procedures

  Materials
  • Pharmaceutical‐grade cocaine HCl (National Institute on Drug Abuse, Rockville, MD)
  • 500‐ml bags of 0.9% sterile physiological saline
  • 30‐ml vial of 1000 U/ml heparin solution
  • Twelve naïve adult male Long‐Evans hooded rats per dose condition instrumented with chronic indwelling jugular catheters at least 5 days prior to start of study (see protocol 6)
  • Catheter lock solution (see protocol 2)
  • Standard laboratory rodent diet
  • Analytical balance with 1 mg accuracy for weighing drugs
  • 20‐ml Luer‐lock sterile disposable plastic syringes
  • 0.2‐µm membrane sterile syringe filters (25‐mm diameter)
  • 18‐G sterile, disposable hypodermic needles
  • 30‐ml sterilized serum vials and stoppers with aluminum crimp seals
  • Twelve operant conditioning chambers enclosed within sound attenuating cubicles and equipped with two retractable levers, two stimulus lights, house light, Sonalert, liquid swivel/balance arm, and drug infusion syringe pump
  • 100‐foot roll, 0.040‐in. (1.02‐mm) i.d. Tygon microbore polyethylene tubing
  • Sterile, blunt 25‐G disposable hypodermic needles
  • Twelve catheter connection assemblies with metal spring covering (PlasticsOne, cat. no. C313CS)
  • Scale with 1 g accuracy and at least 500‐g capacity for weighting rats
  • Control and interface system consisting of Windows computer, interface, control software, and 28 v DC power supply (Med Associates or comparable)
  • Flush syringe assembly (see protocol 4)
  • 1‐ml sterile, disposable tuberculin syringes with 25‐G needles attached

Support Protocol 1: Preparation of Catheter Lock/Antibiotic Solution

  Materials
  • Saline
  • 10‐ml bottle heparin sodium (1000 U/ml concentration)
  • Glycerol USP (Fisher Scientific or similar)
  • 3.1‐g bottle Timentin powder (ticarcillin disodium and clavulanate potassium)
  • 10‐ and 20‐ml sterile disposable syringes
  • 18‐ and 22‐G sterile disposable needles
  • 100‐ml beaker
  • Stir plate and stir bar (optional)
  • Sterile syringe filter (25‐mm diameter, 0.2‐µm pore size)
  • 60‐ml Luer lock sterile disposable syringe
  • 50‐ml sterilized serum vial, butyl rubber stopper, and foil retainer in sterilization peel pack

Support Protocol 2: Construction of a Catheter Introducer

  Materials
  • Safety glasses
  • 3/8‐in. or longer 27‐G disposable needle
  • Rotary tool (Dremel or similar) with mandrel and abrasive cut‐off wheel
  • 1‐ml disposable tuberculin syringes

Support Protocol 3: Construction of a Flush Syringe Assembly and Catheter Cap

  Materials
  • Safety glasses
  • 25‐G disposable needles
  • Rotary tool (Dremel or similar) with mandrel and abrasive cut‐off wheel
  • 1‐ml disposable tuberculin syringes
  • Tygon tubing (5.5‐cm length, 0.040‐in. i.d.)
  • Self‐sealing sterilization pouch

Support Protocol 4: Construction of a Tapered Polyurethane Chronic Intravenous Catheter for Rats

  Materials
  • Sesame oil (Acros Organic/Fisher Scientific)
  • Fragrance‐free liquid hand dishwashing detergent
  • Thin cyanoacrylate glue (Super Glue or similar)
  • Cardstock
  • 20‐ or 50‐ml beaker
  • Hotplate
  • Thermometer capable of reading to 200°C or higher
  • 3.5 French polyurethane tubing (Access Technologies)
  • Dumont no. 5/45° forceps (Fine Science Tools)
  • Safety razor blades
  • 100‐ml or larger wide mouth sealable container
  • 20‐ml syringes
  • 25‐G blunt‐end needle
  • Wooden handled cotton swab

Support Protocol 5: Self‐Administration Catheter Implantation in the Rat

  Materials
  • Rats
  • Anesthesia (see unit 9.20)
  • 500‐ml bag 0.9% sterile saline
  • Blue underpads
  • Temperature‐regulated animal heating pad (e.g., Gaymar Mul·T·Pad, Deltaphase Isothermal Pad or similar)
  • Sterilized jugular catheter (see protocol 5)
  • 1‐ml tuberculin syringes with 25‐G needles, sterile
  • Sterile surgical masks
  • Sterile surgical gloves
  • Steam‐sterilized, double‐wrapped surgical pack consisting of:
    • Straight mosquito hemostats
    • Curved mosquito hemostats
    • 1 × 2–tooth small Adson forceps
    • Fine carbide blade straight scissors
    • Fine Dumont forceps
    • Fine 1 × 2–tooth straight Graefe or iris forceps
    • 1 × 1 gauze pads
    • Wooden handle swabs
    • 12 × 12–in. paper surgical drape
    • No. 2 tapered Kalt suture needle
    • 4‐0 braided silk or nylon suture material (two 10‐cm pieces)
    • 4 × 4 gauze pads (for manipulating non‐sterile objects)
    • 7.5‐mm Michel suture clips (or alternate closure materials)
    • Tygon tubing (0.040‐in. i.d., 5‐cm long)
    • 25‐G blunt‐end needles
    • Catheter introducer (see protocol 3)
    • Catheter connection pedestal (PlasticsOne, cat. no. 313‐000BM)

Basic Protocol 2: Train and Test Rats in Cocaine‐Cue Induced Reinstatement Procedures

  Materials
  • Pharmaceutical‐grade cocaine HCl (National Institute on Drug Abuse, Rockville, MD)
  • 500‐ml bags of 0.9% sterile physiological saline
  • 30‐ml vial of 1000 U/ml heparin solution
  • Twelve naïve adult male Long‐Evans hooded rats per dose condition instrumented with chronic indwelling jugular catheters at least 5 days prior to start of study (see protocol 5 for details of catheterization surgery)
  • Catheter lock solution (see protocol 2)
  • Standard laboratory rodent diet
  • Analytical balance (1 mg accuracy)
  • 20‐ml Luer‐lock sterile disposable plastic syringes
  • 0.2‐µm membrane sterile syringe filters (25‐mm diameter)
  • Sterile 18‐G disposable hypodermic needles
  • 30‐ml sterilized serum vials and stoppers and aluminum crimp seals
  • Twelve operant conditioning chambers enclosed within sound attenuating cubicles equipped with: two retractable levers, two stimulus lights, house light, Sonalert, liquid swivel/balance arm, and drug infusion syringe pump
  • 100‐ft. roll of 0.040‐in. (1.02‐mm) i.d. Tygon microbore polyethylene tubing
  • Individually packaged and sterilized 25‐G blunt‐end disposable hypodermic needles
  • Catheter connection assemblies with metal spring covering (PlasticsOne, cat. no. C313CS)
  • Scale (1 g accuracy and at least 500‐g capacity for weighting rats)
  • Control and interface system consisting of Windows computer, interface, control software, and 28v DC power supply (Med Associates or comparable)
  • Flush syringe assembly (see protocol 4)
  • Catheter connection/infusion tether

Basic Protocol 3: Train and Test Rats in Footshock‐Induced (Stress) Reinstatement Procedures

  Materials
  • Pharmaceutical grade cocaine HCl (National Institute on Drug Abuse, Rockville, MD)
  • 500‐ml bags of 0.9% sterile physiological saline
  • 30‐ml vial of 1000 U/ml heparin solution
  • One 10 ml vial of 100 mg/ml ketamine HCl
  • Ten vials of Timentin antibiotic powder (GlaxoSmithKline)
  • Twelve naïve adult male Long‐Evans hooded rats per dose condition instrumented with chronic indwelling jugular catheters at least 5 days prior to start of study (see protocol 5 for details of catheterization surgery)
  • Catheter lock solution (see protocol 2)
  • Standard laboratory rodent diet
  • Analytical balance (1 mg accuracy)
  • 20‐ml Luer‐lock sterile disposable plastic syringes
  • 0.2‐µm membrane sterile syringe filters (25‐mm diameter)
  • Sterile 18‐G disposable hypodermic needles
  • 30‐ml sterilized serum vials and stoppers and aluminum crimp seals
  • Twelve operant conditioning chambers enclosed within sound attenuating cubicles equipped with: two retractable levers, two stimulus lights, house light, Sonalert, liquid swivel/balance arm, and drug infusion syringe pump
  • 100‐ft. roll of 0.040‐in. (1.02‐mm) i.d. Tygon microbore polyethylene tubing
  • Individually packaged and sterilized 25‐G blunt‐end disposable hypodermic needles
  • Catheter connection assemblies with metal spring covering (PlasticsOne, cat. no. C313CS)
  • Scale (1 g accuracy and at least 500‐g capacity for weighting rats)
  • Control and interface system consisting of Windows computer, interface, control software, and 28v DC power supply (Med Associates or comparable)
  • Flush syringe assembly (see protocol 4)
  • Catheter connection/infusion tether
  • Twelve current‐regulated footshock delivery devices
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Figures

Videos

Literature Cited

   Aguilar, M.A., Rodriguez‐Arias, M., and Minarro, J. 2009. Neurobiological mechanisms of the reinstatement of drug‐conditioned place preference. Brain Res. Rev. 59:253‐277.
   Beardsley, P.M., Howard, J.L., Shelton, K.L., and Carroll, F.I. 2005. Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine‐seeking induced by footshock stressors vs. cocaine primes and its antidepressant‐like effects in rats. Psychopharmacology 183:118‐126.
   Beardsley, P.M., Pollard, G.T., Howard, J.L., and Carroll, F.I. 2010a. Effectiveness of analogs of the kappa opioid receptor antagonist (3R)‐7‐hydroxy‐N‐((1S)‐1‐{[(3R,4R)‐4‐(3‐hydroxyphenyl)‐3,4‐dimethyl‐1‐pipe ridinyl]methyl}‐2‐methylpropyl)‐1,2,3,4‐tetrahydro‐3‐isoquinolinecarboxami de (JDTic) to reduce U50,488‐induced diuresis and stress‐induced cocaine reinstatement in rats. Psychopharmacology (Berl.) 210:189‐198.
   Beardsley, P.M., Shelton, K.L., Hendrick, E., and Johnson, K.W. 2010b. The glial cell modulator and phosphodiesterase inhibitor, AV411 (ibudilast), attenuates prime‐ and stress‐induced methamphetamine relapse. Eur. J. Pharmacol 637:102‐108.
   de Wit, H. and Stewart, J. 1981. Reinstatement of cocaine‐reinforced responding in the rat. Psychopharmacology 75:134‐143.
   de Wit, H. and Stewart, J. 1983. Drug reinstatement of heroin‐reinforced responding in the rat. Psychopharmacology 79:29‐31.
   Dela Pena, I., Yoon, S.Y., Lee, J.C., Dela Pena, J.B., Sohn, A.R., Ryu, J.H., Shin, C.Y., and Cheong, J.H. 2011. Methylphenidate treatment in the spontaneously hypertensive rat: Influence on methylphenidate self‐administration and reinstatement in comparison with Wistar rats. Psychopharmacology (Berl.) 221:217‐226.
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Key References
   UNIT 9.20.
  This protocol describes details of an alternate catheter construction and surgical procedure, as well as procedures for establishing and stabilizing self‐administration behavior.
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